AGE OF THE FATHER AND THE HEALTH OF FUTURE GENERATIONS

James Crow Dies

2012-01-11T10:13:00.000-08:00

James Crow Dies

January 11, 2012

James Crow, who was a population geneticist at the University of Wisconsin-Madison, has died, reports The New York Times. He was 95. Crow studied mutational load, and was part of on a National Academy of Sciences committee that assessed mutational damage to the populations of Hiroshima and Nagasaki following the use of atomic bombs there. He also was on a committee that paved the way for using DNA forensics in court. The Times notes that when Crow began teaching in the 1940s and 1950s, the field of genetics underwent rapid changes. "When anxious students asked Dr. Crow what would be in the exams, he would tell them that the questions were the same every year but that the answers were different," the Times says.

Neuron. 2011 Dec 22;72(6):951-63. High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

2012-01-07T09:41:00.001-08:00

Neuron. 2011 Dec 22;72(6):951-63.

High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nöthen MM, Potash JB, Rietschel M, Schulze TG, Sebat J.

Source

Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 12824, USA.

Abstract

While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

Copyright © 2011 Elsevier Inc. All rights reserved.

The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years

2012-01-04T08:48:00.000-08:00

Encephale. 2011 Jun;37(3):199-206. Epub 2011 Apr 2.

[Influence of paternal age in schizophrenia].

[Article in French]

Hubert A, Szöke A, Leboyer M, Schürhoff F.

Source

Pôle de psychiatrie du CHU de Créteil, groupe hospitalier Henri-Mondor-Albert-Chenevier, AP-HP, 40, rue Mesly, 94000 Créteil, France.

Abstract

BACKGROUND:

Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations.

METHODS:

All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009.

RESULTS:

After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis.

DISCUSSION:

The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA.

CONCLUSION:

APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA.

Copyright © 2010 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

PMID: 21703435 [PubMed - indexed for MEDLINE]

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Advancing paternal age and simplex autism.

2011-12-20T08:40:00.001-08:00

Autism. 2011 Dec 16. [Epub ahead of print]

Advancing paternal age and simplex autism.

Puleo CM, Schmeidler J, Reichenberg A, Kolevzon A, Soorya LV, Buxbaum JD, Silverman JM.

Source

Temple University, Philadelphia, PA, USA.

Abstract

De novo events appear more common in female and simplex autism spectrum disorder (ASD) cases and may underlie greater ASD risk in older fathers' offspring. This study examined whether advancing paternal age predicts an increase in simplex (n = 90) versus multiplex ASD cases (n = 587) in 677 participants (340 families). Whether or not controlling for maternal age, results support a significant interaction of linear paternal age and sex of the child on simplex family type. Female ASD cases were significantly more likely to be simplex as paternal age increased, but the increase for males was not significant. Findings suggest that ASD arising from non-familial, de novo events may be far less prominent in males than in females, even if more prevalent in males, due to the substantially larger number of male cases attributable to other, more strongly male-biased risk factors

Poor sperm quality and advancing age are associated with increased sperm DNA damage in infertile men

2011-11-02T14:55:00.001-07:00

Andrologia. 2011 Nov 1. doi: 10.1111/j.1439-0272.2011.01243.x. [Epub ahead of print]
Poor sperm quality and advancing age are associated with increased sperm DNA damage in infertile men.
Varshini J, Srinag BS, Kalthur G, Krishnamurthy H, Kumar P, Rao SB, Adiga SK.
Source Clinical Embryology, Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Kasturba Medical College, Manipal University, Manipal, India National Centre for Biological Sciences, Tata Institute for Fundamental Research UAS-GKVK Campus, Bangalore, India Department of Radiation Biology and Toxicology, Manipal Life Science Centre, Manipal University, Manipal, India.

Abstract
With increasing evidence for faulty paternal contribution to reproduction, there has been a steady increase in studies highlighting an association between sperm DNA damage, failed/delayed fertilisation and aberrant embryo development. Owing to prevailing ambiguity, the aims of the study were to analyse the genetic integrity of the male gamete and then to understand its association with age, standard semen parameters, lifestyle and occupational factors. The study included 504 subjects, attending university infertility clinic for fertility evaluation and treatment. Semen characteristics were analysed by standard criteria; terminal deoxynucelotidyl transferase-mediated nick end-labelling assay was employed for DNA damage assessment. The average incidence of sperm DNA damage in patients with normozoospermic semen parameters was <10%. Patients with oligozoospermia, severe oligozoospermia, oligoasthenoteratospermia, asthenoteratozoospermia and necrozoospermia had significantly higher level of sperm DNA damage (P < 0.001). Patients above 40 years of age had significantly high levels of DNA damage (P < 0.001) compared with their counterparts. Patients with varicocele and a history of alcohol consumption had higher incidence of spermatozoa with DNA damage (P < 0.01). Poor sperm characteristics in the ejaculate are associated with increased sperm DNA damage. Age-related increase in sperm DNA damage and association of the same with varicocele and alcohol consumption are also demonstrated.

© 2011 Blackwell Verlag GmbH.

PMID:22040161[PubMed - as supplied by publisher]

Advanced paternal and grandpaternal age and schizophrenia

2011-10-18T08:24:00.000-07:00

Schizophr Res. 2011 Oct 13. [Epub ahead of print]
Advanced paternal and grandpaternal age and schizophrenia: A three-generation perspective.
Frans EM, McGrath JJ, Sandin S, Lichtenstein P, Reichenberg A, Långström N, Hultman CM.
SourceDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Abstract
BACKGROUND: Advanced paternal age has been linked with an increased risk of schizophrenia in the offspring. If age-related de novo mutations in the male germ line underlie this association, grandpaternal and paternal age would both be expected to influence the risk of schizophrenia. The aim of the current study was to explore the links between both paternal and grandpaternal age with respect to the risk of schizophrenia in a large, national register-based cohort.

METHOD: We linked the Swedish Multi-Generation and Hospital Discharge Registers and compared parents' ages at offspring birth for 20,582 schizophrenia-affected and 100,176 non-affected individuals. Grandparents' ages at the birth of the parent were compared between 2511 affected and 15,619 non-affected individuals. The risk of schizophrenia was examined with logistic regression when the predictor variable (parent or grandparent age) varied across age strata.

RESULTS: After adjusting for maternal age, birth year and proband sex, we confirmed that offspring of older fathers had an increased risk of schizophrenia. Compared to those with paternal age 20-24years, those with fathers >55years had a two-fold increased risk of schizophrenia. With respect to grandparent age, older maternal (but not paternal) grandfather age was associated with an increased risk of schizophrenia. Compared to maternal grandfather age 20-24years, those with maternal grandfathers >55years had a significantly increased risk of schizophrenia (adjusted odds ratio and 95% confidence intervals; 2.79, 1.71-4.56). The pattern of results was essentially unchanged when we examined male and female probands separately.

CONCLUSION: This is the first study to report an association between grandpaternal age and risk of schizophrenia. The selective effect of advanced maternal grandfather age suggests that the biological mechanisms involving the X-chromosome may differentially contribute to the association between paternal age and offspring risk of schizophrenia.

Copyright © 2011. Published by Elsevier B.V.

De novo copy number variants associated with intellectual disability have a paternal origin and age bias.

2011-10-05T08:45:00.000-07:00

Med Genet. 2011 Oct 3. [Epub ahead of print]
De novo copy number variants associated with intellectual disability have a paternal origin and age bias.
Hehir-Kwa JY, Rodríguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R, Buitelaar JK, Pérez-Jurado LA, Veltman JA.
Source1Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Abstract
BackgroundDe novo mutations and structural rearrangements are a common cause of intellectual disability (ID) and other disorders with reduced or null reproductive fitness. Insight into the genomic and environmental factors predisposing to the generation of these de novo events is therefore of significant clinical importance.MethodsThis study used information from single nucleotide polymorphism microarrays to determine the parent-of-origin of 118 rare de novo copy number variations (CNVs) detected in a cohort of 3443 patients with ID.ResultsThe large majority of these CNVs (76%, p=1.14×10(-8)) originated on the paternal allele. This paternal bias was independent of CNV length and CNV type. Interestingly, the paternal bias was less pronounced for CNVs flanked by segmental duplications (64%), suggesting that molecular mechanisms involved in the formation of rare de novo CNVs may be dependent on the parent-of-origin. In addition, a significantly increased paternal age was only observed for those CNVs which were not flanked by segmental duplications (p=0.02).ConclusionThis indicates that rare de novo CNVs are increasingly being generated with advanced paternal age by replication based mechanisms during spermatogenesis.

PMID:21969336[PubMed - as supplied by publisher]

The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations.

2011-09-16T13:16:00.001-07:00

Mol Reprod Dev. 2011 Aug 5. doi: 10.1002/mrd.21374. [Epub ahead of print]
Age-related instability in spermatogenic cell nuclear and mitochondrial DNA obtained from Apex1 heterozygous mice.
Vogel KS, Perez M, Momand JR, Acevedo-Torres K, Hildreth K, Garcia RA, Torres-Ramos CA, Ayala-Torres S, Prihoda TJ, McMahan CA, Walter CA.
SourceDepartment of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Abstract
The prevalence of spontaneous mutations increases with age in the male germline; consequently, older men have an increased risk of siring children with genetic disease due to de novo mutations. The lacI transgenic mouse can be used to study paternal age effects, and in this system, the prevalence of de novo mutations increases in the male germline at old ages. Mutagenesis is linked with DNA repair capacity, and base excision repair (BER), which can ameliorate spontaneous DNA damage, decreases in nuclear extracts of spermatogenic cells from old mice. Mice heterozygous for a null allele of the Apex1 gene, which encodes apurinic/apyrimidinic endonuclease I (APEN), an essential BER enzyme, display an accelerated increase in spontaneous germline mutagenesis early in life. Here, the consequences of lifelong reduction of APEN on genetic instability in the male germline were examined, for the first time, at middle and old ages. Mutant frequency increased earlier in spermatogenic cells from Apex1(+/-) mice (by 6 months of age). Nuclear DNA damage increased with age in the spermatogenic lineage for both wild-type and Apex1(+/-) mice. By old age, mutant frequencies were similar for wild-type and APEN-deficient mice. Mitochondrial genome repair also depends on APEN, and novel analysis of mitochondrial DNA (mtDNA) damage revealed an increase in the Apex1(+/-) spermatogenic cells by middle age. Thus, Apex1 heterozygosity results in accelerated damage to mtDNA and spontaneous mutagenesis, consistent with an essential role for APEN in maintaining nuclear and mtDNA integrity in spermatogenic cells throughout life. Mol. Reprod. Dev. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

Published 2011 Wiley-Liss, Inc. This article is a U.S. Government work and is in the public domain in the USA.

breast cancer risk in the offspring: the relations with father's age at birth

2011-09-07T08:56:00.000-07:00

Mech Ageing Dev. 2011 Apr;132(4):149-53. Epub 2011 Feb 25.
Leukocyte telomere length, breast cancer risk in the offspring: the relations with father's age at birth.
Arbeev KG, Hunt SC, Kimura M, Aviv A, Yashin AI.
SourceCenter for Population Health and Aging, Duke University, Durham, NC 27708-0408, USA. konstantin.arbeev@duke.edu

Abstract
Recent studies have reported that leukocyte telomere length (LTL) is longer in offspring of older fathers. Longer telomeres might increase cancer risk. We examined the relation of father's age at the birth of the offspring (FAB) with LTL in the offspring in 2177 participants of the Family Heart Study and the probability of developing breast cancer in 1405 women from the Framingham Heart Study (offspring cohort). For each year of increase in FAB (adjusted for mother's age at birth), LTLs in the daughters and sons were longer by 19.4bp and 12.2bp, respectively (p<0.0001). Daughters of older fathers were less likely to stay free of breast cancer compared to daughters of younger fathers in empirical (p=0.014) and Cox regression analyses (p=0.0012) adjusted for relevant covariates. We conclude that older fathers endow their offspring with a longer LTL and their daughters with increased susceptibility to breast cancer. These independent observations cannot provide evidence for a causal relationship, mediated by telomere length, between FAB and increased breast cancer risk in daughters. However, with couples delaying having children in today's society, studies exploring the LTL association with increased breast cancer risk in daughters of older fathers might be timely and relevant.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Fertility concerns for the aging male.

2011-09-03T09:34:00.001-07:00

Urology. 2011 Sep;78(3):496-9.
Fertility concerns for the aging male.
Stewart AF, Kim ED.
SourceDivision of Urology, Department of Surgery, University of Tennessee, Graduate School of Medicine, Knoxville, TN.

Abstract
Because of many societal factors, the number of men over the age of 35 desiring to conceive children has increased over the past 40 years. The purpose of this review is to identify the mechanisms of aging on male fertility, to evaluate the genetic risk for the offspring, and to provide counseling for the older male. Most evidence suggests trends that increased paternal age has negative effects on fertility and some genetic risk for offspring, but the age at which the risk develops and the magnitude of risk are poorly defined.

Copyright © 2011 Elsevier Inc. All rights reserved.

Father Time: Children with Older Dads at Greater Risk for Mental Illness

2011-08-29T14:47:00.000-07:00

The present trend of increasing paternal age is accompanied by concerns for the development of complex multi-gene diseases, e.g. autism and schizophrenia,

2011-08-26T09:48:00.000-07:00

Biol Reprod. 2011 Aug 24. [Epub ahead of print]
Aging Results in Differential Regulation of DNA Repair Pathways in Pachytene Spermatocytes in the Brown Norway Rat.
Paul C, Nagano M, Robaire B.
Abstract
The present trend of increasing paternal age is accompanied by concerns for the development of complex multi-gene diseases, e.g. autism and schizophrenia, in progeny. Recent studies have established strong correlations between male age, increased oxidative stress, decreased sperm quality and structural aberrations of chromatin and DNA in spermatozoa. We tested the hypothesis that increasing age would result in altered gene expression relating to oxidative stress and DNA damage/repair in germ cells. To test this hypothesis, pachytene spermatocytes and round spermatids were isolated from Brown Norway (BN) rats at 4 (young) and 18 (aged) months of age. Microarray analysis was used to compare gene expression between the groups. The probe sets with significantly altered expression were linked to DNA damage/repair and oxidative stress in pachytene spermatocytes but not in round spermatids. Further analysis of pachytene spermatocytes demonstrated that genes involved in the base excision repair (BER) and nucleotide excision repair (NER) pathways were specifically altered. Quantitative RT-PCR confirmed that NER genes were upregulated (>1.5 fold) whereas BER genes were downregulated (>1.5 fold). At the protein level the members of the BER pathway were also altered by up to 2.3 fold; levels of NER proteins remained unchanged. Furthermore there was an increase in 8-oxo-2'-deoxyguanosine (8-oxodG) immunoreactivity in testes from aged males and in the number of spermatozoa positive for 8-oxodG. In conclusion, aging is associated with differential regulation of DNA repair pathways with a decrease in the BER pathway leading to deficient repair of 8-oxo-dG lesions in germ cells and spermatozoa.

Parental Age Effects on Cortical Morphology in Offspring.

2011-08-06T10:22:00.000-07:00

Cereb Cortex. 2011 Aug 4. [Epub ahead of print]
Parental Age Effects on Cortical Morphology in Offspring.
Shaw P, Gilliam M, Malek M, Rodriguez N, Greenstein D, Clasen L, Evans A, Rapoport J, Giedd J.
SourceChild Psychiatry Branch, Intramural Program of the National Institute of Mental Health.

Abstract
The age at which a parent has a child impacts the child's cognition and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased prevalence of some neuropsychiatric disorders. Little is known of the neural mechanisms underpinning this phenomenon. We extracted lobar volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth. Using linear mixed model regression, we determined the association between parental age and offspring's neuroanatomy, adjusting for offspring's age, sex, intelligence, and parental socioeconomic class. For gray matter volumes, quadratic paternal and maternal age terms contributed significantly (maternal quadratic age effect: t = -2.2, P = 0.03; paternal quadratic age effect: t = -2.4, P = 0.02) delineating an inverted "U" relationship between parental age and gray matter volume. Cortical volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on cerebral morphology may form part of the link between parental age extremes and suboptimal neurocognitive outcomes.

PMID:21817090[PubMed - as supplied by publisher]

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia.

2011-06-30T08:44:00.001-07:00

J Vis Exp. 2011 Jun 15;(52). pii: 2534. doi: 10.3791/2534.
A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia.
Julie G, Hamdan FF, Rouleau GA.
SourceCentre of Excellence in Neuromics, CHUM Research Center and the Department of Medicine, Universite de Montreal.

Abstract
There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness(1) and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them(2). This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia(3). The male-to-female ratio of mutation rate is estimated at about 4-6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males(4). A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

PMID:21712793[PubMed - in process]

Influence of paternal age in schizophrenia

2011-06-28T09:05:00.000-07:00

Encephale. 2011 Jun;37(3):199-206. Epub 2011 Apr 2.
[Influence of paternal age in schizophrenia.]
[Article in French]
Hubert A, Szöke A, Leboyer M, Schürhoff F.
SourcePôle de psychiatrie du CHU de Créteil, groupe hospitalier Henri-Mondor-Albert-Chenevier, AP-HP, 40, rue Mesly, 94000 Créteil, France; Inserm unité 955, IMRB, département de génétique, équipe 15, 94000 Créteil, France; Faculté de médecine, université Paris-Est Créteil, IFR10, 94000 Créteil, France; Fondation Fondamental, fondation de coopération scientifique, hôpital Chenevier, 40, rue Mesly, 94000 Créteil, France.

Abstract
BACKGROUND: Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations.

METHODS: All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009.

RESULTS: After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis.

DISCUSSION: The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA.

CONCLUSION: APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA.

Copyright © 2010 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Advanced paternal age is a risk factor for schizophrenia in Iranians.

2011-04-26T08:05:00.000-07:00

Ann Gen Psychiatry. 2011 Apr 24;10(1):15. [Epub ahead of print]
Advanced paternal age is a risk factor for schizophrenia in Iranians.
Naserbakht M, Ahmadkhaniha HR, Mokri B, Smith CL.
Abstract
ABSTRACT:

BACKGROUND: Since 1958 many, but not all studies have demonstrated that paternal age is a risk factor for schizophrenia. There may be many different explanations for differences between studies, including study design, sample size, collection criteria, heterogeneity and the confounding effects of environmental factors that can for example perturb epigenetic programming and lead to an increase in disease risk. The small number of children in Western families makes risk comparisons between siblings born at different paternal ages difficult. In contrast, more Eastern families have children both at early and later periods of life. In the present study, a cross-sectional population study in an Iranian population was performed to compare frequency of schizophrenia in younger offspring (that is, older paternal age) versus older offspring.

METHODS: A total of 220 patients with the diagnosis of schizophrenia (cases) from both psychiatric hospitals and private clinics and 220 individuals from other hospital wards (controls), matched for sex and age were recruited for this study. Patients with neurological problem, substance abuse, mental retardation and mood disorder were excluded from both groups.

RESULTS: Birth rank comparisons revealed that 35% vs 24% of the cases vs the controls were in the third or upper birth rank (P = 0.01). Also, the mean age of fathers at birth in case group (30 +/- 6.26 years) was significantly more than the control group (26.45 +/- 5.64 years; P = 0.0001). The age of 76 fathers at birth in case group was over 32 versus 33 fathers in control group. Individuals whose fathers' age was more than 32 (at birth) were at higher risk (2.77 times) for schizophrenia versus others (P <0.0001, 95% CI 1.80 to 4.27). The maternal age at parturition of the case versus controls groups was 26.1 +/- 5.41 vs 25.07 +/- 4.47 (P = 0.02). Logistic regression analysis suggests that maternal age is less likely to be involved in the higher risk of schizophrenia than advanced parental age.

DISCUSSION: This study demonstrates a relationship between paternal age and schizophrenia in large families of an Iranian population. Arguments have been put forth that DNA bases changes or epigenetic changes in sperm account for the increased risk associated with older fathers. However, it would not be surprising that both de novo germline mutations and epigenetic changes contribute to disease occurrence because DNA replication and DNA methylation are closely linked at both the macromolecular level (that is, methylation closely follows replication), and at the metabolic level (both processes require folate), and susceptible to modulation by the environment. Further research on samples such as those collected here are needed to sort out the contributions of de novo mutations versus epigenetic changes to schizophrenia.

PMID:21513574[PubMed - as supplied by publisher]

Paternal Age Schizophrenia

2011-03-01T10:12:00.000-08:00

Schizophr Res. 2011 Feb 25. [Epub ahead of print]

Paternal age related schizophrenia (PARS): Latent subgroups detected by k-means clustering analysis.
Lee H, Malaspina D, Ahn H, Perrin M, Opler MG, Kleinhaus K, Harlap S, Goetz R, Antonius D.

Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA.

Abstract
BACKGROUND: Paternal age related schizophrenia (PARS) has been proposed as a subgroup of schizophrenia with distinct etiology, pathophysiology and symptoms. This study uses a k-means clustering analysis approach to generate hypotheses about differences between PARS and other cases of schizophrenia.

METHODS: We studied PARS (operationally defined as not having any family history of schizophrenia among first and second-degree relatives and fathers' age at birth ≥35years) in a series of schizophrenia cases recruited from a research unit. Data were available on demographic variables, symptoms (Positive and Negative Syndrome Scale; PANSS), cognitive tests (Wechsler Adult Intelligence Scale-Revised; WAIS-R) and olfaction (University of Pennsylvania Smell Identification Test; UPSIT). We conducted a series of k-means clustering analyses to identify clusters of cases containing high concentrations of PARS.

RESULTS: Two analyses generated clusters with high concentrations of PARS cases. The first analysis (N=136; PARS=34) revealed a cluster containing 83% PARS cases, in which the patients showed a significant discrepancy between verbal and performance intelligence. The mean paternal and maternal ages were 41 and 33, respectively. The second analysis (N=123; PARS=30) revealed a cluster containing 71% PARS cases, of which 93% were females; the mean age of onset of psychosis, at 17.2, was significantly early.

CONCLUSIONS: These results strengthen the evidence that PARS cases differ from other patients with schizophrenia. Hypothesis-generating findings suggest that features of PARS may include a discrepancy between verbal and performance intelligence, and in females, an early age of onset. These findings provide a rationale for separating these phenotypes from others in future clinical, genetic and pathophysiologic studies of schizophrenia and in considering responses to treatment.

Copyright © 2011 Elsevier B.V. All rights reserved.
PMID: 21353765 [PubMed - as supplied by publisher]

Delayed fathering and risk of mental disorders in adult offspring.

2011-01-12T08:09:00.000-08:00

Early Hum Dev. 2011 Jan 8. [Epub ahead of print]

Delayed fathering and risk of mental disorders in adult offspring.
Krishnaswamy S, Subramaniam K, Ramachandran P, Indran T, Abdul Aziz J.

University of New England, Locked bag 4, NSW 2351, Australia.

Abstract
INTRODUCTION: Delayed parenting and child bearing at a very young age impose various risks to development of the offspring.

OBJECTIVE: This study aims to investigate the association between disparities in parental age and increased risk factor for common mental disorders in the progenies during adulthood.

METHODOLOGY: The Malaysian Mental Health Survey (MMHS) was analysed for this study. Respondents were asked to estimate the age of their parents at their birth. Presence of common mental disorders (CMD) was determined by referring to the diagnosis given by the Clinical Interview Schedule-Revised (CIS-R) instrument in the Programmed Questionnaire System (PROQSY) format. The association between parental age disparities and CMD was studied using logistic regression.

RESULT: Fifty three percent (n=1972) of the MMHS respondents (N=3666) knew the age of both parents and were included in the study. Three percent (n=53) had significant disparity in parental age, or a difference of 11years or more. Respondents born to parents with significant age disparity had a prevalence rate of 24% (95% CI=22.12-25.89) for CMD in comparison to 6% (95% CI=5.99-6.11) in their counterparts and 3.4 times higher risk for CMD, after adjusting for demographic factors, paternal age at birth and presence of family history of mental disorders. Amongst those born to older fathers aged 50 and above, the presence of disparity increased the rate for CMD to 42% (95% CI=39.82-44.18).

DISCUSSION: Disparity in parental age was significantly associated with increased risk for CMD. Various psychosocial factors contributing to age disparity in both the father and the mother could predispose to stress and mental health problems.

Copyright Â© 2010 Elsevier Ltd. All rights reserved.

Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.

2010-12-01T11:13:00.000-08:00

Mol Psychiatry. 2010 Nov 30. [Epub ahead of print]

Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.
Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Abstract
Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged 50 years were 2.2 times (95% confidence interval: 1.26-3.88: P=0.006) more likely to have autism than offspring of men aged 29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.Molecular Psychiatry advance online publication, 30 November 2010; doi:10.1038/mp.2010.121.

PMID: 21116277 [PubMed - as supplied by publisher]

the relationship between a father’s age and his adult offspring’s likelihood of developing certain cancers.

2010-11-12T14:44:00.000-08:00

Study could change the way doctors understand certain cancers

Dr. Yani Lu’s latest research discovery at City of Hope could change the way doctors understand and treat certain cancers.

Lu, a postdoctoral fellow in the Division of Cancer Etiology, looked into the relationship between a father’s age and his adult offspring’s likelihood of developing certain cancers.

Dr. Yani Lu discovered a connection between a father’s age and his children’s chances to develop certain cancers.
Dr. Lu concluded that the children of older fathers face an increased risk of non-Hodgkin’s lymphoma later in life.

“As a man, you may think you can have a baby at 50 or 60” with no real repercussions, Lu says. “But there may be other risks for your child down the line.”

The idea of a “biological clock” is commonly associated with women alone, but Lu’s research challenges that double standard. In the study, Lu points out that older parents are prone to passing on undesirable genetic traits.

Lu believes the male biological clock might relate to mutations that can accumulate in a man’s reproductive cells over the course of a lifetime. Such cells divide more rapidly than a woman’s reproductive cells. More divisions lead to more chances for abnormalities.

But because many non-Hodgkin’s lymphoma patients are well into their 60s or 70s at the time of diagnosis, most research on the disease has failed to consider genetic effects at all.

Lu and her research team recognized that being born to older parents can have consequences extending well into adulthood.

“For adult-onset malignancies, people seldom think back to factors early in life,” Lu says.

Lu plans to continue her research on the male biological clock by focusing on other, similar cancers.

The epidemiology of schizophrenia: replacing dogma with knowledge.

2010-10-20T08:56:00.000-07:00

Dialogues Clin Neurosci. 2010;12(3):305-15.

The epidemiology of schizophrenia: replacing dogma with knowledge.
Stilo SA, Murray RM.

Psychosis Clinical Academic Group, Institute of Psychiatry, King's Health Partners, King's College London, UK.

Abstract
Major advances have been made in our understanding of the epidemiology of schizophrenia. We now know that the disorder is more common and severe in young men, and that the incidence varies geographically and temporally. Risk factors have been elucidated; biological risks include a family history of the disorder, advanced paternal age, obstetric complications, and abuse of drugs such as stimulants and cannabis. In addition, recent research has also identified social risk factors such as being born and brought up in a city, migration, and certain types of childhood adversity such as physical abuse and bullying, as well as social isolation and adverse events in adult life. Current research is focussing on the significance of minor psychotic symptoms in the general population, gene-environmental interaction, and how risk factors impact on pathogenesis; perhaps all risk factors ultimately impact on striatal dopamine as the final common pathway.

These results support the claim that increased paternal age is associated with a birth of a child with autism spectrum disorder

2010-09-15T08:07:00.000-07:00

Pediatr Neurol. 2010 Oct;43(4):300-302.

Paternal Age in Autism Spectrum Disorders and ADHD.
Gabis L, Raz R, Kesner-Baruch Y.

Weinberg Child Development Center, Safra Children's Hospital, Sheba Medical Center (affiliated with the Sackler School of Medicine, Tel-Aviv University, Israel), Tel Hashomer, Israel.

Abstract
Increased paternal age has been associated with an increased risk for autism spectrum disorders. The present study compared the paternal age distribution in autism spectrum disorders children with that of the general population and among children with attention deficit hyperactivity disorder. Study participants were drawn from the records of children diagnosed with one of these conditions in the years 1998-2006 at the Weinberg Child Development Center, Israel. Data regarding paternal age distribution in the general Israeli population were drawn from the yearly official publications of the Central Bureau of Statistics, Israel. Paternal age at the child's birth was found for autism spectrum disorders children (n = 268) and attention deficit hyperactivity disorders children (n = 320). Paternal age distribution of the attention deficit hyperactivity disorder children was similar to that of the general population in Israel, whereas autism spectrum disorders children were born to older fathers, compared with either the general population (P < 0.001) or children with attention deficit hyperactivity disorder (P = 0.04). These results support the claim that increased paternal age is associated with a birth of a child with autism spectrum disorders, but indicate that this finding cannot be generalized to attention deficit hyperactivity disorder.

In cases of sporadic achondroplasia as well as in fibrodysplasia ossificans progressiva, there is a strong association with paternal age,

2010-09-09T08:23:00.000-07:00

Adv Exp Med Biol. 2010;686:335-48.

Osteochondral diseases and fibrodysplasia ossificans progressiva.
Morales-Piga A, Kaplan FS.

Jefe de Servicio de Proyectos Clínicos del Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Sinesio Delgado, 6, 28029, Madrid, Spain, amorales@isciii.es.

Abstract
Osteochondrodysplasias like thanatophoric dysplasia, osteogenesis imperfecta, achondroplasia, and other genetic skeletal disorders like fibrodysplasia ossificans progressiva are infrequently seen in clinical practice. In cases of sporadic achondroplasia as well as in fibrodysplasia ossificans progressiva, there is a strong association with paternal age, a relationship that is less evident in other genetic osteochondral diseases. No other constitutional or environmental factor has proven to be associated with these disorders. The use of prenatal ultrasonography as a routine component of prenatal care is crucial in the early suspicion of osteochondrodysplasias whereas definitive diagnosis is usually obtained by pre-natal molecular analysis. In the case of fibrodysplasia ossificans progressiva, recognition of congenital great toe malformations associated with rapidly-appearing soft tissue swelling is sufficient to make the proper clinical diagnosis, which can be confirmed by genetic testing. Large regional centres will improve diagnosis performance, provide accurate genetic counselling, and ensure an integral assistance for these often severe and incapacitating conditions.

Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

2010-09-04T08:09:00.000-07:00

J Gynecol Obstet Biol Reprod (Paris). 2010 Apr;39(1 Suppl):36-8.

[Influence of paternal age]
[Article in French]

Velez de la Calle JF, Broussin B, Lelaidier C, Fallet C.

Unité FIV, Clinique Pasteur, 34, Rue du Moulin à Poudre, Brest, France.

Abstract
Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

PMID: 20728806 [PubMed - in process]

Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females.

2010-08-19T08:12:00.000-07:00

Am J Med Genet B Neuropsychiatr Genet. 2010 Aug 17. [Epub ahead of print]

Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females.
Perrin M, Harlap S, Kleinhaus K, Lichtenberg P, Manor O, Draiman B, Fennig S, Malaspina D.

Department of Psychiatry, New York University School of Medicine, New York, New York.

Abstract
The effect of a family history of schizophrenia on the risk for this disorder in the offspring has rarely been examined in a prospective population cohort accounting for the sex of the proband and the first-degree relatives, and certainly not with respect to later paternal age. The influence of affected relatives on offspring risk of schizophrenia was estimated using Cox proportional hazards regression in models that accounted for sex, relation of affected first degree relatives and paternal age in the prospective population-based cohort of the Jerusalem Perinatal Schizophrenia Study. Of all first-degree relatives, an affected mother conferred the highest risk to male and female offspring among the cases with paternal age <35 years, however, female offspring of fathers >/=35 years with an affected sister had the highest risk (RR = 8.8; 95% CI = 3.9-19.8). The risk seen between sisters of older fathers was fourfold greater than the risk to sisters of affected females of younger fathers (RR = 2.2, 95% CI 0.7-6.7). The test for interaction was significant (P = 0.03). By contrast, the risk of schizophrenia to brothers of affected males was only doubled between older (RR = 3.3, 95% 1.6-6.6) and younger fathers (RR = 1.6, 95% CI 0.7-3.5). The most striking finding from this study was the very large increase in risk of schizophrenia to sisters of affected females born to older fathers. The authors speculate that the hypothesized paternally expressed genes on the X chromosome might play some role in these observations. (c) 2010 Wiley-Liss, Inc.

PMID: 20718003 [PubMed - as supplied by publisher]

Paternal age increases the risk for autism in an Iranian population sample.

2010-08-04T09:35:00.000-07:00

Mol Autism. 2010 Feb 22;1(1):2.

Paternal age increases the risk for autism in an Iranian population sample.
Sasanfar R, Haddad SA, Tolouei A, Ghadami M, Yu D, Santangelo SL.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA. ssantangelo@pngu.mgh.harvard.edu.

Abstract
ABSTRACT: BACKGROUND: Autism is a neurodevelopmental disorder which is known to have a strong genetic component and is most likely oligogenic. However, the necessary role of environmental factors has been well documented. Prior research suggests that parental characteristics, such as age and level of education, may be associated with a risk of autism. Parental age has been shown to be associated with many disorders, such as schizophrenia, childhood cancer and fetal death. However, results from studies of parental age and autism are inconsistent. METHODS: In the present study, we investigated the association of autism with parental age in 179 autism cases and 1611 matched cohort children from Iran. Each case was matched with nine cohort controls on parental education, sex, order of birth, consanguineous marriage, urbanism and province of residence. The Cox regression model was used to carry out conditional logistic regression on the matched data. RESULTS: There was a significant association between higher paternal age, but not maternal age, and an increasing risk of autism. An analysis of the combined effect of parental age and education also revealed that parents with higher education had an increased risk of having autistic children, with a dose-response effect of parental age. CONCLUSIONS: This study, which is the first epidemiological study of autism in Iran, provides evidence of the association of paternal age and risk of autism.

PMID: 20678245 [PubMed - in process]

There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age

2010-06-30T08:43:00.000-07:00

Arch Dis Child. 2010 Jun 28. [Epub ahead of print]

Case-control analysis of paternal age and trisomic anomalies.
De Souza E, Morris JK; EUROCAT Working Group.

Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, Charterhouse Square, London, UK.

Abstract
Objectives To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome. Design Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months. Setting Data from 22 EUROCAT congenital anomaly registers in 12 European countries. Participants Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age >/=20 weeks and terminations after prenatal diagnosis of the anomaly. Data include 374 cases of Patau syndrome, 929 of Edwards syndrome, 295 of Klinefelter syndrome, 28 of XYY syndrome and 5627 controls with Down syndrome. Main outcome measures Odds ratio (OR) associated with a 10-year increase in paternal age for each anomaly was estimated using conditional logistic regression. Results were adjusted to take account of the estimated association of paternal age with Down syndrome (1.11; 95% CI 1.01 to 1.23). Results The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26). Conclusions There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age. The larger positive associations of Klinefelter and XYY syndromes with paternal age compared with Patau and Edwards syndromes are consistent with the greater percentage of these sex chromosome anomalies being of paternal origin.

PMID: 20584846 [PubMed - as supplied by publisher]

Supplemental ContentRelated citations
Trisomy 18 in Kuwait. [Int J Epidemiol. 1999]
Trisomy 18 in Kuwait.
Naguib KK, Al-Awadi SA, Moussa MA, Bastaki L, Gouda S, Redha MA, Mustafa F, Tayel SM, Abulhassan SA, Murthy DS.
Int J Epidemiol. 1999 Aug; 28(4):711-6. Down syndrome and paternal age, a new analysis of case-control data collected in the 1960s. [Am J Med Genet A. 2009]
Down syndrome and paternal age, a new analysis of case-control data collected in the 1960s.
De Souza E, Alberman E, Morris JK.
Am J Med Genet A. 2009 Jun; 149A(6):1205-8. Maternal age-specific risk of non-chromosomal anomalies. [BJOG. 2009]
Maternal age-specific risk of non-chromosomal anomalies.
Loane M, Dolk H, Morris JK, EUROCAT Working Group.
BJOG. 2009 Jul; 116(8):1111-9. Epub 2009 May 29.[Prenatal diagnostics of chromosomal aberrations Czech Republic: 1994-2007] [Ceska Gynekol. 2009]
[Prenatal diagnostics of chromosomal aberrations Czech Republic: 1994-2007]
Gregor V, Sípek A, Sípek A Jr, Horácek J, Langhammer P, Petrzílková L, Calda P.
Ceska Gynekol. 2009 Feb; 74(1):44-54. Review Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes. [Am J Med Genet A. 2005]
Review Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes.
Kovaleva NV, Mutton DE.
Am J Med Genet A. 2005 Apr 1; 134A(1):24-32. See reviews...

ntists show children of older fathers face a higher risk of a type of lymphoma

2010-06-26T15:10:00.000-07:00

Scientists show children of older fathers face a higher risk of a type of lymphoma

By Wayne Lewis

Risk of non-Hodgkin’s lymphoma is higher for children of older men, according to City of Hope researchers — a finding that adds to a growing body of evidence suggesting that men, too, may have a biological clock.

The study is one of the first to examine the relationship between parents’ age and their adult offspring’s likelihood of facing cancers of the blood and immune system. Yani Lu, Ph.D., a postdoctoral fellow in the Division of Cancer Etiology, led the study, which was released online in the American Journal of Epidemiology on June 3.

Yani Lu (Photo by p.cunningham)

“As a man, you may think, ‘I can have a baby at 50 or 60 and live long enough to see him go through college.’ But there may be other risks for your child down the line, and you may want to be conscious of those risks,” said Lu.

Lu’s research drew upon data from the California Teachers Study. Initiated in 1995, this project tracks the health, lifestyle choices and demographic information of nearly 133,500 female teachers and administrators in the California public schools’ retirement system. The teachers study is led by Leslie Bernstein, Ph.D., director of the Division of Cancer Etiology in the Department of Population Sciences and Lu’s mentor.

In the latest project, researchers focused on 110,999 women, 819 of whom had been diagnosed with a hematological malignancy. The study revealed that participants born to fathers older than age 40 faced a 59 percent greater risk of non-Hodgkin’s lymphoma compared to similar women born to fathers younger than 25.

“For adult-onset malignancies, people seldom think back” to factors early in life, Lu said. “Diagnosis for non-Hodgkin’s lymphoma occurs closer to the age of 70, so why would in utero factors be related to risk?”

In the study, the fathers’ age had no effect on risk for acute myeloid leukemia or multiple myeloma. Maternal age did not significantly influence risk for blood cancers.

Science has shown that the ticking biological clock is associated with a higher incidence of health issues in children of older mothers. These women face greater risk of miscarriage and increased risks of bearing children with low birth weight or serious health issues such as Down’s syndrome. A recent, large study suggested that children of women over 40 have a greater chance of having autism.

Similar findings among older fathers are scanty, although research going back almost 100 years suggests that these men are more likely to produce children with certain rare birth defects. Numerous studies also show that offspring of older men have a greater risk of developing schizophrenia.

As Lu noted, however, a burgeoning field of research suggests a father’s age at conception may play a more significant role in his progeny’s health than once thought. Recent investigations indicate that children of older fathers have a greater chance of prostate and breast cancers in adulthood as well as some blood cancers during childhood.

Lu believes the male biological clock might relate to mutations that can accumulate in a man’s reproductive cells over the course of a lifetime. Such cells divide more rapidly than a woman’s reproductive cells. More divisions lead to more chances for abnormalities to arise.

Older parental age also appears to be associated with longer length of offspring’s telomeres, the end caps on chromosomes, which might be linked to non-Hodgkin’s lymphoma risk, Lu suggested.

Because non-Hodgkin’s lymphoma is actually a cluster of related diseases with about 30 subtypes, Lu plans to examine how paternal age and other health factors during the early years of life influence risk for specific disease subtypes.

Sophia S. Wang, Ph.D., associate professor of population sciences, was the paper’s senior author. The National Institutes of Health and the California Breast Cancer Research Fund funded the research.

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In females but not in males, increasing paternal age was associated with a linear increased risk of suicide

2010-06-10T10:53:00.000-07:00

J Nerv Ment Dis. 2010 Jun;198(6):404-411.

Advanced Paternal Age, Mortality, and Suicide in the General Population.
Miller B, Alaräisänen A, Miettunen J, Järvelin MR, Koponen H, Räsänen P, Isohanni M, Kirkpatrick B.

*Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia; daggerDepartment of Psychiatry, University of Oulu, Oulu, Finland; double daggerDivision of Epidemiology, Public Health, and Primary Care, Imperial College, London, United Kingdom; section signDepartment of Public Health and General Practice, University of Oulu, Oulu, Finland; and paragraph signDepartment of Psychiatry, University of Kuopio, Kuopio, Finland.

Abstract
Advanced paternal age is a risk factor for adverse health outcomes in the offspring. In a population-based birth cohort from Finland, 10,965 singleton offspring born in 1966 and alive at age 1 were followed to age 39. Hazard ratios were calculated, adjusting for maternal age, gender, paternal social class, and maternal parity. In females but not in males, increasing paternal age was associated with a linear increased risk of suicide (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.04-1.24, p < 0.01) and all-causes mortality (HR = 1.06, 95% CI = 1.01-1.10, p = 0.02). Increasing maternal age was associated with a significantly decreased risk of suicide (HR = 0.93, 95% CI = 0.86-1.00, p = 0.04) and all-causes mortality (HR = 0.96, 95% CI = 0.93-1, p = 0.02) in the entire cohort. For paternal age >/=30, the population attributable risk percentage was 13.7% for all deaths and 7.5% for suicides. Parental age at birth may affect suicide and all-causes mortality risk in the offspring in the general population. The causal pathways and specific disorders associated with this increased mortality are largely unknown.

PMID: 20531118 [PubMed - as supplied by publisher]

Advanced paternal age may play a role in non-Hodgkin lymphoma etiology.

2010-05-29T06:45:00.000-07:00

Am J Epidemiol. 2010 May 27. [Epub ahead of print]

Parents' Ages at Birth and Risk of Adult-onset Hematologic Malignancies Among Female Teachers in California.
Lu Y, Ma H, Sullivan-Halley J, Henderson KD, Chang ET, Clarke CA, Neuhausen SL, West DW, Bernstein L, Wang SS.

Abstract
Although advanced parental age at one's birth has been associated with increased risk of breast and prostate cancers, few studies have examined its effect on adult-onset sporadic hematologic malignancies. The authors examined the association of parents' ages at women's births with risk of hematologic malignancies among 110,999 eligible women aged 22-84 years recruited into the prospective California Teachers Study. Between 1995 and 2007, 819 women without a family history of hematologic malignancies were diagnosed with incident lymphoma, leukemia (primarily acute myeloid leukemia), or multiple myeloma. Multivariable-adjusted Cox proportional hazards models provided estimates of relative risks and 95% confidence intervals. Paternal age was positively associated with non-Hodgkin lymphoma after adjustment for race and birth order (relative risk for age >/=40 vs. <25 years = 1.51, 95% confidence interval: 1.08, 2.13; P-trend = 0.01). Further adjustment for maternal age did not materially alter the association. By contrast, the elevated non-Hodgkin lymphoma risk associated with advanced maternal age (>/=40 years) became null when paternal age was included in the statistical model. No association was observed for acute myeloid leukemia or multiple myeloma. Advanced paternal age may play a role in non-Hodgkin lymphoma etiology. Potential etiologic mechanisms include de novo gene mutations, aberrant paternal gene imprinting, or telomere/telomerase biology.

PMID: 20507900 [PubMed - as supplied by publisher]

Male Biological Clock

2010-05-28T07:02:00.000-07:00

Naked Fatherhood
Parenting for Smart DadsCategory
Select Category Balanced Parenting (3) Early Daze (3) Happy Daze (5) Mad Ramblings (2) The Recent Fathers’ Club (4) Uncategorized (1)
HomeMen’s Biological Clock
by justin on May 24, 2010
in Happy Daze
Share Your Thoughts
There were rumours a while back that Hugh Hefner, the octogenarian founder of the Playboy empire was planning to father a child with Holly Madison (53 years his junior), the alpha female of his three live-in girlfriends. Of course that was before the jam hit the fan and all three moved out of the mansion.

But, apropos the baby – why not? Charlie Chaplin and Picasso both fathered children well into their 70s, with no ill-effects. There are even anecdotal reports in the medical press of men in their 90s becoming fathers. Everyone knows that we men can just carry on having children until very late in life, (although it’s possible that having kids just makes you feel 100 hundred years old).

Photo by: judepics
But is it all true? It seems that medical evidence is mounting that men are not immune from the ticking of the biological clock (although we often battle to hear it quite as loudly as our partners).

The first part of the problem lies with the decline in fertility of men as they age. Testosterone levels fall over time which not only makes it harder for men to hold their tummies in at the beach, but also affects sexual performance. There is also a decline in sperm count and sperm quality which means that it takes men over 45 significantly longer to produce a pregnancy than men under 25 – up to 5 times longer according to some research.

Still, it was thought that even with a decline in fertility, any genetic issues with the pregnancy or resulting child lay with the mother. This was because while a woman is born with her full quota of eggs, men manufacture sperm continually without even having to think about it, so conception between an older couple might be the meeting of a forty-year-old egg with a three-month-old sperm (the time taken to manufacture mature spermatozoa).

However, it now seems that there’s also a deterioration in the quality of the genetic material that each sperm carries. This is first seen in an increase in the number of miscarriages – three times greater where fathers are older than 35 compared to those younger than 25. The incidence of pre-eclampsia also rises with increasing paternal age.

This deterioration of genetic material is thought to arise from a number of causes. The cells which divide to produce sperm cells replicate around 23 times per year starting from puberty, so by the time a man hits 50, those cells have divided about 800 times, increasing the risk of errors.

With age, the frequency of sporadic single-gene mutations also increases four to five times for a person over 45. On top of that, the enzymes that repair faulty DNA decrease in efficiency as one gets older.

All of which means an increase in a list of medical problems now totalling about 20.

A study of data from a huge Israeli health database showed that, for example, schizophrenia is twice as likely to occur in the children of men over forty as in those in their twenties. Men over fifty lead to a three-time increase in risk.

A further study on the same database showed that autism too is six times more frequent where fathers are over forty than those under 30.

An earlier study by Dr Harry Fisch (author of the book The Male Biological Clock) concluded that parents over 40 have a six-times higher risk of having a child affected by Down Syndrome than where both are under 35. And where a woman over forty has a child affected by Down Syndrome, the genetic blame is now thought to lie 50% with the father.

And the list goes on, with various studies linking advanced paternal age to disorders such as dwarfism, progeria (an extremely rare accelerated aging disease), skeletal disorders, congenital heart defects, certain types of cancer and even reduced scores in nonverbal IQ tests.

All of which helps explain why the cutoff age for sperm donors in The States is set at 40. So that’s another paying hobby limited to the youth – smacks of ageism, doesn’t it?

And yet more and more couples are leaving it later to have children for any number of reasons. Many want to feel like they’ve experienced something of a life and a career before the little tyrants arrive. Some prefer to wait until they’re in a more financially stable phase of their lives before committing. Maybe its just that there are more frogs to kiss nowadays in search of princes. Or even that the kiss-per-frog ratio has risen.

And really, what’s the downside? You may be more likely to spend time in casualty with a back problem from flinging your toddler around and there’s the danger of injuring yourself by tripping over your Zimmer frame when playing cricket with the young ‘uns.

Having kids later probably means that you’re going to have a bit less energy for them, but then again, that depends on how well you’ve looked after yourself in getting to where you are. Also, a decrease in the time available to spend with children can be offset to a certain degree by an increase in the quality of the time spent.

Many parents are finding that they’re having children later without even planning it that way – life often gets in the way of our plans. Then when one’s finally ready to make this life-altering commitment it takes a little while to get everything ready to even start trying (especially when you discover that the whole house has to be remodelled before you can even start).

And then it doesn’t just happen right away, and where there are miscarriages, recovery, both physical and emotional, takes time before you can start again.

All of which means an upswing in the number of parents who battle to remember where they left the children a few minutes before.

Then again, children of older parents should be more independent when they grow up, if only because they’re used to being able to easily outpace their pursuers.

From a selfish point of view, having kids later means that you’ll have someone around who is able to intuitively figure out how to use the new DVD player that has been standing unused because you can’t work out what the instruction manual is trying to tell you.

Also, you don’t resent the loss of your social life to the same degree as those that have their children while they are young (the parents, not the children) – you’re giving up a whole lot less when your idea of a good time is staying in with a good book and listening to Smooth Classics.

And when you’re lucky enough to have your mid-life crisis with small children you’re much less likely to embarrass yourself by running off and buying a convertible or any motorcycle that comes with tassles hanging from the handlebars.

The bottom line? Don’t leave it too late. While it is physiologically possible for a man to produce heirs at a very late stage of life, the risks do rise along the way.

And Hef? I think that at his age, he’s just perfected the art of saying ‘Yes Dear’ without really listening to what anyone is actually saying.

Share and Enjoy:

Tags: fathers, old dads, senior fathers

2010-04-03T16:44:00.001-07:00

Oh my goodness Late paternal age starts at 30

2010-03-30T17:29:00.000-07:00

Speaking of Biological Clocks
Women aren’t the only ones who should pay attention to their biological clocks…

While men can still have kids at 50, it turns out there are increased health and psychological risks to the child:

Is Your Sperm Too Old?

Are you still bearing healthy fruit? Turns out that it’s not just women who have a biological clock—your sperm may be going to seed a lot faster than you think.

By Kevin Conley,
Photographs by Christian Weber

While you’ve never been against the idea of a serious relationship, you are in no particular rush to become a schlub. The attendant trappings of new fatherhood—the preschool viewings, the sleepless nights, the humiliation of carrying a diaper bag—aren’t exactly calling out to you the way, say, another night slinging Pisco sours would. The ever-intensifying din of the proverbial biological clock? That’s for the opposite sex to worry about—you know, like periods, frizz, and whether Mr. Big will dump Carrie in the Sex and the City sequel. As far as you know, your little swim team of DNA carriers will be competing at Olympic level into Letterman age. So what’s the rush?

“I always thought my biological clock was the 36 hours I had left after I took my Cialis pill,” says Zack, a 30-year-old producer in Los Angeles. “That’s the only clock I’ve ever felt ticking.” Turns out, Zack might want to consider the unsung glories of fatherhood.

According to a study released last March in the Public Library of Science Medicine, children born to fathers who were 20 scored an average of 2 points higher on an IQ test than children born to 50-year-old fathers. And that’s not all. Recent studies from Israel, California, and Sweden have connected “late paternal age” with any number of serious medical conditions: The longer you wait, the more likely it is that your kid will be affected by schizophrenia, dwarfism, bipolar disorder, autism, Marfan syndrome, certain childhood cancers, or even, later in life, Alzheimer’s. In some cases, the risk factors skyrocket. A 2005 study conducted by the University of California, Los Angeles, found a fourfold rise in Down syndrome among babies born to men 50 and older. Worse still, those risk factors aren’t limited to your tweed-sporting years: Statistically, “late paternal age” starts at 30, as in Zack’s age. A 2006 study conducted by Mount Sinai School of Medicine found that fathers in their thirties have children with about 1.5 times the risk of developing autism compared with fathers in their teens and twenties. That factor jumps to five times for dads in their forties. The cherry on the cake? The American Society for Reproductive Medicine recommends that sperm banks do not accept specimens from men over 40.

“The biological clock for men and women is really the same,” says Dr. Dolores Malaspina of Bellevue Hospital Center in New York City and New York University, who conducted one of the first studies. “It’s just that men can keep having babies.”

The biology behind this isn’t hard to grasp: Starting in puberty, spermatogonia, the master copies for sperm production, replicate themselves every couple of weeks. After 300 to 500 copies—somewhere in your thirties—a meaningful number of small copy errors, or point mutations, start to emerge, which accumulate over time.

Yet, despite the alarming new science, most men greet parenthood with a sense of urgency that’s more in line with Zack’s than Angelina Jolie’s. The reason is simple: While women are inculcated with the risks of late-age motherhood in sixth-grade sex ed, men remain blissfully ignorant. Since the recent studies have been published, the bad news still doesn’t seem to be making it to the doctor’s office. Scott, a 32-year-old schoolteacher from Babylon, New York, decided to start a family when he was Zack’s age, strictly because he wanted to raise his child while he was young. “For me the doctors were like, ‘Hey, this is going to be good. You’re still active,’” Scott says. “Nobody ever told me about the medical risks of being an older dad.”

That’s because men don’t usually get this news flash until they’re looking through a microscope at a batch of fugly sperm with no sense of direction. Swain, a 37-year-old IT professional in Dallas, wishes he had heard sooner. “Who cares if the baby is born with six fingers we can’t get that far,” he says. “I’d be thrilled to have that problem.” His wife is four years younger than he is, and they decided to wait. “What I did was let her clock be the one in control,” Swain says. “I would have been happy having kids five, six years ago, but she just wasn’t ready. The female clock seems to dominate the conversation.”

But don’t expect sweeping social change anytime soon. “Tell a man he’s got a chance of having kids with genetic abnormalities, and it’s like he’s going through the stages of the acceptance of death,” says Dr. Harry Fisch, a professor of urology and the author of The Male Biological Clock. “They’ll say, ‘I’m losing my manliness, my sexual ability.’ To them it all comes under the same umbrella.”

The good news is that no one, not even Malaspina, is suggesting that older men eschew the joys of fatherhood. But if you’re a younger guy who hasn’t thought twice about postponing it, be forewarned: The female of the species is about to get her just rewards. That bell tolling? It’s for you.

______________________________________________________________

Oh my goodness! Late paternal age starts at 30? I think most men don’t even consider babies until then..

2010-03-19T15:26:00.001-07:00

Paternal age and mortality in nonaffective psychosis

2010-02-19T07:13:00.000-08:00

Schizophr Res. 2010 Feb 16. [Epub ahead of print]

Paternal age and mortality in nonaffective psychosis.
Miller B, Pihlajamaa J, Haukka J, Cannon M, Henriksson M, Heilä H, Huttunen M, Tanskanen A, Lönnqvist J, Suvisaari J, Kirkpatrick B.

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Georgia, United States; Department of Psychiatry, University of Oulu, Oulu, Finland.

INTRODUCTION: Advanced paternal age (APA) is associated with an increased mortality in the general population, and is a risk factor for schizophrenia. We aimed to test if APA is associated with increased mortality in people with nonaffective psychosis. METHODS: Subjects with nonaffective psychosis who were born in Helsinki, Finland, between 1951 and 1960 (n=529) were followed until June 2006 (age 46 to 55). Hazard ratios were calculated, adjusting for subject age, age of the other parent, and gender. RESULTS: In females but not males, there was a significant increase in all-causes mortality (HR=7.04, 95% CI 1.60-31.04, p=0.01) and natural deaths (HR=7.64, 95% CI 1.20-48.66, p=0.03) in offspring of fathers age >/=40, after adjustment for potential confounders. In males but not females, there was a significant decrease in suicides (HR=0.89, 95% CI 0.81-0.97, p=0.01) with increasing maternal age (as a continuous variable). In the entire sample, there was also a trend for decreased all-cause mortality (HR=0.96, 95% CI 0.92-1.01, p=0.08) with increasing maternal age (as a continuous variable). DISCUSSION: Both paternal and maternal age may affect mortality risk in offspring with psychosis. The specific disorders and pathway(s) associated with the increase in natural cause mortality remain to be determined. Copyright © 2010 Elsevier B.V. All rights reserved.

PMID: 20163936 [PubMed - as supplied by publisher]

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Tick tock goes the male biological clock

2010-02-18T17:39:00.000-08:00

Men: Your Biological Clocks are Ticking

2010-01-30T21:54:00.000-08:00

Men: Your Biological Clocks are Ticking!
by Whitney Rhodes on January 30, 2010

For many years, it was tacitly assumed that while women have a “Sell By” date when it comes to fertility, men become fertile at puberty and remain so until a ripe old age.

Actually, although there is some truth in that myth, to the extent that males do not have a hormonal menopause as women do; the fact is that fertility in men does begin to decline after a certain age.

Men don’t completely stop being fertile at any age.

However, older fathers are prone to problems that younger fathers usually don’t experience.

What are Some of the Problems Experienced by Older Fathers?

A study that was conducted recently at the University of California, Berkeley, on a test group of men aged 22 to 80 showed that the sperm of older men are fewer in number with less mobility, as well as being less able to move in a straight line.

This research also showed an increased risk of achondroplasia, a genetic mutation that produces a kind of dwarfism.

Nor was this the only risk.

Older fathers were shown to have an increased risk of siring children with autism, or who were mentally retarded, or have behavioral problems with conditions such as schizophrenia.

Downs Syndrome, although associated with older mothers, doesn’t seem so far to be one of the risks of older fathers, but testing is still in progress.

It is believed that many times, male fertility problems caused by age and/or a medical condition might be mistaken as a potency issue, and mistakenly treated with a prescription for Viagra or a similar medication.

Investigating male infertility, and research of male sperm is gaining much new ground these days, as specialists recognize that infertility is not any more likely to rest with the female half of a couple than the male.

Today, more than ever, men and women alike are waiting longer to start families. This has given rise to an increasing frequency of fertility problems encountered with older parents.

So, although men are never completely infertile due to age, research has shown that the quality and quantity of sperm decrease with age.

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.

2010-01-29T08:16:00.000-08:00

Eur J Neurosci. 2010 Jan 25. [Epub ahead of print]

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.
Foldi CJ, Eyles DW, McGrath JJ, Burne TH.

Queensland Brain Institute, The University of Queensland, St Lucia, Qld 4072, Australia.

Abstract Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia. A previous study in mice suggested that the offspring of aged sires have altered locomotion and avoidance learning. The aim of the current study was to conduct a comprehensive behavioural screen in adult offspring of mice of APA. We also examined brain morphology in neonate and adult mice. The adult offspring of 12- to18-month-old (APA) and 4-month-old (control) male C57BL/6J mice underwent a behavioural test battery comprising tests for locomotion, anxiety, exploration, social behaviour, learned helplessness and sensorimotor gating. The brains of these mice were collected at 3 months and imaged ex vivo using a 16.4T MRI scanner to assess gross neuroanatomy. Neuroanatomy was also examined at birth in a separate cohort of animals. Overall, the APA mouse model was associated with subtle behavioural changes and altered cortical morphology. The behavioural phenotype of female APA mice included increased anxiety-related behaviour, increased exploration and decreased learned helplessness compared to control females. Male APA mice had thinner cortices at birth and increased cortical volume as adults. This animal model may assist in exploring the mechanism of action linking APA with disorders such as schizophrenia and autism.

PMID: 20105239 [PubMed - as supplied by publisher]

Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects

2010-01-09T09:15:00.000-08:00

Ann Epidemiol. 2010 Jan 5. [Epub ahead of print]

Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004.
Green RF, Devine O, Crider KS, Olney RS, Archer N, Olshan AF, Shapira SK; The National Birth Defects Prevention Study.

National Center on Birth Defects and Developmental Disabilities; Centers for Disease Control and Prevention; Atlanta, GA (R.F.G., O.D., K.S.C., R.S.O., S.K.S.); Texas Department of State Health Services; Austin, TX (N.A.); and Department of Epidemiology; University of North Carolina; Chapel Hill, NC (A.F.O.).

PURPOSE: The objective of this study was to examine the associations between paternal age and birth defects of unknown etiologies while carefully controlling for maternal age. METHODS: By using 1997 to 2004 data from the National Birth Defects Prevention Study, we fit logistic regression models with paternal and maternal age as continuous variables while adjusting for demographic and other factors. RESULTS: Elevated odds ratios (ORs) for each year increase in paternal age were found for cleft palate (OR. 1.02, 95% confidence interval [95% CI], 1.00-1.04), diaphragmatic hernia (OR, 1.04; 95% CI, 1.02-1.06), right ventricular outflow tract obstruction (OR, 1.03; 95% CI, 1.01-1.04), and pulmonary valve stenosis (OR, 1.02, 95% CI, 1.01-1.04). At younger paternal ages, each year increase in paternal age correlated with increased odds of having offspring with encephalocele, cataract, esophageal atresia, anomalous pulmonary venous return, and coarctation of the aorta, but these increased odds were not observed at older paternal ages. The effect of paternal age was modified by maternal age for gastroschisis, omphalocele, spina bifida, all orofacial clefts, and septal heart defects. CONCLUSIONS: Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects. Published by Elsevier Inc.

PMID: 20056435 [PubMed - as supplied by publisher]

Paternal Age and Schizophrenia

2010-01-08T07:39:00.000-08:00

Paternal Age and Schizophrenia
Research Date:
03/23/2006
An Expert Interview with Dolores Malaspina, M.D., M.P.H.

Great Neck, NY - March 23, 2006) — Scientists have linked paternal age to genetic diseases since the 1950s, and some have suggested an association between the age of the father and the risk for schizophrenia. In 2001, Dolores Malaspina, M.D., M.P.H., and her colleagues reported their research identifying a relationship between paternal age and the occurrence of schizophrenia. On behalf of Medscape* Jessica Gould interviewed Dr. Malaspina, Professor of Clinical Psychiatry at Columbia University and Research Psychiatrist at New York State Psychiatric Institute in New York City. Dr. Malaspina elaborates on her research and speaks about new directions in genetic research on schizophrenia. (NARSAD NOTE: Dr. Malaspina was a NARSAD 1993 and 1995 Young Investigator and a 2001 Independent Investigator.)

Medscape: Tell me about your research on paternal age and schizophrenia.

Dolores Malaspina: I have been compelled by the idea that schizophrenia is not a single disease. The consensus in the field is that schizophrenia is a syndrome, and a syndrome is a collection of different disorders. Yet there is still some controversy over whether or not there are variants of schizophrenia that might have separate causes and respond differently to various medications.

Since beginning my research in the late 1980s, I have focused on this heterogeneity, and one way that I've done that is by examining aspects of the disease in people who come from densely affected families, where two or more relatives have schizophrenia, and comparing them with cases of schizophrenia that have no family history of any chronic psychosis.

Now, in genetic research, it's known that for human genetic diseases, when a new case presents itself in a family, the mutation almost always arises during spermatogenesis. We have known for almost 100 years that the late born children in a family have more new genetic diseases. In the 1950s, a scientist named Penrose showed that only the age of the father predicts these genetic diseases. Over the last decade, it was shown that the risk for many complex genetic diseases was also correlated with paternal age. I thought that if schizophrenia cases with no family history were due to new genetic events, maybe they would also be correlated with the father's age.

I have the good fortune to be funded by the National Institutes of Health to study a very special birth cohort in Israel of about 100,000 pregnancies. We have a rich amount of demographic and clinical data on the parents, including the age of the father. The analysis showed what we considered to be a striking effect of the age of the father on the risk for schizophrenia.

Medscape: Could you tell me more about this group of research subjects from Israel?

Dr. Malaspina: The offspring were born between 1964 and 1976, and the original birth cohort was designed to examine the health of women during pregnancy as well as fetal outcomes. Israel maintains a high-quality psychiatric case registry. Working with the people at the Ministry of Health in Israel, my colleagues linked the birth cohort data to the psychiatric case registry data. The results showed that the risk of schizophrenia was tripled for the offspring of the oldest group of fathers.

We found that paternal age explained over a quarter of the risk for schizophrenia in the population. At the time, people were skeptical. But the findings have been replicated many times now, and not a single study has failed to find this strong relationship between father's age and the risk for schizophrenia. And at this point, other explanations for the relationship have been ruled out, including social factors in the family, prenatal care, and parental psychiatric ailments. There simply seems to be a relationship between paternal age and schizophrenia risk.

Medscape: Can you explain why the relationship between paternal age and schizophrenia exists?

Dr. Malaspina: When Penrose found that paternal age predicted new human genetic diseases, he proposed the Copy Error Theory. He said that each time the spermatozoa are copied there's an opportunity for a new mutation. Sperm cells divide every 16 days after puberty, so the DNA in the sperm of a 20-year-old father has been copied 100 times, but sperm DNA from a 50-year-old father has been copied more than 800 times. By comparison, egg cells from the mother only undergo a few dozen cell divisions all together. It is clear that there are many more opportunities for mutations to occur during spermatogenesis and that these increase with the age of the father. That is why new mutations are introduced in mammals in proportion to paternal age.

To further establish that paternal age is associated with schizophrenia risk, we went back to examine if paternal age is related to other factors associated with schizophrenia risk. We looked at intellectual functioning at age 17 in our birth cohort. Those data were available because adolescents in Israel are screened for military service. Working with personnel at the Israeli Defense Force, we examined whether intelligence was related to paternal age. And what we found was a very strong specific effect of paternal age on performance IQ. Very young mothers and very old mothers had offspring with impairments in verbal and performance intelligence. While there was no effect of late fathers' age on verbal IQ, there was a strong effect on performance intelligence, or nonverbal intelligence, which we have published.

In a parallel study, we examined the effect of late paternal age in a mouse model. Working with my colleague, Jay Gingrich, we studied several cohorts of inbred mice to compare offspring with younger and older fathers. The mouse model demonstrated striking effects of paternal age on the behavior of mice.

Those three lines of evidence provide converging data that paternal age does influence neural functioning and that paternal age is a plausible risk factor for schizophrenia.

Medscape: Could you describe what is meant by sporadic schizophrenia and how that relates to paternal age?

Dr. Malaspina: This goes along with the issue of whether schizophrenia is one single disease or several different variants, several different diseases. If it is several diseases, we could make much more progress if we knew how to separate individuals who have one variant of the disease from individuals who have the other variant, such as for treatment studies.

So, we have this finding that father's age predicts schizophrenia, but we don't know if the genetic changes are in the same genes that cause familial schizophrenia or if they occur at a different place. Some of the birth cohorts have actually looked to see how the risk of schizophrenia with paternal age is related to the family history of schizophrenia. The finding is that father's age is not connected to the risk of schizophrenia when it runs in families, but only for cases with no family history. That is called sporadic schizophrenia.

We have also looked at patients, with the help of funding from the National Alliance for Research on Schizophrenia and Depression, and we have examined whether or not cases with late paternal age and no family history have different symptoms and brain abnormalities from those of other cases. That work is under way.

Medscape: You also looked at the duration of the parents' marriage.

Dr. Malaspina: Yes, and we found that the duration of marriage was protective against the risk for schizophrenia. This goes in the opposite direction of paternal age, but it's an independent factor. Couples that have a very long marriage are less likely to have offspring with schizophrenia. One possibility is that parents who have mental disorders themselves may have shorter marriages. Another possibility is that there is an increased risk of schizophrenia when there is a marital separation.

Medscape: A variety of environmental factors can influence the development of schizophrenia. How do you control for that?

Dr. Malaspina: On the one hand, there may be scores of different intrauterine exposures that increase the risk for schizophrenia through different pathways. Another possibility, though, is that there are only a few final common pathways through which various intrauterine adversities are linked to the risk for schizophrenia.

The Barker hypothesis deals with the area of fetal programming. Research shows that the risk for many adult-onset chronic diseases, such as cardiovascular disease, obesity, diabetes, and hypertension, is related to fetal development. The mechanism may be that an adverse fetal environment compromises the development of organs and tissues and changes lifelong gene expression. The fetus survives, but its health is compromised. Effects on the developing nervous system could contribute to schizophrenia risk. So that's a possible pathway for the risk for schizophrenia, through a variety of prenatal exposures.

The benefit of our study in Israel is that we had such a wealth of obstetric data. The birth cohort involved early pregnancy interviews with the mom. It also involved evaluations of the progress of the pregnancy and records of the delivery. Our study was able to show that other prenatal exposures did not explain the linkage of paternal age to the risk of schizophrenia. Also, there have been many excellent studies after ours was conducted that have looked at numerous fetal exposures and found that those also do not explain the risk of paternal age for schizophrenia.

I do, however, believe that many fetal exposures can increase the risk of schizophrenia. I would suggest that the mechanism of these events may be via changes in lifelong gene expression.

Medscape: What about the influence of environmental factors after birth, during childhood and adolescence?

Dr. Malaspina: I think three of the interesting factors that have been linked to the risk of schizophrenia are severe stress in a stress-sensitive person who has underlying genes for schizophrenia, traumatic brain injury in those with underlying genes for schizophrenia, and, very importantly, cannabis exposure in early adolescence.

Medscape: Your research about paternal age became public in 2001. Do you think fewer men over a certain age might choose to have children as a result?

Dr. Malaspina: I haven't heard that. I would personally not discourage anyone from having a child at any age. People weigh their own risks. For the offspring of older fathers, the risk of schizophrenia is about 3 percent. That means that 97percent of the offspring do not have schizophrenia. Other cognitive diseases linked to paternal age include mental retardation of unknown etiology and Alzheimer's disease, and there is a strong relationship between paternal age and autism.

Medscape: What do you expect to be the future of your research in this area?

Dr. Malaspina: The genes for schizophrenia that we have identified lately are very interesting; they explain a large degree of the risk of the disease. Attention probably should turn toward factors that affect the expression of these genes and other genes. This is the area of epigenetics, the code that determines whether or not genes will be expressed.

We're pursuing a gene expression hypothesis for paternal age and schizophrenia. Humans have dozens or hundreds of genes that are expressed, not on the basis of being dominant or recessive, but on the basis of which parent we have inherited them from. So genes that control the growth of the fetus tend to be expressed on the basis of inheritance from the father. Other genes are expressed only on the basis of inheritance from the mother. These are called "parent of origin genes" or "parentally-imprinted genes." In these genes, the father's copy is expressed and the mother's is silenced, or vice versa. We are interested in this mechanism of gene-silencing. For the male parent, the silencing, or the activation/expression of genes from dad, takes place late in spermatogenesis. So our hypothesis and model right now for how paternal age affects the risk for schizophrenia is that it has altered the expression of genes inherited from the father.

Even exposures that interact with genetic susceptibility may act by changing gene expression, such as traumatic brain injury, cannabis, and stress. Maybe we can integrate our understanding of the many exposures tied to schizophrenia and the many genes tied to schizophrenia with the understanding that certain exposures may act by changing gene expression.

Meanwhile, some individuals who develop schizophrenia have a good outcome and stability without much deterioration -- but not as many as we would like. If we can't prevent the disease, perhaps we can learn the risk factors for deterioration and how to prevent it.

Although I see schizophrenia as a syndrome of separate illness variants, I think the field has benefited from considering it as a single disease. From here forwards, we may be diluting our ability to find risk factors and optimize outcome by considering the disease as a whole. To go forward in schizophrenia, we need to better understand how similar symptoms may arise from abnormalities in different neural circuits; that the set of symptoms we call schizophrenia could reflect a common pathway, but that the underlying biology may differ for groups of people, and that those differences may explain which medications they should receive, or which factors are more adverse for them. I think the field needs to move toward a finer understanding of the variants that exist. The identified genes may be clearly explanatory for some cases but not for others.

Funding Information

This interview is published in collaboration with NARSAD: The Mental Health Research Association, and is supported by an educational grant from Pfizer.

Dolores Malaspina, M.D., Professor of Clinical Psychiatry, Columbia University, New York, NY;
Director of Clinical Neurobiology, New York State Psychiatric Institute and Columbia University Medical Center, New York, N.Y.

Disclosure: Jessica Gould has disclosed no relevant financial relationships.

Disclosure: Dolores Malaspina, MD, has disclosed no relevant financial relationships.

*Reprinted with permission from Medscape Psychiatry & Mental Health 2006:11(1) http://www.medscape.com/viewarticle/520009 © 2006, Medscape. Please be advised that Medscape requires free registration to view articles.

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

2009-12-30T08:14:00.000-08:00

Open Access

Research Article

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

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Abstract
Introduction
Results
Discussion
Methods
Author Contributions
References
Rebecca G. Smith1#, Rachel L. Kember1#, Jonathan Mill1, Cathy Fernandes2*, Leonard C. Schalkwyk1, Joseph D. Buxbaum3,4, Abraham Reichenberg1,3

1 Medical Research Council Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom, 2 Department of Psychological Medicine and Psychiatry, King's College London, London, United Kingdom, 3 Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America, 4 Laboratory of Molecular Neuropsychiatry, and the Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York, United States of America

Abstract Top
Background
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

Methods
C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

Principal Findings
The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Conclusions
Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

Citation: Smith RG, Kember RL, Mill J, Fernandes C, Schalkwyk LC, et al. (2009) Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model. PLoS ONE 4(12): e8456. doi:10.1371/journal.pone.0008456

Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan

Received: October 28, 2009; Accepted: December 2, 2009; Published: December 30, 2009

Copyright: © 2009 Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the Beatrice and Samuel A. Seaver Foundation, by a British Medical Association Margaret Temple Award, and National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) for Mental Health at the South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry, King's College London (KCL) Pilot Award to Drs. Jonathan Mill and Abraham (Avi) Reichenberg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: cathy.fernandes@kcl.ac.uk

# These authors contributed equally to this work.

Introduction Top
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism [1], schizophrenia [2] and early-onset bipolar disorder [3]. Despite the methodological advantages of epidemiological research, a major limitation is that techniques are limited to observation. In order to establish causality, experimental evidence in the form of randomized-controlled trials or the development of animal models is required [4]. Animal models are particularly important as they allow environmental and genetic confounds to be controlled.

The lack of complete specificity in the association between advancing paternal age and psychiatric disorders may suggest that advancing paternal age is related to phenotypes shared across disorders. One phenotype in-common to schizophrenia, autism and bipolar disorder is abnormalities in social cognition broadly defined severe social deficit [5], [6], [7], [8]. A recent epidemiological study found an association between advancing paternal age and impaired social functioning in male offspring in the general population [9].

In this study we examined the effect of older paternal age on social and non-social behavior in mice. To the best of our knowledge this is the first fully-controlled animal study of the effects of paternal age on these behaviors.

Results Top
Social Behavior
Offspring of old fathers engaged in less social activity than the offspring of young fathers, spending less time socially-interacting with the conspecific mice (t = 2.23, d.f. = 22, p = 0.02, one-tailed test, Figure 1). This result was consistently observed across all measures of social behavior. There were no significant differences in overall locomotor activity.

Figure 1. Results of social behavioral data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05, † shows p-value of 0.06. A. Mean time (±SEM) displaying all social behaviors toward a conspecific mouse (broken down into components in B, C and D). B. Mean time (±SEM) displaying allogrooming behavior towards a conspecific mouse. C. Mean time (±SEM) displaying anogenital sniffing behavior towards a conspecific mouse. D. Mean time (±SEM) displaying sniffing behavior towards a conspecific mouse.

doi:10.1371/journal.pone.0008456.g001
Exploration in the Holeboard
Offspring of old fathers demonstrated reduced exploration in the holeboard, making fewer nose pokes and spending less time nose poking than offspring of young fathers (t = −2.21, d.f. = 22, p = 0.02; Figure 2A). No significant differences were evident in distance moved or time spent in the centre of the Holeboard arena.

Figure 2. Results of holeboard and open field data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05. A. Mean number of nose pokes (±SEM) into holes in the holeboard trial. B. Mean time spent in each area of arena (±SEM) in the open field task.

doi:10.1371/journal.pone.0008456.g002
Exploration in the Open Field
Offspring of old fathers were less exploratory in the Open Field, taking longer to enter the central zone of the arena (t = 1.7837, d.f. = 22, p = 0.04). However, there were no significant differences inthe time spent in the middle (t = −0.9548, d.f. = 22, p = 0.1785) or central zones (t = −1.3166, d.f. = 22, p = 0.1056) (Figure 2B) or in overall locomotor activity between offspring of old fathers and offspring of young fathers in the open field.

To further explore these findings we examined the same set of behaviors in a small group of mice that were the offspring of very old fathers (aged >12 months, n = 9 male offspring generated from 7 breeding pairs). The behavioral results of reduced social behavior and exploration were seen in the offspring of very old fathers, but the numbers are too small to allow for a reliable statistical test (data not shown).

Discussion Top
Using a mouse model we documented deleterious effects of advancing paternal age on offspring behavior. Male offspring of older fathers engaged in less social behavior and exhibited less exploration in a novel environment. These effects were not confounded by differences in overall locomotor activity. Abnormalities in social behavior characterize psychiatric disorders previously linked to advancing paternal age, suggesting a common phenotype affected by paternal age.

There are several advantages for the mouse model used in this study. First, given the tractable nature of animal work, the environment was tightly controlled, minimizing any environmental confounds. Second, the age of all the mothers of the offspring was standard such that differences observed in the offspring cannot be accounted for by maternal age.

Finally, the most common reference inbred strain of mouse was used (C57BL/6J), reducing genetic variation.

In men, it is thought that the spermatogonial stem cell divisions occurring over the life-course of males result in higher mutational rates and cytogenetic abnormalities in the sperm of older men [10], [11]. Numerous neurological and psychiatric disorders have been related to genomic alterations [12]. A number of studies have uncovered an increased prevalence of de-novo copy-number variants (CNVs), and other forms of genomic alterations in autistic and in schizophrenia cases [13], [14].

An alternative explanation is that epigenetic dysfunction underlies some paternal age effects. Epigenetic dysfunction has been associated with several neuropsychiatric disorders, including schizophrenia and bipolar disorder [15]. A study by Flanagan and colleagues [16] reported intra- and inter-individual epigenetic variability in the male germline, and found a number of genes that demonstrated age-related DNA-methylation changes. Epigenetic signals are generally reprogrammed in the germline, although it appears that such reprogramming may not be fully complete across all regions of the genome [17]. In particular, repetitive and transposable elements in the genome, which are generally hypermethylated, are often not efficiently reprogrammed [18]. It is thus plausible that de novo structural mutations, which are often associated with repetitive DNA sequence motifs, may also be subjected to differential epigenetic reprogramming implicating both mutagenic and epigenetic processes in the phenotypic manifestation of increased paternal age.

Despite the advantages of this model, the results of this study should be interpreted in light of some limitations. We only examined one strain of male mice. This was a-priori decided in order to follow common practice in animal research aimed at limiting variation caused by sex differences in behaviors. Hence, findings should not be generalized across sexes. In addition, behavior was assessed at one developmental stage (12 weeks, young adulthood). Thus, the developmental nature of these differences could not be determined.

In conclusion, this study provides the strongest evidence to date for the behavioral effects of advancing paternal age on the offspring. Studies are ongoing to investigate the role of molecular changes in mediating the effects of advancing paternal age on social and exploratory behaviors in offspring, by assessing de-novo CNV events and alterations in DNA methylation.

Methods Top
Breeding Strategy
C57BL/6J mice were bred and maintained in the Biological Services Unit at the Institute of Psychiatry, Kings College London using stocks purchased from Charles River Laboratories. All housing and experimental procedures were performed in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986. Typical breeding age for mice starts at 2 months. Male breeders are generally retired after 7–8 months. Therefore, females aged 2 months were bred with males of two different ages; young males of 2 months (n = 6 breeding pairs), and old males of 10 months (n = 6 breeding pairs). The average litter size within each age group was 7 (male to female ratio 1:1) and total progeny generated was 40 mice in the young fathers group and 44 mice in the old fathers group. Two males were randomly selected from each litter (n = 12 males per group) and weaned aged 4–5 weeks and pair housed with their siblings and then individually housed for two weeks prior to testing. Mice were housed in standard cages measuring 30.5×13×11 cm, with food and water available ad libitum. The housing room was maintained on a standard light/dark cycle with white lights on from 08:00 to 20:00. Ambient temperature in all rooms was maintained at 21±2°C with 45% humidity.

Offspring Behavioral Testing
Offspring were aged 12 weeks at the start of testing and all testing took place during the light phase with a light level <30 lux in the test room. Each apparatus was wiped clean with 1% Trigene® between subjects to avoid olfactory cueing behaviors. Behaviors for all tests were recorded on videotapes for further detailed analysis. Mice were returned to their home cage at the end of each test.

Social Behavior
The social behavior of the test mice towards a juvenile conspecific was assessed in a 5 minute trial [19]. The test mouse is habituated in an arena (36×20×14 cm) for 5 minutes, after which a male juvenile conspecific of the same strain (aged 4 weeks) was introduced for a further 5 minutes. During this trial, social behavior (including social sniffing, anogenital sniffing and allogrooming) by the test mouse towards the conspecific were scored from videotape by an observer blind to the group factor of paternal age.

Holeboard
The holeboard test is used to measure activity and exploration in a novel arena [20]. The Truscan Photo Beam Activity System (Coulbourn Instruments, Whitehall, PA) was used, which consists of an arena (25.4 cm square) and a nose poke floor with 16 holes (4×4 array) with sensor rings to track movement. The beams are spaced 1.52 cm apart providing a 0.76 cm spatial resolution. Animals were placed in the arena and the movement, the number of nose pokes and the time spent nose poking were recorded automatically by beam breaks for 5 minutes using the Truscan program.

Open Field
The open field [21] used a square white acrylic box with dimensions 72×72×33 cm. The animal was placed in the outer part of the arena facing an outer wall and allowed to freely explore the arena for 5 minutes. A video camera placed above the arena allowed movement to be tracked using an automated tracking system (Ethovision, Noldus Information Technologies). The number of faecal boli and urination were recorded at the end of the test. A square of equal distance from the periphery (36×36 cm) was defined in Ethovision as the ‘outer’, ‘middle’ and ‘central’ zones in order to determine the number of entries into, and time spent in, these zones in the arena. In addition, the latency to enter the inner zones as well as locomotor activity in all three zones of the arena were measured by the tracking system.

Statistical Analysis
Behavioral performances of offspring of young fathers and offspring of old fathers in the social interaction task, holeboard and open field were compared using unpaired, one-tailed Students t-tests. Significance level was set at 0.05.

Author Contributions Top
Conceived and designed the experiments: JM CF LCS AR. Performed the experiments: RGS RLK. Analyzed the data: RGS RLK CF. Contributed reagents/materials/analysis tools: JDB. Wrote the paper: RGS RLK JM CF LCS AR.

References Top
Kolevzon A, Gross R, Reichenberg A (2007) Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 161: 326–333. Find this article online
Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, et al. (2009) Paternal age as a risk factor for schizophrenia: how important is it? Schizophr Res 114: 1–5. Find this article online
Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Langstrom N, et al. (2008) Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 65: 1034–1040. Find this article online
Rothman KJ, Greenland S (1997) Modern Epidemiology: Lippincott Williams and Wilkins.
Geschwind DH (2009) Advances in autism. Annu Rev Med 60: 367–380. Find this article online
Green MF, Penn DL, Bentall R, Carpenter WT, Gaebel W, et al. (2008) Social cognition in schizophrenia: an NIMH workshop on definitions, assessment, and research opportunities. Schizophr Bull 34: 1211–1220. Find this article online
Green MF (2006) Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 67: e12. Find this article online
Brotman MA, Skup M, Rich BA, Blair KS, Pine DS, et al. (2008) Risk for bipolar disorder is associated with face-processing deficits across emotions. J Am Acad Child Adolesc Psychiatry 47: 1455–1461. Find this article online
Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, et al. (2008) Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism. Schizophr Bull 34: 1042–1046. Find this article online
Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1: 40–47. Find this article online
Buwe A, Guttenbach M, Schmid M (2005) Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa. Cytogenet Genome Res 111: 213–228. Find this article online
Reichenberg A, Mill J, MacCabe J (In Press) Epigenetics, Genomic Mutations and Cognitive Function. Cognitive Neuropsychitry. Find this article online
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82: 477–488. Find this article online
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, et al. (2007) Strong association of de novo copy number mutations with autism. Science 316: 445–449. Find this article online
Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, et al. (2008) Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82: 696–711. Find this article online
Flanagan JM, Popendikyte V, Pozdniakovaite N, Sobolev M, Assadzadeh A, et al. (2006) Intra- and interindividual epigenetic variation in human germ cells. Am J Hum Genet 79: 67–84. Find this article online
Lane N, Dean W, Erhardt S, Hajkova P, Surani A, et al. (2003) Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35: 88–93. Find this article online
Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293–5300. Find this article online
Winslow JT (2003) Mouse social recognition and preference. Curr Protoc Neurosci Chapter 8: Unit 8 16. Find this article online
Nolan NA, Parkes MW (1973) The effects of benzodiazepines on the behaviour of mice on a hole-board. Psychopharmacologia 29: 277–286. Find this article online
Hall CS (1951) The genetics of behaviour. In: Steven SS, editor. Handbook of Experimental Psychology. New York: John Wiley & Sons Inc. pp. 304–329.

Limb malformations with associated congenital constriction rings in two unrelated Egyptian males

2009-11-27T06:21:00.000-08:00

Clin Dysmorphol. 2009 Nov 24. [Epub ahead of print]

Limb malformations with associated congenital constriction rings in two unrelated Egyptian males, one with a disorganization-like spectrum and the other with a probable distinct type of septo-optic dysplasia.
Temtamy SA, Aglan MS, Ashour AM, El-Badry TH.

Departments of aClinical Genetics bOrodental Genetics, Division of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt.

In this report, we describe two unrelated Egyptian male infants with limb malformations and constriction rings. The first case is developing normally but has severe limb anomalies, congenital constriction rings, scoliosis because of vertebral anomalies, a left accessory nipple, a small tumor-like swelling on his lower back with tiny skin tubular appendages, a hypoplastic scrotum, and an anchored penis. The second case is developmentally delayed with limb malformations, congenital constriction rings, a lumbar myelomeningeocele, hemangioma, and tiny tubular skin appendages on the back. The patient also had bilateral optic atrophy. The constellation of features in our patients cannot be fully explained by the amniotic disruption complex. The first patient may represent an additional case of the human homolog of the mouse disorganization mutant. The presence of bilateral optic atrophy in the second case, although without an absent septum pellucidum nor other brain anomalies resembles the infrequently reported disorder of septo-optic dysplasia with limb anomalies. Both cases were sporadic and could be caused by a new dominant mutation because of the high paternal age of case 1 and the history of paternal occupational exposure to heat for both fathers. We draw attention to the phenotypic overlap between the disorganization-like syndrome and septo-optic dysplasia with limb anomalies.

PMID: 19940763 [PubMed - as supplied by publisher]

"The biological clock for men and women is really the same," says Dr. Dolores Malaspina

2009-11-22T18:25:00.000-08:00

According to a study released last March in the Public Library of Science Medicine, children born to fathers who were 20 scored an average of 2 points higher on an IQ test than children born to 50-year-old fathers. And that's not all. Recent studies from Israel, California and Sweden have connected "late paternal age" with any number of serious medical conditions: The longer you wait, the more likely it is that your kid will be affected by schizophrenia, dwarfism, bipolar disorder, autism, Marfan syndrome, certain childhood cancers, or even, later in life, Alzheimer's. In some cases, the risk factors skyrocket. A 2005 study conducted by the University of California, Los Angeles, found a fourfold rise in Down syndrome among babies born to men 50 and older. Worse still, those risk factors aren't limited to your tweed-sporting years: Statistically, "late paternal age" starts at 30, as in Zack's age. A 2006 study conducted by Mount Sinai School of Medicine found that fathers in their 30s have children with about 1.5 times the risk of developing autism compared with fathers in their teens and 20s. That factor jumps to five times for dads in their 40s. The cherry on the cake? The American Society for Reproductive Medicine recommends that sperm banks do not accept specimens from men over 40.

"The biological clock for men and women is really the same," says Dr. Dolores Malaspina of Bellevue Hospital Center in New York City and New York University, who conducted one of the first studies. "It's just that men can keep having babies."

Later Paternal Age and Sex Differences in Schizophrenia Symptoms.

2009-11-21T06:58:00.000-08:00

Later paternal age >35 accounts for one quarter of all schizophrenia cases.

Scientists discover link between older dads and genetic diseases

2009-10-26T07:41:00.000-07:00

October 26, 2009
Scientists discover link between older dads and genetic diseases
Mark Henderson
http://www.timesonline.co.uk/tol/news/science/genetics/article6889878.ece");
Recommend? (4)
Scientists have moved a step closer to understanding why older fathers are more likely to have children with certain genetic diseases.
They have discovered a surprising genetic link between the formation of benign testicular tumours called spermocytic seminomas and several rare growth disorders, which are more common among the children of older fathers.
The abnormal testicular cells that form these rare tumours also produce sperm carrying mutant genes that cause serious inherited diseases, research at the University of Oxford and Copenhagen University Hospital in Denmark has shown.
The findings offer important new insights into the origin of several rare genetic disorders, including a cause of dwarfism called achondroplasia, and also promise to illuminate more common conditions such as autism, schizophrenia and breast cancer.

All three of these are known to be affected by genetics, and to be more prevalent among the children of older fathers, but few of the DNA mutations responsible have yet been identified. Scientists behind the research believe that abnormal testicular cells of the sort that develop into tumours could be partially responsible.
Professor Andrew Wilkie, of the University of Oxford, who led the research, said: “What we have seen so far may just be the tip of a large iceberg of mildly harmful mutations being introduced into our genome. These mutations would be too weak and too rare to be picked up by our current technology, but their sheer number would have a cumulative effect, leading to disease.
“It may be that process we have identified might contribute to part of the excess risk for older fathers to have children with higher risks of, for example, breast cancer, schizophrenia, or autism. We have no direct evidence for this as yet.”
Details of the research are published in the journal Nature Genetics . Professor Wilkie’s team, which is funded by the Wellcome Trust, is now planning further research to investigate whether testicular abnormalities might be linked to conditions such as autism and schizophrenia.
Spermatocytic seminomas are rare tumours of the testes, almost always benign, which affect about one in 100,000 men. They are caused by the accumulation of genetic mutations in testicular cells, which can sometimes then divide to trigger tumours.
“We think most men develop these tiny clumps of mutant cells in their testicles as they age,” Professor Wilkie said. “They are rather like moles in the skin, usually harmless in themselves. But by being located in the testicle, they also make sperm - causing children to be born with a variety of serious conditions.”
The new study, has identified genetic mutations of the sort that cause achondroplasia and other rare inherited conditions in cells from spermatocytic seminomas. It appears that these mutations help the tumour cells to divide, but cause abnormal growth when transmitted to the offspring via sperm. “We call them ‘selfish’ because the mutations benefit the germ cell but are harmful to offspring,” Professor Wilkie said.
As the mutations cause the tumour cells to profilerate in the testes, they also increase the chances that a sperm that fertilises an egg will be abnormal.
The results will help doctors to explain to parents why children have developed these disorders, and to advise them about the risks of having further children. In most cases, these families will not have a high risk of having another affected child, though it will be higher than in the general population.
“The major implication is for older fathers,” Professor Wilkie said. “We already knew that men in their 50s have a risk of having children with various individually rare genetic disorders — achondroplasia is a well known one — about tenfold higher than men in their early 20s.
“Adding all these risks together, the total additional risk is still only a fraction of 1 per cent because each of these disorders is rare.” (How come up to 1/3 of all schizophrenia is due to having an older father? if the disorder is a fraction of 1 per cent) Concerned Heart

Advanced paternal age: How old is too old?

2009-10-11T07:45:00.000-07:00

J Epidemiol Community Health. 2006 October; 60(10): 851–853.
doi: 10.1136/jech.2005.045179. PMCID: PMC2566050

Copyright ©2006 BMJ Publishing Group Ltd.
Advanced paternal age: How old is too old?
Isabelle Bray and David Gunnell, George Davey Smith
I Bray, D Gunnell, G Davey Smith, Department of Social Medicine, University of Bristol, UK
Correspondence to: Dr I Bray
Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK; Issy.Bray@bristol.ac.uk
Accepted March 25, 2006.
This article has been cited by other articles in PMC.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References AbstractAverage paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. This commentary aims to contribute to such a debate. Accumulated chromosomal aberrations and mutations occurring during the maturation of male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers, and schizophrenia. Adverse health outcomes should be weighed up against advantages for children born to older parents, mindful that these societal advantages are likely to change over time.
Keywords: paternal age, DNA damage, fertility, abnormalities, schizophrenia
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Changing patterns of education, employment, and marriage mean that the average age of childbearing for women is increasing, resulting in higher risks of adverse reproductive outcomes.1,2 It has recently been suggested that the decade 25–35 years is the optimal age for women in Westernised societies to have their children balancing education, career, and family.3 In England and Wales, the mean age at childbearing increased from 26.4 years in 1974 to 29.3 years in 2002.1 Healthcare systems have responded to the increased risk associated with delaying maternity by offering screening for congenital abnormalities and treatment for infertility.4,5 Meanwhile, the average paternal age is also increasing. The mean age of fathers in England and Wales increased from 29.2 years in 1980 to 32.1 in 2002.6 The public health implications of this trend have not been widely anticipated or debated.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Time trends in paternal ageBirths within marriage
In 1993, fathers aged <35 years accounted for 74% of live births within marriage in England and Wales, while only 25% of such births were to fathers aged 35–54 years. Ten years later, these percentages were 60% and 40%. Figure 1 1 illustrates these trends. If this trend continues, the proportion of fathers >35 years will further increase.
Figure 1Trends in paternal age for live births within marriage in England and Wales, 1993–2003: (A) decreasing trends <35 years, (B) increasing trends 35–54 years. Source: Series FM1 no 32 (ONS, 2003). (Births to fathers (more ...)

Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References All birthsData on time trends in paternal ages for all births in England and Wales are not available, and it could be argued that the increasing proportion of births occurring outside marriage will lead to declining paternal ages as the fathers of such children are younger than those for children born to married couples. Figure 2 2 shows the age distribution of fathers for all births in England and Wales in 2003, which reaches a maximum at age 32. While this approximately normal distribution is mirrored closely for the 60% of births that occurred within marriage, the paternal ages for births outside marriage is more uniform between the ages of 22 and 33 years, with a lower mean age at fatherhood. Between 1993 and 2003 the percentage of births occurring outside marriage increased steadily from 32% to 41%. However, the demographic composition of the group having children outside marriage is changing.
Figure 2Distribution of paternal age for births in England and Wales in 2003: total births* and live births within and outside marriage to fathers aged 13–49. Source: Series FM1 no 32 (ONS, 2003). *All births within marriage, (more ...)

Maternal age data are available for all births (within and outside marriage) in England and Wales6 and they show that the proportion and number of births to women of 30 and over are increasing.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Reasons for increasing age at parenthoodChanges in the population structure (different sizes of birth cohorts across the span of reproductive ages) explain the trend towards older parents to some extent,1 but there is no doubt that societal changes have led to both men and women beginning families later. Advances in reproductive technologies are also contributing to this trend.7 Some 3%–6% of births in most developed countries are now the result of assisted reproduction.8 While the UK government directs substantial efforts towards reducing teenage pregnancy rates, little guidance is given on the risks of delaying childbearing until advanced maternal age, and less still on the risks of advanced paternal age. In the USA, the American Society for Reproductive Medicine has begun to publicise the risks of delaying childbearing, although their Patient Guide on Age and Fertility9 focuses mainly on the mechanisms and risks of maternal, rather than paternal, aging.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Risks associated with advanced paternal ageIt is thought that accumulation of chromosomal aberrations and mutations during the maturation of male germ cells are responsible for increasing risks of certain conditions with advancing paternal age. The amount of DNA damage in sperm of men aged 36–57 is three times that of men <35 years.8 There is a recent body of literature discussing the possible effects on reproductive outcomes, which has been summarised by Kühnert and Nieschlag.10
Fertility and birth
Regarding fertility, Kühnert and Nieschlag10 conclude that men start to contribute to the reduced fertility of a couple in their late 30s, and to a reduced fecundity in their early 40s. For example, a descriptive study of birth rates in married couples in Ireland before the widespread use of contraception found that the probability of birth decreased for men from 42–43 years of age.11 A more recent prospective cohort study of 5121 pregnant women in California concluded that the risk of spontaneous abortion increased with increasing paternal age, and found that the association was stronger for first trimester losses,12 while another prospective cohort study of 23821 pregnant women (based on the Danish national birth cohort) reported that the paternal age related risk of late fetal death was higher than the risk of early fetal death, and started to increase from age 45 years.13 It has been suggested that advanced paternal age (>50 years) increases the risk of preterm delivery and low birth weight,14 although others have found no such effect.15 Although aneuploidy is the leading genetic cause of pregnancy loss, there is no substantial evidence for an effect of paternal age on the presence of extra or missing chromosomes10 and the proportion of fetal deaths attributable to advanced paternal age is currently probably small.13
Birth defects, developmental illnesses, and childhood cancer
A Danish population based study of 1920 affected births of 1489014 live births concluded that paternal age is associated with cleft lip and cleft palate, independently of maternal age.16 Single gene mutations are the suggested mechanism. Many autosomal dominant diseases (for example, achondroplasia) have been shown to be associated with increasing paternal age.10 A population based study of childhood brain cancers reported to the Swedish Cancer Registry between 1960 and 1994 concluded that there is a paternal age affect, estimated to confer about 25% excess risk in fathers >35 years of age.17 A case‐control study of 10162 matched pairs reported a threefold increase in risk of retinoblastoma for fathers 45 years18 and a 50% increased risk of childhood acute lymphoblastic leukaemia for fathers aged 35 years or more was found in a historical cohort of 434933 live births.19 There is conflicting evidence regarding congenital heart defects, although it has been estimated that among offspring of men aged >35 years, about 5% of cases may be attributable to advanced paternal age.10
What is already known on the topic
The average paternal age in the UK in increasing, and the public health implications of this trend have not been widely anticipated or debated
Accumulation of chromosomal aberrations and mutations during the maturation of male germ cells are thought to be responsible for increasing risks of certain conditions with advancing paternal age
There is a growing literature on the effects for offspring of advanced paternal age. Risks include reduced fertility and increased risk of birth defects, schizophrenia, and cancer

Policy implications
Adverse health outcomes should be weighed up against potential social advantages and disadvantages for children born to older parents, mindful that these societal effects are likely to change over time

Illnesses in adulthood
Some diseases of complex aetiology such as schizophrenia are associated with advanced paternal age.10 This may be because of an increase in mutations arising in paternal germ cells, although the possibility of confounding (for example, by schizoid personality traits) cannot be ruled out.16 To illustrate the possible scale of the effects, results from a Swedish population based cohort study have been used to estimate that the increase in paternal age since 1980 could account for about 10% of new cases of schizophrenia diagnosed in the UK in 2002.20 Advanced paternal age is associated with increased risk of cancers in offspring (for example, breast, prostate, nervous system).10 There is less conclusive data regarding Alzheimer's disease.10
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References ConclusionsA recent report concluded that “even if the genetic risk for progeny from older fathers is slightly increased, the risk to the individual is low”.9 But as our appreciation of the genetic contribution to disease risk develops it seems probable that, if the current trends in timing of fatherhood continue, the consequences at a population level may nevertheless be worth considering further. The adverse health outcomes discussed here should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security. For example, data from the national child development study show that young fathers are more likely to come from economically disadvantaged families and to have lower educational attainment21; the labour force survey22 found increasing income with age for men up to their early 40s. Socioeconomic factors such as educational level and occupation are currently associated with many health outcomes. For example people from less affluent backgrounds are less likely to use prenatal care services23 but more likely to give birth to premature or low birthweight infants.24 However, potential social disadvantages of increased paternal age should also be considered, such as less energetic parents and decreased likelihood of the child benefiting from long term relationships with grandparents. Furthermore, as it becomes more common for men to become parents in later adulthood, the current (relatively affluent) socioeconomic composition of older fathers will change, and therefore the relative socioeconomic advantages of having an older father are likely to diminish. An evaluation of various scenarios may help to determine an optimal period of fatherhood balancing the social and economic advantages for the offspring of delayed paternity against the corresponding small, but increasingly well reported, genetic disadvantages. Such an evaluation would inform policy. Possible interventions might include health promotion advising people about the risk of delaying childbearing or changes at a societal level (for example, family benefits, flexible working) that encourage couples to have children earlier rather than later.
Contributors and sourcesAll authors contributed to the conception of the article. IB wrote the initial draft of the paper and subsequent drafts including comments from DG and GDS. All authors have seen and approved the final version. The article arises from a review of the literature and analysis of data available from the Office for National Statistics. All authors are epidemiologists with an interest in public health applications. DG and GDS are members of the Faculty of Public Health.
FootnotesCompeting interests: none.
Ethical approval: not needed.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References References1. Chamberlain J, Corbin T. Trends in reproductive epidemiology and women's health. In: Moody J, ed. Why mothers die 2000–2002—report on confidential enquiries into maternal deaths in the United Kingdom. London: RCOG Press at the Royal College of Obstetricians and Gynaecologists, 2004.
2. Bewley S, Davies M, Braude P. Which career first? BMJ 2005. 331589.
3. Heffner L J. Advanced maternal age—how old is too old? N Engl J Med 2005. 3511927–1929. [PubMed]
4. National Collaborating Centre for Women's and Children's Health. Fertility: assessment and treatment for people with fertility problems. London: NICE, 2004.
5. Nicolaides K H, Azar G, Byrne D. et al Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ 1992. 304867–869. [PubMed]
6. Office for National Statistics. Birth statistics: review of the registrar general on births and family building patterns in England and Wales. London: Stationery Office, 2002.
7. Blickstein I. Motherhood at or beyond the edge of reproductive age. International Journal Fertlilty and Womens Medicine 2003. 4817–24.
8. Aitken R J, Koopman P, Lewis S E M. Seeds of concern. Nature 2004. 43248–52. [PubMed]
9. American Society for Reproductive Medicine. Age and fertility: a guide for patients. Birmingham, AL: American Society for Reproductive Medicine 2003.
10. Kühnert B, Nieschlag E. Reproductive functions of the ageing male. Human Reproduction Update 2004. 10327–339. [PubMed]
11. Anderson B A. Male age and infertility. Result from Ireland prior to 1911. Population Index 1975. 41561–567.
12. Slama R, Bouyer J, Windham G. et al Influence of paternal age on the risk of spontaneous abortion. Am J Epidemiol 2005. 161816–823. [PubMed]
13. Anderson A‐M N, Hansen K D, Anderson P K. et al Advanced paternal age and risk of fetal death: a cohort study. Am J Epidemiol 2004. 1601214–1222. [PubMed]
14. Tough S C, Faber A J, Svenson L W. et al Is paternal age associated with an increased risk of low birthweight, preterm delivery, and multiple birth? Can J Public Health 2003. 9488–92. [PubMed]
15. Nahum G G, Stainslow H. Relationship of paternal factors to birth weight. J Rerod Med 2003. 48963–968.
16. Bille C, Skytthe A, Vach W. et al Parent's age and the risk of oral clefts. Epidemiology 2005. 16311–316. [PubMed]
17. Hemminki K, Kyyronen P, Vaittinen P. Parental age as a risk factor of childhood leukaemia and brain cancer in offspring. Epidemiology 1999. 10271–275. [PubMed]
18. Dockerty J D, Draper G, Vincent T. et al Case‐control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol 2001. 301428–1437. [PubMed]
19. Murray L, McCarron P, Bailie K. et al Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study. Br J Cancer 2002. 86356–361. [PubMed]
20. Sipos A, Rasmussen F, Harrison G. et al Paternal age and schizophrenia: a population based cohort study. BMJ 2004. 3291070–1073. [PubMed]
21. Kiernan K E. Becoming a young parent: a longitudinal study of associated factors. British Journal of Sociology 1997. 48406–408. [PubMed]
22. Office for National Statistics. Social trends 36. Income and health. Basingstoke: Palgrave Macmillan, 2006 .
23. D'Ascoli P T, Alexander G R, Peterson D J. et al Parental factors influencing patterns of prenatal care utilization. J Perinatol 1997. 17283–287. [PubMed]
24. Parker J D, Schoendorf K C, Kiely J L. Associations between measures of socioeconomic status and low birth weight, small for gestational age, and premature delivery in the United States. Ann Epidemiol 1994. 4271–278. [PubMed]

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Fertility: women aren't to blame any more

2009-09-25T18:31:00.000-07:00

Fertility: women aren't to blame any morePosted:
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CHARLESTON, SC (WCSC) - When it comes to getting pregnant, many times fertility problems are blamed on the woman, but medical experts say 40 percent of the time the problem is with the man.
"Men are in denial, denial, denial, when it comes to fertility and sexual function," Dr. Harry Fisch said. Fisch says that denial often results in couples blaming the woman's body and prematurely trying extreme measures.
"If In Vitro Fertilization was a drug it probably would not be approved by the FDA because there's no long term data," Fisch said.
In fact, Fisch says more than 40 percent of fertility problems are caused by the man -- namely a low sperm count.
But there are ways you can increase that count, like increasing l-arginine, an amino-acid in your diet. "Soy, oats, blueberries, salmon, and tuna are high in l-arginine," Fisch said.
And keep in mind, biological clocks aren't just for women. "There is a male biological clock and after 30 that clock starts ticking," he said.
And while we've all heard of men in their later years reproducing, Fisch doesn't recommend it. "Turns out sperm from older men have a much larger chance of having babies with genetic problems. We know autism, downs syndrome, schizophrenia increases with the paternal father's age," Fisch said.
So how can you slow down your biological clock? Slow down your drinking.
"Two drinks a day is the max I recommend, if you're trying to have a child I don't recommend that much," Fisch said.
And when it comes to your belly, size does matter. "If you've got a beer gut, you're out acting like you're macho but when no one's looking you're tired, and fatigued," Fisch said.
And your sperm count is lower. Fisch also recommends couples coupling every other day. The longer sperm stays in a man's system the lower the sperm's mobility.
Even if you're not trying to get pregnant, you still need to pay attention. "The penis is the dipstick of the body's health so anything you do to increase vascular health will go to helping your penis," Fisch said.
Since sexual dysfunction can show up 3-5 years before heart disease, it's like the canary in the coal mine for a man's body.
Dr. Fisch is the only male fertility expert in the state and he doesn't even live here. He flies down from New York once a month. He says that's because the focus has been on the female factor, but MUSC wants to change that, so Fisch is teaching students about the role the man plays.

Older Men with Tired Sperm: Health Blog

2009-09-06T16:53:00.001-07:00

Older Men with Tired Sperm: Health Blog
For a while now, scientists have known that men lose fertility as they age just as fast as women do — even faster, in fact. Women start heading “over the hill” reproductively at around age 30, but men begin the decline a full six years earlier, by age 24. Plus, studies have shown that older men stand a higher chance of fathering babies with autism, dwarfism, and schizophrenia. So much for the stereotype of the virile codger being a suitable match for the fertile young coed. In fact, several Israeli studies found that the likelihood of autism increases by almost 600 percent when the father is over 40 (immunization shots aside), while the risk of schizophrenia doubles.
And now, in a further blow to the macho dream, a new study of 80,000 people by researchers at Karolinska Institute in Sweden has found that once men reach age 29, their chances of fathering a bipolar child increase by 11 percent. That risk climbs by 37 percent by the time men reach age 55, when compared to men still in their 20s. And bipolar illness tends to have an earlier onset in children of older fathers: those born to dads over age 55 are twice as likely to develop manic-depressive illness before their 20th birthday. In contrast, maternal age doesn’t seem to be much of a factor in the development of the disease.
Historically, scientists have pointed to the correlation between maternal age and birth defects, while men have been comparatively left “off the hook.” The role of women in contributing to fertility and fetal problems seems more obvious. Women carry their eggs around for a long time before they conceive — they have all their eggs at birth (no new eggs are ever created again in their lifetime), and those eggs degrade over time due to biological stresses and environmental factors. But men keep producing new sperm throughout their lives. Until recently, the assumption has been that new sperm is fresh and healthy because it is new, even if it comes from an older man. Not so, the evidence shows because sperm production involves duplicating DNA, and as men age, their ability to accurately replicate DNA declines. This results in DNA copy errors, and the mutated DNA can lead to a host of complications.
One of the most surprising of the complications is that older sperm contributes to miscarriages. A study out of the University of California, Berkeley, found that the sperm of men aged 40-49 was twice as likely to have DNA fragmentation as the sperm of men in their 20s — possibly leading to spontaneous abortion. Given that it’s almost a universal assumption that “something is wrong with the woman” when she suffers multiple miscarriages, this fact comes as a revelation that may take some of the pressure off of prospective moms.
Commenting on the bipolar study, Dr. Harry Fisch, author of The Male Biological Clock, said, “The message here for men is: don’t wait too long. [The male biological clock] starts ticking after the age of 30….We are seeing problems in men over the age of 40, and there is an increase in disorders when the father is over the age of 45.”
In spite of all this gloomy news for men at midlife and beyond, it’s obvious that some older men do, in fact, father healthy children. In other words, there are things men can do to minimize the likelihood of having hormonal imbalances and genetic abnormalities that affect their sperm. For instance, the aforementioned Dr. Fisch suggests that men quit smoking, stay out of jacuzzis (which heat testicles and lower fertility), and rid the body of infections.
The biological clock does indeed keep ticking (for both men and women), but you can slow its beat by following a healthy lifestyle. Heck, you might as well just follow the Baseline of Health Program as outlined Lessons from the Miracle Doctors. For specific recommendations on supplements, check out Supplements from Preconception on Up.
Oh, and I almost forgot — apparently marijuana decreases male fertility (it’s directly sperm toxic). Man, that’s such a bummer! And so does Viagra, as it causes sperm to ejaculate its enzyme load too soon to penetrate the egg. And that’s just too darn poetic!
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Older Men with Tired Sperm: Health Blog

2009-09-06T16:53:00.000-07:00

Mens' biological clocks are ticking, too

2009-09-03T10:11:00.000-07:00

Mens' biological clocks are ticking, too

A Warning

2009-08-24T19:51:00.000-07:00

Best before
Posted By MARILYN LINTON, SUN MEDIA
Posted 12 hours ago
Do men have a best-before date when it comes to fathering kids? Ridiculous, most of us would answer. Just look at these celebrity old guys who became dads in their 50's, 60's, and beyond: Charlie Chaplin at 73; former Prime Minister Pierre Trudeau at 72, Pablo Picasso at 68; Larry King at 65; Warren Beatty at 63; and Dave Letterman at 56.
"Women are born with a fixed number of oocytes," says Dr. Bernard Robaire, describing the female germ cells crucial to reproduction. The McGill University researcher who is funded by the Canadian Institutes of Health Research or CIHR, says that men have no such limitation. Unlike women who, after the age of 35 find it more difficult to get pregnant, men produce 1,000 sperm a heartbeat - about 100 million sperm each day.
Theoretically speaking, then, men can go forth and multiply forever - or as long as their hearts beat. "The argument has always been that because men keep producing sperm that are fresh all the time it makes no difference whether you have sperm from an 85 year old man or a 35 year old man," says Robaire.
However, there's a growing body of research that suggests there may be limits to men's fertility, too. Recent studies have shown that men over the age of 40 have a lower chance of producing children than their younger counterparts. And they have an elevated risk of having children with autism, bipolar disease and schizophrenia.
In addition to concerns about mental illness, some studies have also shown that children born to older fathers score lower on intelligence tests. One study found that the incidence of down syndrome was related to sperm approximately 50% of the time.
"What we found was that if you put old males with young females the development of the embryos was different," says Robaire, explaining his work with lab rats. "We found a change in the weight of the embryos, but what was most striking was an increase in the post-natal death right after birth. Development was not normal.
"It seems that, as men age, the quality of their sperm changes," he explains. "The sperm's swimming ability changes, and the quality of its DNA decreases." So even though men continue to produce fresh sperm, the quality suffers because the sperm, which come from aging stem cells in the testes, accumulate oxidative damage over time.
"Fertility doesn't decline - only the quality of the sperm," he stresses. So is there a biological clock for men? "Yes, because a biological clock doesn't just refer to the number of sperm produced but also their quality." Robaire adds that there are many older men who produce children who are normal in every way. Nonetheless, studies show that the best age for perfect sperm is under 40.
With older men increasingly fathering children, the issue of sperm quality needs to be heard, says Robaire. "All our worries are about women having kids over the age of 35. But a man's sperm quality decreases with age and so therefore do the chances of his children being normal."
Maybe there should be screening for a 60 year old male's sperm, he says. "We have tests for women, but a 25 year-old woman married to a 60 year old wouldn't have an amniocentesis (a prenatal test that diagnoses chromosomal problems and birth defects.) We have to develop a good method of assessing the quality of the payload that is being delivered to the egg."
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Late bloomers spark intellectual debate
There are some benefits for men who head into parenthood later in life, according to psychologist Ross D. Park. They felt more self-confidence in their roles, are more likely to engage in caregiving and their kids report feeling more appreciated.
British Prime Minister Gordon Brown became a father after the age of 50. He told media after the birth of his son John in 2003 that he was adapting well to sleepless nights -- joking "this time not because of the economy."
Become an older dad can also be the impetus for a few new tricks.
Former U.S. presidential candidate and Law & Order actor Fred Thompson, 67, who has two children under age five and said having two young children was " a large part" of why he ran for office.
But research also shows that children of older dad also score lower on intelligence tests during infancy and early childhood, according to a study done at the Queensland Brain Institute of the University of Queensland in Australia.
The study published in March found the older the father, the more likely the child was to score lower on the tests 00 except for one measure of motor skills.
"There is a growing body of evidence suggesting that the sperm of older dads develops more mutations, that is, spelling mistakes in the DNA code," says researcher John McGrath.
Article ID# 1712847

old sperm may be contributing to increases in autism, schizophrenia and Alzheimer's.

2009-08-19T17:38:00.000-07:00

The Pros and Cons of Being a Grandpa-Daddy
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Wednesday, August 19, 2009
filed under: pregnancy & baby logic
There are physical and emotional consequences to having kids at such a late stage of life.

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Michelle Golland, Psy.D.: With the wonderful news that Celine Dion, 41, is pregnant with her second child with her husband Rene, who is 67 years old, I wanted to share the pros and cons of being a Grandpa-Daddy. I choose that title because most of the men who are conceiving children beyond their 60s are most likely on their second wife and have older kids from their first marriage who have kids of their own as well.

There are physical and emotional consequences to having children at such a late stage of life. Because Celine Dion is a relatively young woman, she will be around to raise the children if anything were to happen to Rene. Let's be honest -- another positive is the fact that these children will not be concerned for their financial future in any way, which is usually a concern when becoming a parent at the age of 67. So when this child is 18, Rene will be 85.

Cons
Old sperm: Researchers are finding that it is not just our eggs that get old and cause all the problems, but old sperm may be contributing to increases in autism, schizophrenia and Alzheimer's.

Death/lost role model: Your children won't get to see you in your middle ages and you certainly won't see them in their 30's and having children. Your kids will most likely bury you.

Social stigma: You will be mistaken for the grandpa. Your kids' friends and their parents will assume that you are grandpa due to your age -- plain and simple. This will be embarrassing for your children -- and it will be a topic they will continue to explain their whole life.

Pros
Older dads are more involved in parenting, and are typically more nurturing, affectionate and gentle. Studies have shown that this may be caused by the drop in testosterone as men age.

Older dads are three times more likely to show equality in parenting. They change diapers, feed and bathe their children more often than younger dads.

Kids of older dads usually have higher self-esteem, more confidence, greater sense of security, better ability to handle stress and are more empathic.

Paternal age as a risk factor for schizophrenia: How important is it?

2009-08-18T14:07:00.000-07:00

Schizophr Res. 2009 Aug 13. [Epub ahead of print]
Paternal age as a risk factor for schizophrenia: How important is it?
Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, Liu T, Hadley T, Rosso IM, Bearden C, Yolken RH.
The Stanley Medical Research Institute, 8401 Connecticut Ave., Suite 200, Chevy Chase, MD 20815, USA.

Advanced paternal age has been widely cited as a risk factor for schizophrenia among offspring and even claimed to account for one-quarter of all cases. We carried out a new study on 25,025 offspring from the Collaborative Perinatal Project (CPP), including 168 diagnosed with psychosis and 88 with narrowly defined schizophrenia. We also conducted a meta-analysis of this and nine other studies for which comparable age-cohort data were available. The mean paternal age for the CPP cases was slightly, but not significantly, higher than the matched controls (p=0.28). Meta-analyses including these new results were conducted to determine the relative risk associated with alternative definitions of advanced paternal age (35, 45 or 55years and older). These yielded pooled odds ratios and 95% confidence intervals of 1.28 (1.10, 1.48), 1.38 (0.95, 2.01) and 2.22 (1.46, 3.37), respectively. Thus, increased paternal age appears to be a risk factor for schizophrenia primarily among offspring of fathers ages 55 and over. In these 10 studies, such fathers accounted for only 0.6% of all births. Compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude. Advanced paternal age is also known to be a risk factor for some chromosomal and neoplastic diseases in the offspring where the cause is thought to be chromosomal aberrations and mutations of the aging germline. Similar mechanisms may account for the relationship between advanced paternal age and schizophrenia risk.

Paternal Age and De Novo Nonrecurrent Translocations

2009-07-30T13:36:00.000-07:00

: J Med Genet. 2009 Jul 27. [Epub ahead of print]
De novo apparently balanced translocations in man are predominantly paternal in origin and associated with a significant increase in paternal age.Thomas NS, Morris JK, Baptista J, Ng BL, Crolla JA, Jacobs PA.
Salisbury District Hospital, United Kingdom.

BACKGROUND: Congenital chromosome abnormalities are relatively common in our species and among structural abnormalities the most common class is balanced reciprocal translocations. Determining the parental origin of de novo balanced translocations may provide insights into how and when they arise. While there is a general paternal bias in the origin of non-recurrent unbalanced rearrangements, there are few data on parental origin of non-recurrent balanced rearrangements. METHODS: The parental origin of a series of de novo balanced reciprocal translocations was determined using DNA from flow sorted derivative chromosomes and linkage analysis. RESULTS: Of 27 translocations, we found 26 to be of paternal origin and only one of maternal origin. We also found the paternally derived translocations to be associated with a significantly increased paternal age (p<0.008). CONCLUSION: Our results suggest there is a very marked paternal bias in the origin of all non-recurrent reciprocal translocations and that they may arise during one of the numerous mitotic divisions that occur in the spermatogonial germ cells prior to meiosis.

PMID: 19638350 [PubMed - as supplied by publisher]

Unlike schizophrenia, the risk of BPAD seems to be associated with both paternal and maternal ages

2009-07-25T18:48:00.000-07:00

Psychol Med. 2009 Jul 23:1-9. [Epub ahead of print]
Paternal and maternal ages at conception and risk of bipolar affective disorder in their offspring.
Menezes PR, Lewis G, Rasmussen F, Zammit S, Sipos A, Harrison GL, Tynelius P, Gunnell D.
Department of Preventive Medicine, University of Sao Paulo, Brazil.
BACKGROUND: A consistent association between paternal age and their offspring's risk of schizophrenia has been observed, with no independent association with maternal age. The relationship of paternal and maternal ages with risk of bipolar affective disorders (BPAD) in the offspring is less clear. The present study aimed at testing the hypothesis that paternal age is associated with their offspring's risk of BPAD, whereas maternal age is not.MethodThis population-based cohort study was conducted with individuals born in Sweden during 1973-1980 and still resident there at age 16 years. Outcome was first hospital admission with a diagnosis of BPAD. Hazard ratios (HRs) were calculated using Cox's proportional hazard regression. RESULTS: After adjustment for all potential confounding variables except maternal age, the HR for risk of BPAD for each 10-year increase in paternal age was 1.28 [95% confidence interval (CI) 1.11-1.48], but this fell to 1.20 (95% CI 0.97-1.48) after adjusting for maternal age. A similar result was found for maternal age and risk of BPAD [HR 1.30 (95% CI 1.08-1.56) before adjustment for paternal age, HR 1.12 (95% CI 0.86-1.45) after adjustment]. The HR associated with having either parent aged 30 years or over was 1.26 (95% CI 1.01-1.57) and it was 1.45 (95% CI 1.16-1.81) if both parents were >30 years. CONCLUSIONS: Unlike schizophrenia, the risk of BPAD seems to be associated with both paternal and maternal ages.
PMID: 19627644 [PubMed - as supplied by publisher]
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Data Converges About Older Fathers

2009-07-14T15:08:00.000-07:00

Data Converges About Older Fathers
A recent post in the New York Times presents some evidence that men who become fathers at a later age have unhealthier children. It is well recognized that men retain their reproductive potential longer, and lose it in a more gradual manner, than do women. Whereas women's fertility declines sharply after age 35 or so, men retain their ability to father children, albeit to a diminished degree, for several decades longer. Recently, some evidence has been presented in the scientific literature that suggests that children conceived with sperm from an older male may have cognitive or psychological challenges compared to those fathered by younger males. A recent study performed by Australian scientists concluded that older dads have children with slightly lower IQs. Others have shown increased rates of schizophrenia, bipolar disorder, and autism in children fathered by older vs. younger men. This evidence suggests that men are susceptible to age-related effects on reproductive ability. This should not surprise anyone. However, the effects of reproductive ageing appear to be expressed differently in males than in females. Dr. Dolores Malaspina, a professor of psychiatry at New York University Medical Center, puts it this way: “It turns out the optimal age for being a mother is the same as the optimal age for being a father.”

Overcome Infertility - Understanding the Male Biological Clock

2009-06-25T15:19:00.000-07:00

Overcome Infertility - Understanding the Male Biological Clock
By Kyle J Norton

Infertility is defined as the inability of a couple to conceive after 12 months of unprotected sexual intercourse or the cannot carry the pregnancy full term. It effects over 5 million couples alone in the U. S. and many times more in the world. Because of an unawareness of treatments, only 10% seek help from professional specialists. In fact, about 35% of infertility is caused by the male's inability to fertilize. 35% is caused by the female's inability to conceive, 10% attributes to both, and 10 % is considered a failure with an unknown cause.

Even though the sperm in the male reproductive organ do not change much, the quality and quantity of sperm may be reduced by low levels of testosterone due to ageing. Therefore, you can see why a couple in their late 20's is easier to conceive than a couple with a wife in her 20's and a husband at the age of 40 and more. Study shows that the odds of male fertility rate decreases at an alarming rate of 11% every year and the chance for his partner to conceive declines even further.

According to the study of European Society of Human Reproduction and Embryology, the rate of miscarriage also increases substantially when the father was over the age of 35.
1. Nearly 17 percent if the father was over 34 years old.
2. Around 20 percent if the father was between the ages of 35 and 39.
3. Over 32 percent if the father was older than 44.

Most couple delay unwanted conception by having the female partner take contraceptive pill or by using condoms, or other methods. Unfortunately, by the time they think that they are ready to have children, they are in their mid thirties and according to the above statistics, the rate of fertility is low and the risk of miscarriage is increased substantially, not counting the risk of giving birth to a child with a defection, including chromosomal abnormalities. Like an old car, no matter how much money which you spend each year to fix it, it will never work like when it was new.

It is wise for a couple to conceive no later then the age of late 20's and early 30's to prevent any unnecessary stress caused by infertility within 12 months after they decide to have a baby.

For the best pregnancy self help program review, please visit http://bestfertility.blogspot.com/
For series of Infertility Articles, please visit http://fertility-infertility.blogspot.com/

All rights reserved. Any reproducing of this article must have the author name and all the links intact.
"Let Take Care Your Health, Your Health Will Take Care You" Kyle J. Norton
I have been studying natural remedies for disease prevention for over 20 years and working as a financial consultant since 1990. Master degree in Mathematics, teaching and tutoring math at colleges and universities before joining insurance industries. Part time Health and entertainment Article Writer.

Article Source: http://EzineArticles.com/?expert=Kyle_J_Norton

Older Fathers: Increased risk of having children with autism, schizophrenia

2009-06-21T08:11:00.000-07:00

Older Fathers: Increased risk of having children with autism, schizophrenia
Older fathers: link to autism, schizophrenia.
By Paul Raeburn on January 28, 2009 - 1:52pm in About Fathers

Just after my two-year-old son, Henry, was born, I was surprised and disturbed to learn that he was at increased risk of autism, schizophrenia, bipolar disorder and other ills-because of my age.

My wife, Elizabeth, and I knew about the risks associated with the children of older mothers, with Down syndrome being the most widely recognized. She was tested for whatever was testable while she was pregnant with Henry, and he seemed to be healthy in every respect.

There is, however, no pre-natal test for autism or schizophrenia. And yet the risks are substantial: A 40-year-old man has the same chance of fathering a child with schizophrenia as does a 40-year-old woman of giving birth to a child with Down syndrome.

Why do we know so much about the genetic ailments associated with older mothers, but almost nothing about the diseases associated with older fathers?

In an article I've just written for Scientific American Mind, I note that the number of older fathers is on the rise, meaning the number of children at increased risk for autism and schizophrenia is also on the rise.

Nobody understand why this should be true. A woman's eggs are constructed and stored before she is born. It's reasonable to think that as they age, they might acquire genetic errors that could lead to disease. But sperm are freshly manufactured whenever they're needed; they are not stored. So what could be going on there?

The speculation is that something is going wrong with the so-called spermatogonial cells, the factories that make sperm. It's unclear what is happening, but the situation clearly deserves further research.

And why are older fathers not told of the risks?

That seems wrong to me. Some time ago, I called Charles J. Epstein, past president of the college of medical genetics, and Marilyn C. Jones, the current president, and asked them if they could explain why this don't ask-don't tell policy made sense, especially considering the new findings. "To put it out there every time somebody comes to you for counseling probably engenders more fear than light," Epstein said.

Jones agreed. "Paternal age is usually not addressed in counseling couples of advanced age because there is no simple test to address the risk," she said. "If there is nothing to offer a couple but increasing anxiety, many counselors and physicians do not bring the issue up."

Why then all the fuss about Down syndrome in the children of older women, when the risks for the children of older fathers are about the same? "You bring up Down syndrome, because you get sued if you don't," Epstein said. "And there are options. You can go through prenatal diagnosis, you have the option to terminate."

Epstein points out that the general rate of abnormalities of all kinds in newborns is about 2-4%. So even a 3% risk of schizophrenia in the children of men over 50 is not out of line with other risks. And it sounds less frightening when put this way: A 50-year-old man has a 97% chance of having a child without schizophrenia.

Still, I wish I had known what the risks were before we decided to have children. Would we have gone ahead anyway? That's difficult to say. But at least we would have had all the information we needed to make an intelligent decision.

Father's Sperm Delivers Much More Complex Material Than Previously Thought

2009-06-15T08:30:00.000-07:00

Father's Sperm Delivers Much More Complex Material Than Previously Thought
ScienceDaily (June 15, 2009) — It was long believed that conception does not involve a meeting of equals. The egg is a relatively large, impressive biological factory compared with the tiny sperm, which delivers to the egg one copy of the father's genes. However, a new study from Huntsman Cancer Institute (HCI) at the University of Utah reveals that the father's sperm delivers much more complex genetic material than previously thought. The findings could lead to a diagnostic test to help couples deal with infertility.

Researchers discovered particular genes packaged in a special way within the sperm, and that may promote the development of the fetus.

"Our findings show that the father plays an active role in packaging his genome to help ensure a healthy baby," says study co-leader Brad Cairns, Ph.D., investigator with HCI and the Howard Hughes Medical Institute, and professor of oncological sciences at the University of Utah. "However, they also raise the possibility that a man's aging, health and lifestyle may alter this packaging and negatively affect fertility and embryo development."

During fetal development, certain genes make decisions about organ and tissue development. The new research shows that in sperm, these genes are wrapped in special packaging materials called 'modified histones.' These modified histones appear to be key factors in ensuring genes are activated or repressed at the right level, place and time, which helps the fertilized egg develop properly.

Chromosomes are long strands of DNA containing thousands of genes, and their packaging helps determine which genes turn on and off. Understanding how these genes are activated or repressed leads to a better understanding of how disorders like birth defects and cancer develop.

"Genes have on-and-off switches, and understanding them allows us to target them, leading to possible treatments, cures or prevention strategies," says Cairns. "That's the good news."

The study is set for publication June 14 – a week before Father's Day – in the online edition of the journal Nature. The research involved collaboration between Cairns' lab at HCI and the University of Utah's in vitro fertilization (IVF) and andrology lab led by Doug Carrell – along with their joint graduate student, Sue Hammoud.

An implication of this study is that factors such as genetic mutations, age or lifestyle may affect sperm chromosome packaging, leading to infertility. "We are hopeful that this work will soon lead to a clinical diagnostic test that will help couples with infertility problems make better informed decisions regarding their prospects for a healthy child. We will also be testing if aspects of a man's lifestyle – such as age, diet or health – affect proper packaging and fertility," says Cairns. Other future work includes how decision-making genes are packaged in eggs, which remains a major mystery.

--------------------------------------------------------------------------------

Adapted from materials provided by University of Utah Health Sciences.
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The Male Genetic Biological Clock

2009-05-26T17:39:00.000-07:00

This study suggests that the M:F ratio is reduced with increasing paternal age in autism

2009-05-20T17:02:00.000-07:00

: J Autism Dev Disord. 2009 May 19. [Epub ahead of print] Links
Brief Report: Parental Age and the Sex Ratio in Autism.Anello A, Reichenberg A, Luo X, Schmeidler J, Hollander E, Smith CJ, Puleo CM, Kryzak LA, Silverman JM.
Harvard University, Cambridge, MA, USA.

The male-to-female (M:F) ratio for autism spectrum disorders (ASD), typically about 4:1, appears to decrease with increasing paternal age, but this relationship has not been systematically tested. With 393 ASD cases from families with two or more ASD cases, we categorized paternal age into five age groups (<30, 30-34, 35-39, 40-44, 45+) and found that the M:F ratio was significantly decreased with increasing paternal age groups and remained so after also adjusting for maternal age. No significant relationship between maternal age group and the M:F ratio was observed. This study suggests that the M:F ratio is reduced with increasing paternal age consistent with de novo genetic or genomic anomalies arising more frequently as men age and then conceive children.

Men’s Biological Clocks. Will the Risks of Fathering a Baby After Age 35 Start A New Dating Trend?

2009-05-04T18:18:00.000-07:00

May
4

Men’s Biological Clocks. Will the Risks of Fathering a Baby After Age 35 Start A New Dating Trend?

Posted by admin in POW WOW SHOW Topic, Your Guide To Healthy Relationships Today’s 50 may be yesterday’s 30 in some aspects of men’s aging, but medical studies reveal this isn’t true for a 50 year old’s sperm. Men are learning about about the genetic risks of fathering a baby after age 35. Will their newly-found biological clocks start a new dating trend?

What is a biological clock?

It commonly refers to the declining fertility, increasing risk for fetal birth defects, and altered hormone levels experienced by women as they age. Abundant scientific evidence now suggests that men also have a biological clock.

What are some risks of fathering a child after age 40?

A team of UK and US researchers recently reported that children born to men over 40 had a six times higher risk of autism than those born to men under 30.

Other studies have linked older fathers to an increased risk of miscarriages, and to children with bipolar disorder and the rare birth disorders like dwarfism.

Researchers at Columbia University College of Physicians and Surgeons found that men older than 40 were more than twice as likely to have a child who develops schizophrenia as men in their 20’s.

Why is older fatherhood a new cause for concern?

The theory linking paternal age with an offspring’s health rests on spontaneous mutations in the genes of a man’s sperm cells as he ages. New studies refute the earlier theory that men could father children into their old age with no ill effects.

What is the ideal age for men to father children?

To minimize genetic abnormalities, the American Society for Reproductive Medicine has set an upper age limit of 40 years old for semen donors, while UK fertility clinics only accept sperm donations from men aged 39 and under.

Studies suggest that to minimize the risk of autism, the paternal age should be under 32.

Could a man’s biological clock start a new dating trend?

A young man’s biological clock may encourage him seek a serious relationship with a young woman who is ready and willing to have children before he reaches the age of 35 or 40. These young men will have fewer years to date cougars.

A young woman who desires children may be less likely to date a father figure, unless he agrees to use a sperm donor if they decide to have children after his 50th birthday. Or she may simply prefer to date men under age 35 to increase the odds of having healthy babies with a mate closer to her age.

If more men and women over 40 spend less time dating younger, will they find unexpected delights in dating each other? Let us know if you notice these new trends in your dating life.

Dedicated to your relationship happiness,

Check Out this Excellent Newsweek Article On the Genetic Male Biological Clock

2009-04-22T16:43:00.000-07:00

For Whom The Clock Ticks
A growing body of research supports the idea that there are biological disadvantages to late-in-life fatherhood. But will society's view of male fertility ever change?

By Daniel Heimpel | Newsweek Web Exclusive
Apr 22, 2009
From the Editors (2) How Diet Affects Fertility How Women Around the World Cope With Infertility See All Recommended (6) The 10 Most Overlooked Stories of 2008 Religion Helps You Get Pregnant? My Turn: AIDS & Crystal Meth The Cost of the Katrina Effect Chlamydia's Cost A Resistance To Reason See All Topics (2) Patti Stanger John McGrath See All 1 Comments Add Yours Share: Buzz up! (2) Type Size Print
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In season two of Bravo's wildly popular television series "Millionaire Matchmaker," host Patti Stanger rants against older men who perpetually search for 20-somethings to date. What Stanger knows intuitively and what researchers are illustrating empirically, is that men 50 and older, no matter their financial stability, aren't always the greatest catch.

Even if they can theoretically father children till the day they die, a growing compendium of knowledge points to a male "biological clock" largely driven by the replication of sperm with damaged DNA. According to a number of recent studies, offspring of older men have increased chances of a wide range of problems from autism to psychiatric disorders such as schizophrenia. Unlike women, who are equipped with their life's supply of eggs at birth, men replicate sperm from their bar mitzvah to their funeral. It's like a Xerox copy of a Xerox copy millions of times over. The damage can be caused by glitches in the process of replicating DNA millions of times over, reduced efficiency of the DNA repair mechanism, or attributed to environmental factors like stress, smoking or heavy drinking.

But the bottom line is: as men age, the percentage of damaged sperm they carry in their testes tends to increase. "Men are making millions of sperm all the time, and the chance for a copy error is much higher," says Dr. Ethylin Jabs, director of the Center for Craniofacial Development and Disorders at Johns Hopkins, who has conducted extensive research on paternal age and mutations within sperm. Where older women may be concerned about the viability of their remaining eggs, the problem for men, says Jabs, is "quantity not quality."

Semen samples of men over 45 showed impairment to sperm in three categories: their motility (swimming capability), vitality and DNA integrity, according to Dr. Sergey Moskovtsev of Mount Sinai Hospital's Department of Pathology and Laboratory Medicine in New York. Moskovtsev's research shows that men older than 45 have twice as much damage to their sperm as men under 30. Researchers believe that an increase in the percentage of damaged sperm can have a number of consequences.

A report released in PLoS Medicine last month establishes a link between reduced intelligence and children who were fathered by older men. Using a sample of 33,000 children tested at the ages of 8 months, 4 years and 7 years, John McGrath of Australia's Queensland Centre for Mental Health Research and colleagues found that children of older fathers ranked consistently lower in cognitive ability tests than the offspring of younger fathers. For example, 7-year-old children born to 50-year-old dads performed two IQ points lower than peers born to 20-year-old fathers. This difference in IQ is of course subtle, and McGrath says that the results of his study shouldn't be cause for individual men to stop having children.

But he cautions that the mounting studies pointing to a male biological clock are worth considering on a macro level. "As a researcher, I am concerned that we have neglected the issue of paternal age," McGrath says. "Worryingly, the mutations associated with advanced paternal age can be passed on to the next generation. As the population delays parenthood, these mutations could, theoretically, accumulate. Other researchers—not me—have called this process a 'mutational time-bomb'."

Normally, individual sperm with impaired DNA would perform a kind of cell hara-kiri, killing themselves in a process called apoptosis. But research out of the University of Washington has shown that the sperm of men over 35 are less likely to go through that process. Coupled with higher amounts of semen bearing damaged DNA, the likelihood of a child born with an abnormality increases. In a study of hundreds of thousands of psychiatric records conducted by the Israeli draft board in the 1980s, Dr. Abraham Reichenberg of the Mount Sinai School of Medicine, New York, and the Institute of Psychiatry, King's College London, and colleagues showed a six-time increase in autism spectrum disorders for children of fathers over 40, compared with those 29 years and younger.

Since that report came out in 2006, Reichenberg says that efforts to link autism and other psychological disorders to older dads have been bolstered by similar results among sample groups from different countries. Another psychological disorder that has been linked to damaged sperm is schizophrenia. Men over 50 are 3 times as likely to have offspring with the debilitating mental disorder than fathers under the age of 25....

Your Old Man

2009-04-01T08:40:00.000-07:00

The Way We Live Now
Your Old Man
LISA BELKIN
Published: April 1, 2009
Read between the lines of a recent study out of Australia and you can see hints of a coming shift in the gender conversation. Researchers at the University of Queensland found that children born to older fathers have, on average, lower scores on tests of intelligence than those born to younger dads. Data they analyzed from more than 33,000 American children showed that the older the man when a child is conceived, the lower a child’s score is likely to be on tests of concentration, memory, reasoning and reading skills, at least through age 7.

It was a small difference — just a few I.Q. points separated a child born to a 20-year-old and a child born to a 50-year-old. But it adds weight to a new consensus-in-the-making: there is no fountain of youth for sperm, no “get out of aging free” card. The little swimmers, scientists are finding, one study at a time, get older and less dependable along with every other cell in the male body.

And men don’t have to be all that old to be “too old.” French researchers reported last year that the chance of a couple’s conceiving begins to fall when the man is older than 35 and falls sharply if he is older than 40. British and Swedish researchers, in turn, have calculated that the risk of schizophrenia begins to rise for those whose fathers were over 30 when their babies were born. And another Swedish study has found that the risk of bipolar disorder in children begins to increase when fathers are older than 29 and is highest if they are older than 55. British and American researchers found that babies born to men over the age of 40 have significantly greater risk of autism than do those born to men under 30. (The age of the mother, in most of these studies, showed little or no correlation.)

Lay this latest I.Q. news atop the pile, and you find yourself reaching the same conclusion as Dr. Dolores Malaspina, a professor of psychiatry at New York University Medical Center, who has done some of the schizophrenia research: “It turns out the optimal age for being a mother is the same as the optimal age for being a father.”...

Scientists concluded that the 20s and early 30s are the ideal years for fatherhood

2009-03-10T12:41:00.000-07:00

Older fathers have low-IQ babies Tue, 10 Mar 2009 18:23:36 GMT

Children fathered by older men are less intelligent and perform worse in brainpower and neurocognitive tests in their early years. Previous studies had linked advanced maternal age to reduced fertility rate, adding that increased paternal age is associated with certain health problems such as an increased risk of birth deformities and neuropsychiatric conditions (schizophrenia, autism and bipolar disorder). These studies had also reported that children born from older mothers score above average in intelligence tests. According to a study published in the PLoS Medicine, increased paternal age lowers the child's cognitive function in abilities such as memory, learning and concentration. These children, however, have a better access to health and educational services. The average score on the Stanford Binet Intelligence Scale is nearly 6 points lower in children born to fathers aged 50 compared to those born to fathers aged 20. Genetic mutation commonly seen in male sperm with aging is believed to be the factor contributing to this problem as well as the higher number of genetic defects in such children. Scientists concluded that the 20s and early 30s are the ideal years for fatherhood. PKH/HGH

Time is not on the side of older dads

2009-03-10T08:36:00.000-07:00

Time is not on the side of older dads

March 10, 2009University of Queensland research has revealed the older a dad is the more likely his children will have reduced cognitive abilities.Professor John McGrath, from UQ's Queensland Brain Institute, said the study could have implications for a society that is having children later in life.

He said while recent research had shown a link between the age of a father and an increased chance of schizophrenia and autism in the children, there has been less focus on the age of father and cognition."The results were quite startling as it was thought that the age of the father was less of a concern compared to the age of the mother," Professor McGrath said."Now we are getting more evidence of the age of the father being just as important."The older a dad is, the worse his children tend to do in intelligence tests."The research, published in medical journal PLoS Medicine today (Tuesday, March 10), re-analysed data from one of the largest studies of children in the United States, the Collaborative Perinatal Project.More than 33,000 children were tested at eight months, four years and seven years on a variety of intelligence tests, and when Professor McGrath and his colleagues looked at the results against the age of the fathers a pattern soon became clear."Frankly, we were surprised to come up with such a clear cut finding," Professor McGrath said."We are concerned that older men accumulate more mutations in the developing sperm cells."These mistakes then pile up and increase the risks of problems in the children, and it is possible that these mistakes will carry on into the next generation."Professor McGrath said the difference in intelligence was the exact opposite for children of older women, which made the findings even more startling."Offspring of older women do better in similar tests, but this is usually put down to socio-economic status of women," he said."But with the older dads, we wonder if the association is related to mutations in the developing sperm."Professor McGrath and colleagues at QBI and the Queensland Institute of Medical Research are currently using mouse models in order to find the underlying genetic factors that may explain the association between advance paternal age and child development. Research Australia

Also non-familial autism, schizophrenia cancers results

2009-03-09T08:49:00.000-07:00

Kids with older fathers ‘are less intelligent’
Submitted by Mohit Joshi on Sun, 03/08/2009 - 08:14.
Featured
Science News
United Kingdom
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London, Mar 8 Are you delaying fatherhood? Well, then you should reconsider your family plan, for a new study has found that kids with older dads perform badly in intelligence tests.
The research, led by John McGrath, of the Queensland Brain Institute at the University of Queensland in Australia, found children with older fathers tended to obtain significantly lower scores in a variety of cognitive tests than those born to younger fathers.
"The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood," The Times quoted John, as saying.
"In light of the trends to delay fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny," he added.
To reach the conclusion, McGrath analysed data on 33,437 Americans born between 1959 and 1965. All were tested at eight months, four years and seven. The data set, despite its age, remains one of the best resources.
The underlying biological mechanisms are the key questions, according to McGrath. One idea is that as men age the cells that produce sperm suffer increasing numbers of mutations, which are passed on to an offspring. (ANI)

James Watson co-discoverer of DNA structure makes the connection between older paternal age and his son's schizophrenia

2009-03-07T19:57:00.000-08:00

Sunday Times
March 8, 2009
Not too bright? Now the blame is on your old man
Jonathan Leake, Science Editor

CHILDREN with older fathers seem to perform worse in intelligence tests, according to a study due out this week.
They tended to obtain significantly lower scores in a variety of cognitive tests than those born to younger fathers, researchers have found.
The results could be controversial. Until recent years it had been thought that it was a mother’s age that had most impact on the health and abilities of children. The father’s age, by contrast, was thought to be much less important.
The research, led by John McGrath, of the Queensland Brain Institute at the University of Queensland in Australia, suggests such ideas need rethinking.
“The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood,” he said. “In light of the trends to delay fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.”
Other research has shown linkage between advanced paternal age (men over 35) and an increased risk of neurodevelopmental disorders, such as autism and schizophrenia, as well as dyslexia. Such findings prompted James Watson, co-discoverer of the structure of DNA, to speak of his concern. His son Rufus suffers from schizophrenia and as more is uncovered about its causes Watson has publicly questioned if he is to blame. “I worry that I was 42 with Rufus,” he says. “I read that the frequency of schizophrenia goes up with the age of both parents.”
The tests, designed to measure the ability to think and reason, also generated a second startling finding — that children with older mothers gain higher intelligence scores.
McGrath analysed data on 33,437 Americans born between 1959 and 1965. All were tested at eight months, four years and seven. The data set, despite its age, remains one of the best resources. McGrath also used advanced statistical techniques to remove environmental influences.
For McGrath one of the key questions is the underlying biological mechanisms. One idea is that as men age the cells that produce sperm suffer increasing numbers of mutations, which are passed on to an offspring.
Why, though, would children born to older mothers tend to have higher intelligence? McGrath suggests this is because women’s eggs are formed when they are still in the womb and so their DNA is protected from mutation until they are used.

Male Biological Clock and Autism, Bipolar, Schizophrenia, Alzheimer's .Type 1 diabetes

2009-02-20T07:19:00.000-08:00

http://www.cbsnews.com/video/watch/?id=2187759n

Men Must Contend With a Biological Clock, Too Older males face higher risk of fathering children with medical problems, research finds

2009-02-14T08:54:00.000-08:00

Men Must Contend With a Biological Clock, Too Older males face higher risk of fathering children with medical problems, research finds
By Kathleen DohenyHealthDay Reporter
SATURDAY, Feb. 14 (HealthDay News) -- It wasn't all that long ago that any suggestion that a man had a "biological clock" like a woman, and should father children sooner rather than later, would have been given short scientific shrift.
Not anymore. Today, a growing body of evidence suggests that as men get older, fertility can and does decline, while the chances of fathering a child with serious birth defects and medical problems increase.
Some studies have linked higher rates of serious health problems such as autism and schizophrenia in children born to men as young as their mid-40s.
And doctors and researchers are busy trying to figure out how men who choose to delay fatherhood -- either by choice or necessity, such as a lack of a partner -- can offset the effects of their biological clocks as those clocks wind down.
Interestingly, problems with reduced fertility can start long before middle age, said Dr. Harry Fisch, one of the pioneers in the field in male fertility and director of the Columbia University College of Physicians and Surgeons' Male Reproductive Center, in New York City.
"We know after age 30, testosterone levels decline about 1 percent per year," said Fisch, author of the book The Male Biological Clock.
Research done at the University of Washington has found that "as men age, DNA damage occurs to their sperm," said Dr. Narendra P. Singh, a research associate professor in the department of bioengineering, who co-authored a study on the subject.
Several other studies point to problems in the offspring of older fathers, as well as older men experiencing fertility problems.
For instance, Fisch and his colleagues found that if a woman and a man were both older than age 35 at the time of conception, the father's age played a significant role in the prevalence of Down syndrome. And this effect was most detectable if the woman was 40 or older -- the incidence of Down syndrome was about 50 percent attributable to the sperm.
Other researchers have found that children born to fathers 45 or older are more likely to have poor social skills, and that children born to men 55 and older are more likely to have bipolar disorder than those born to men 20 to 24 years of age at the time of conception.
On other fronts, researchers at Mount Sinai School of Medicine in New York City found that children of men aged 40 or older were about six times more likely to have autism. Still another study found that the children of fathers who were 50 or older when they were born were almost three times more likely to be diagnosed with schizophrenia....
But Fisch did say, "The sooner, the better."...

Gender equality: Aging egg and sperm are both problematic

2009-02-13T12:40:00.000-08:00

Gender equality: Aging egg and sperm are both problematic

By Cindy Haines, M.D., Special to the Beacon
Posted 10:30 a.m. Fri., Feb. 13 - The trend is clear. Women and men are postponing starting -- or adding to -- their families until their mid to late 30's and beyond. While the proverbial biological clock has historically been in reference solely to females, a growing body of evidence points to a tick-tick factor for males, as well. The number of births in the United States to men aged 40 to 49 has almost tripled between 1980 and 2004, according to the National Center for Health Statistics, making this biological clock analysis more relevant than ever.
Aging dad and infertility
When one thinks of infertility, thoughts may go directly to the female, with a secondary thought of whether or not the male is able to produce viable sperm. If sperm production is a "go", a common assumption may be made that difficulties conceiving or delivering a healthy baby are factors resting exclusively on the woman. Not necessarily so, according to accumulating data on the subject.
In an analysis of couples struggling with fertility problems, lower pregnancy rates and increased risk of miscarriage were seen in cases whereupon the man was age 35 and older. This finding comes from study presented in 2008 at the European Society of Human Reproduction and Embryology annual conference in Barcelona.
French researchers studied over 12,000 couples seeking care at a fertility clinic where the majority was being treated due to the man's infertility. Collectively, the couples underwent a total of 21,239 intrauterine inseminations (IUIs). Not surprisingly, women over age 35 had a reduced pregnancy rate compared to younger women (8.9 vs. 14.5 percent, respectively).
"But we also found that the age of the father was important in pregnancy rates -- men over 35 had a negative effect. And, perhaps more surprisingly, miscarriage rates increased where the father was over 35," said Dr. Stephanie Belloc, of the Eylau Center for Assisted Reproduction in Paris and author of the study. "Our research proves for the first time that there is a strong paternal age-related effect on IUI outcomes, and this information should be considered by both doctors and patients in assisted reproduction outcomes."
Dr. Peter Ahlering, medical director of SHER Institutes for Reproductive Medicine in St. Louis, agrees that age of would-be fathers may well have an effect on successful pregnancies. "Much of this impact is likely due to environmental exposures which may have an impact on sperm quality," he said
More information
The American Society for Reproductive Medicine on infertility
SHER-St. Louis
Archives of General Psychiatry:
Abstract - Frans
Full Text (subscription or payment may be required)
Ahlering uses HRSS -- high resolution sperm selection -- in the quest for the highest quality sperm. "You can select out under high magnification the sperm to use during [assisted reproductive technologies]," he explains. "You can select out sperm with visible abnormalities which has the effect of increasing fertilization efforts." And the chance of a healthy baby, to boot.
Aging dad and mental illness in his offspring
Advanced paternal age has also been linked with an increased risk of birth defects, including cleft palate and dwarfism. Recent reports have also suggested that children of men who were 40 or older may be up to 6 times more likely to develop autism, jumping to a nine-fold risk when the father's age reaches 50 and beyond. Other mental illness seen more commonly in offspring of aging dads: schizophrenia. A child born to a 40-year-old father may have double the risk of schizophrenia than if the child is born to a father 30 years old or younger. Children of older fathers may also have a higher risk of bipolar disorder (alternating bouts of mania and depression), according to the results of research published in the September issue of the Archives of General Psychiatry. Over 13,420 subjects with a diagnosis of bipolar disorder were studied. Children of men who were at least 55 years old had a 37 percent greater chance of a bipolar diagnosis compared to children of men ages 20 to 24. The risk was even greater in cases of early-onset disease, suggesting greater severity of disease linked with advancing paternal age.

The Father Factor: How Dad's Age Increases Baby's Risk of Mental Illness

2009-01-28T17:46:00.000-08:00

February, 2009 in Biology

The Father Factor: How Dad's Age Increases Baby's Risk of Mental Illness
Could becoming a father after age 40 raise the risks that your children will have a mental illness?
By Paul Raeburn

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Key Concepts
It is widely recognized that a 40-year-old woman has an increased risk of bearing a child with Down syndrome. What is not known is that a 40-year-old man has the same risk of fathering a child with schizophrenia—and even higher odds of his offspring having autism. The risk of bipolar disorder appears to rise as well.
In the past couple of decades, the number of older fathers has increased. Birth rates for men older than 40 have jumped as much as 40 percent since 1980.
The mechanisms behind the higher risks are still being investigated, although scientists have several hypotheses that could someday lead to better therapies or possibly even cures for these mental illnesses.
When my wife, Elizabeth, was pregnant, she had a routine ultrasound exam, and I was astonished by the images. The baby’s ears, his tiny lips, the lenses of his eyes and even the feathery, fluttering valves in his heart were as crisp and clear as the muscles and tendons in a Leonardo da Vinci drawing. Months before he was born, we were already squabbling about whom he looked like. Mostly, though, we were relieved; everything seemed to be fine.

Elizabeth was 40, and we knew about all the things that can go wrong in the children of older mothers. We worried about Down syndrome, which is more common in the offspring of older women. Elizabeth had the tests to rule out Down syndrome and a few other genetic abnormalities. That was no guarantee the baby would be okay, but the results were reassuring to us.

The day after Henry was born, while we were still bleary-eyed from a late-night cesarean delivery, we caught part of a report on the hospital television about an increased risk of autism in the children of older fathers. Until then, all we’d thought about was Elizabeth’s age—not mine. We’d had no idea that my age could be an important factor in our baby’s health.

When we got home, I looked up the study. Researchers had analyzed medical records in Israel, where all young men and most women must report to the draft board for mandatory medical, intelligence and psychiatric screening. They found that children born to fathers 40 or older had nearly a sixfold increase in the risk of autism as compared with kids whose fathers were younger than 30. Children of fathers older than 50—that includes me—had a ninefold risk of autism.

The researchers said that advanced paternal age, as they call it, has also been linked to an increased risk of birth defects, cleft lip and palate, water on the brain, dwarfism, miscarriage and “decreased intellectual capacity.”

What was most frightening to me, as someone with mental illness in the family, is that older fatherhood was also associated with an increased risk of schizophrenia. The risk rises for fathers with each passing year. The child of a 40-year-old father has a 2 percent chance of having schizophrenia—double the risk of a child whose father is younger than 30. A 40-year-old man’s risk of having a child with schizophrenia is the same as a 40-year-old woman’s risk of having a child with Down syndrome.

We wouldn’t know for two years or so whether Henry had autism. And because schizophrenia does not usually appear until the early 20s, we had decades to wait before we would know if Henry was affected.

Advancing Years
Data collected by the National Center for Health Statistics, part of the Centers for Disease Control and Prevention, show that in the U.S. the number of births to men aged 40 to 49 nearly tripled between 1980 and 2004, rising from 120,702 to 328,465. Much of that jump is the result of an increase in the overall population. But there has been a shift over the past generation toward more older fathers beyond what can be accounted for by the growth in population. Birth rates for men in their 40s (a number that takes population growth into account) have risen by up to 40 percent since 1980—whereas birth rates for men younger than 30 have fallen by as much as 21 percent.

The idea that a father’s age could affect the health of his children was first hinted at a century ago by an unusually perceptive and industrious doctor in private practice in Stuttgart, Germany. Wilhelm Weinberg was a loner who devoted much of his time to caring for the poor, including delivering 3,500 babies during a 40-year career. He also managed to publish 160 scientific papers without the benefit of colleagues, students or grants. His papers, written in German, did not attract much attention initially; most geneticists spoke English. It was not until years later that some of Weinberg’s papers were recognized as landmarks.

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E-mail | Print | Text Size The Father Factor: How Dad's Age Increases Baby's Risk of Mental Illness
Could becoming a father after age 40 raise the risks that your children will have a mental illness?
By Paul Raeburn

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One of these was a 1912 study noting that a form of dwarfism called achondroplasia was more common among the last-born children in families than among the first-born. Weinberg didn’t know why that was so, but he speculated that it might be related to the age of the parents, who were obviously older when their last children were born. Weinberg’s prescient observation was confirmed decades later when research showed that he was half right: the risk of dwarfism rose with the father’s age but not the mother’s.

Since then, about 20 inherited ailments have been linked to paternal age, including progeria, the disorder of rapid aging, and Marfan syndrome, a disorder marked by very long arms, legs, fingers and toes, as well as life-threatening heart defects. More recent studies have linked fathers’ age to prostate and other cancers in their children. And in September 2008 researchers linked older fathers to an increased risk of bipolar disorder in their children.

Eggs vs. Sperm
Dolores Malaspina, a professor of psychiatry at the New York University Langone Medical Center, was in college when her sister, Eileen, who was two years younger, began behaving in ways the family couldn’t explain. At first, Malaspina recalls, Eileen seemed like she was going through the usual problems of adolescence. Eileen’s behavior became harder to overlook, however, and she was soon diagnosed with schizophrenia.

It was the early 1970s, when many psychiatrists believed schizophrenia was caused by a dominant, overpowering mother who rejected her child. Further, Eileen’s doctors said, there was no treatment. The damage done by a schizophrenia-inducing mother was irreparable.

At the same time Eileen was deteriorating, Malaspina earned a master’s in zoology and took a job at a drug company, where she drifted into research on substances that could alter brain chemistry. She was in the job for a while before she made the connection with her sister. “I was looking at molecules in the lab that might be related to psychosis,” she says. “My sister had very bad psychosis.” Researchers were then beginning to establish a biological basis for schizophrenia that would ultimately demolish the so-called schizophrenogenic-mother theory. Malaspina quit her job, went to medical school, became a psychiatrist and focused her research on schizophrenia.

While schizophrenia was being recast as a biological illness, most researchers still looked to mothers as the cause of the illness. A woman’s eggs age as she does, and it seemed reasonable to conclude that they deteriorate over the years, giving rise to increased problems in her offspring. Sperm are freshly manufactured all the time.

That’s not quite the way biology works, however. Because sperm are being continuously manufactured, genetic copying is going on constantly. Geneticists think it is that incessant copying and recopying that gives rise to the genetic errors that cause dwarfism, Marfan syndrome and the other inherited ailments. Malaspina decided to explore whether genetic errors in sperm might be at least partly responsible for schizophrenia. It was an unfashionable line of research. Nobody worried about fathers because everybody assumed mothers were the source of most problems in children. But Malaspina and others were beginning to think about it differently.

Schizophrenia and Autism
Later, while doing her residency at Columbia University, Malaspina learned about a unique research opportunity in Israel. During the 1960s and 1970s, all births in and around Jerusalem were recorded in conjunction with information on the infants’ families, including the ages of the parents. And all those children received a battery of medical tests as young adults, a requirement of Israel’s military draft. Because the records cover an entire population, the data are free from the biases that might creep in if researchers looked at, say, only people who graduated from college or only those who went to see a doctor.

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E-mail | Print | Text Size The Father Factor: How Dad's Age Increases Baby's Risk of Mental Illness
Could becoming a father after age 40 raise the risks that your children will have a mental illness?
By Paul Raeburn

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Malaspina used the Israeli group to look first at the risk of schizophrenia in children of older fathers—and then at the risk of autism. Then she correlated birth and family information on some 90,000 children with information on which of them had developed schizophrenia as recorded on their military physicals. In 2001 Malaspina and her colleagues reported that paternal age was strongly linked to the risk of schizophrenia, as she had suspected.

It was the first large-scale study to link sporadic cases of schizophrenia to fathers’ age, and few researchers believed it. “We were absolutely convinced it was real, but other people didn’t think it was,” Malaspina says. “Everybody thought men who waited to have children must be different.” That is, maybe these older fathers had some of the makings of schizophrenia themselves—not enough for the disease to be recognized but enough that it took them a little longer to get settled, married and have children.

Other groups tried to repeat the study using different populations. In all these studies, researchers took a close look at whether there was something about the older fathers—unrelated to age—that increased the risk of schizophrenia in their children. When they did, the link with age became even clearer. “That result has been replicated at least seven times,” says Robert K. Heinssen, chief of the schizophrenia research program at the National Institute of Mental Health (which has funded some of Malaspina’s work). “We’re talking about samples from Scandinavia, cohorts in the United States, Japan. This is not just a finding that pertains to Israeli citizens or people of Jewish background.”

Malaspina knew that the draft-induction tests identified young men and women with autism, and she realized that, too, could be looked at to see whether it was linked to paternal age. “There are similarities between autism and schizophrenia—they both have very severe social deficits,” says one of her collaborators, Abraham Reichenberg, a neuropsychologist at the Mount Sinai School of Medicine and the Institute of Psychiatry at King’s College London. “There was some reason to think similar risk factors might be involved.” In 2006 they and their colleagues published a report showing that the children of men who were 40 or older were nearly six times as likely as the kids of men who were younger than 30 to develop autism or a related disorder.

Autism and related disorders—referred to as autism spectrum disorders—occurred at a rate of six in 10,000 among the children of the younger fathers and 32 in 10,000 among the children of the older fathers. (That is closer to five times the risk, but statistical adjustments showed the risk was actually about six times higher in the offspring of the older dads.) In the children of fathers older than 50, the risk was 52 in 10,000.

That was the study I heard about the day after my son Henry was born.

Reichenberg interprets these results as very solid findings: “In epidemiology, you look for an odds ratio of two. Anything above that, you’re happy. When you have an odds ratio more than five, you’re excited.” The study could not absolutely rule out some effect of older mothers, but “we’re pretty confident that the paternal age risk holds no matter what the maternal age,” he says.

As these studies were being done, Malaspina asked Jay Gingrich, a psychiatrist and neuroscientist at Columbia who works with mice, whether he could look for the same effect in the offspring of older mouse fathers.

Gingrich can’t ask his mice whether they are suffering delusions or hearing voices. But he can give them tests that people with schizophrenia have difficulty passing. In one such test he looked at how mice reacted when startled by a loud sound. Mice are like people—when they hear a loud noise, they jump. And there is more similarity than that: when mice or people hear a soft sound before being startled, they don’t jump as much. It is called prepulse inhibition; the soft pulse inhibits the reaction to the louder one. “It’s abnormal in a number of neuropsychiatric disorders, including schizophrenia, autism, obsessive-compulsive disorders and some of the others,” Gingrich says. And he found that the response was abnormal in mice with older fathers.

The results were so striking that Gingrich thought they were too good to be true. He and a postdoctoral researcher, Maria Milekic, collected data on 100 offspring of younger dads and another 100 offspring of older dads before they decided the results were correct.

Missing a Mechanism?
Not everyone agrees on what Malaspina’s results mean. Daniel R. Weinberger, a psychiatrist and schizophrenia expert at the National Institute of Mental Health, for instance, accepts the findings—that the incidence of schizophrenia is higher in the children of older fathers. But he does not agree with Malaspina that this could be one of the most important causes of schizophrenia. The reason, he says, is researchers know too little about which genes conspire to cause schizophrenia: “It’s a seminal observation, but like many seminal observations, it doesn’t identify a mechanism.” Weinberger wants to know exactly how this happens before he can say what it means.

Malaspina has thought a lot about the mechanism. What happens to the sperm of men as they age that could give rise to these increased risks in their offspring? The first thought was a classic kind of genetic mutation—a typo in the DNA, a stutter or some other scramble of the code.

There is, however, another possibility. The genetic code we are familiar with is expressed in the DNA itself. But there is a second genetic code, separate from what is embedded in the DNA. To distinguish it from the genetic code, it is referred to as “epigenetic” information. It is like a bar code imprinted on the outside of a gene. The information in that bar code can turn the gene on or off—sometimes inappropriately. If it turns the wrong genes on or off, it can affect health and disease just as surely as can changes in the DNA itself.

Malaspina has not yet proved it, but she suspects that as men grow older they develop defects in the machinery that stamps this code on the genes. These imprinting defects may give rise to the increased risk of schizophrenia, autism and perhaps some of the other ailments related to paternal age.

It is not possible to poke around in people’s brains to see whether those who have schizophrenia show errors in this imprinting. But that can be done in Gingrich’s mice. He is just now beginning to examine the imprinting in the brain tissue of his mice, and he is betting he will find errors there. That is precisely the kind of research that could address Weinberger’s concerns about the mechanism responsible for increasing the incidence of schizophrenia in the children of older dads.

This research could represent an important advance in understanding schizophrenia and autism. “This is work that we will pursue and fund, because we’re so eager to get the genetics worked out,” says Thomas R. Insel, a psychiatrist and director of the National Institute of Mental Health. “It’s a very interesting observation.” With persistence—and some luck—the research could lead to better treatments or even, one day, a cure for schizophrenia and autism.

Some researchers worry that these new findings are just among the first of the problems that might ultimately be associated with older dads. “If there is one common disease that we know is associated with older biological fathers, we can safely assume there are more remaining to be discovered,” says University of Chicago psychiatrist Elliot S. Gershon.

Gershon’s prediction has already come true. In September 2008 researchers in Sweden, in collaboration with Reichenberg, reported that the children of older fathers had an increased risk of acquiring bipolar disorder. And the risk increased as the fathers’ age rose, encouraging confidence in the results.

For now, prospective parents might want to rethink their plans about when to have children, says Herbert Meltzer, a psychiatrist and widely recognized schizophrenia expert at Vanderbilt University. He believes the risks for children of older fathers will eventually be seen to be as noteworthy as the risks facing older mothers. “It’s going to be more and more of an issue to society,” he notes. “Schizophrenia is a terrible disease, and anything that can be done to reduce it is terribly important.”

Meltzer thinks women should take a man’s age into consideration when choosing a partner to have children with. And men might want to think about having sperm stored when they are young. Because despite the advances in understanding autism and schizophrenia, treatment is limited and difficult, and a cure remains elusive.

As for Henry, that decision has been made. The question, for me, is whether I would make the same choice, knowing what I know now. Despite the increase in risks, the absolute risks “to any individual child of a man at any age are quite small,” Malaspina says.

My answer: I don’t know.

Note: This article was originally printed with the title, "The Father Factor".

Men also have a biological clock

2009-01-21T14:37:00.000-08:00

Men also have a biological clock
Published: Jan. 21, 2009 at 4:04 PMOrder reprints | Feedback
VALENCIA, Spain, Jan. 21 (UPI) -- Mammalian males can reproduce until late in life, but their children may have more abnormalities, researchers in Spain said.

Although mammalian males can reproduce until late in life, evidence of hazards to offspring has emerged in human and animal models, the researchers said.

Silvia Garcia-Palomares of the University of Valencia in Spain and colleagues said that their study, published in the Biology of Reproduction, provides clear, well-controlled data of deleterious effects on the offspring of aged male mice mated to females of prime reproductive age.

The offspring from the elderly males exhibit abnormalities not only in several behavioral traits, but also in reproductive fitness and longevity -- the offspring fathered by old mice had a shorter life span.

Moreover, mating the offspring from aged males resulted in the production of pups exhibiting decreased weights at weaning when compared with pups from the offspring of younger males.

Garcia-Palomares said the defects causing these abnormalities in offspring are unknown and should be the objective of intriguing studies in the future.

Older men are having children, but the reality of a male biological clock makes this trend worrisome

2009-01-17T09:34:00.000-08:00

January 15, 2009
Older men are having children, but the reality of a male biological clock makes this trend worrisome
By Harry Fisch, MD

Feature Article
Dr Fisch is Professor of Clinical Urology, Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York City.

Disclosure: The author states that he has no financial relationship with any manufacturers in this area of medicine.

ABSTRACT

Couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. The age-related changes associated with the male biological clock affect sperm quality, fertility, hormone levels, libido, erectile function, and a host of non-reproductive physiological issues. This article focuses on the potentially adverse effects of the male biological clock on fertility in older men. Advanced paternal age increases the risk for spontaneous abortion as well as genetic abnormalities in offspring due to multiple factors, including DNA damage from abnormal apoptosis and reactive oxygen species. Increased paternal age is also associated with a decrease in semen volume, percentage of normal sperm, and sperm motility. Older men considering parenthood should have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response. Older men should also be counseled regarding the effects of paternal age on spermatogenesis and pregnancy.

Fisch H. The aging male and his biological clock. Geriatrics. 2009;64(1):14-17.

Keywords: apoptosis, hypogonadism, male biological clock, male infertility, paternal age, spermatogenesis, testosterone

The phrase "biological clock" commonly refers to the declining fertility, increasing risk for fetal birth defects, and altered hormone levels experienced by women as they age. Abundant scientific evidence suggests that men also have a biological clock.1,2 The hormonal and physiological effects of the male clock are linked with testosterone and fertility declines, as well as pregnancy loss and an increased risk of birth defects.3 In this article, we review the effects of the male biological clock, and the association between advanced paternal age and decreased spermatogenesis, pregnancy rates, and birth outcomes.

Male testosterone levels (both total and free) decline roughly 1% per year after age 30.4 The rate of decline in one study4 was not significantly different between healthy men and those with chronic illnesses or multiple comorbidities. This decline can shift men whose testosterone levels are in the low end of the normal spectrum to levels considered below-normal, or hypogonadal (testosterone <325 ng/mL) as they age. An estimated 2 to 4 million men in the United States fall in this category, either from age-related declines, illness, injury, or congenital conditions.5 The population of hypogonadal men is increasing due both to the aging of the general population and unknown factors that appear to be suppressing the average levels of testosterone in more recent birth cohorts.6 The increasing prevalence of abnormally low testosterone levels in elderly men was demonstrated in the Baltimore Longitudinal Study on Aging, which determined that hypogonadal testosterone levels were present in approximately 20% of men over 60, 30% over 70, and 50% over 80 years of age.7

Sub-normal testosterone levels are associated not only with decrements in fertility and sexual response, but also a wide range of other health problems such as declines in muscle mass/strength, energy levels, and cognitive function, as well as increased incidence of weight gain (particularly central adiposity), type 2 diabetes, the metabolic syndrome, and cardiovascular disease. Testosterone replacement therapy to address the wide range of health problems related to hypogonadism is becoming increasingly popular. Delivery via gels or transdermal patches can result in physiologically normal levels of testosterone, which is preferable to the spiky levels obtained via testosterone injections. Oral formulations are under development but none have progressed beyond the clinical trial phase. Fears that testosterone replacement therapy may promote the growth of prostate carcinomas has abated in light of findings from several studies that find no such link.8

Declining fertility and increasing birth defects

It has long been recognized that female fertility declines with age and, obviously, ceases with menopause. Only relatively recently, however, has it been proven that male fertility also declines with age—often significantly so—and that semen quality and the related risk for birth defects is also sensitive to aging. Studies demonstrate that men older than age 35 are twice as likely to be infertile (defined as the inability to initiate a pregnancy within 12 months) as men younger than 25 years.9 Among couples undergoing fertility treatments with intra-uterine insemination, the amount of time necessary to achieve a pregnancy rises significantly with the age of the male. Further, after controlling for maternal age, couples in which the male is older than 35 have a 50% lower pregnancy rate compared with couples in which men are 30 or younger.10

The risk of birth defects is also now known to be related to paternal age. A significant association has been found between advancing paternal age and the risk of autism spectrum disorder (ASD) in children.11 Offspring of men 40 years or older were 5.75 times more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age.

Another study finds a link between paternal age and a higher risk of fathering a child with schizophrenia.12 Men older than 40 were more than twice as likely to have a child with schizophrenia as men in their 20s. A similar influence of paternal age on the risk of having a child with Down syndrome has been reported by several research teams,1 with paternal age a factor in half the cases of Down syndrome when maternal age exceeded 35 years. Other investigators have found that the rate of miscarriages increases with rising paternal age when maternal age was older than 35.13 Thus, there is convincing evidence for an effect of paternal age alone, as well as a combined effect of advancing paternal and maternal age, on increased risks of genetic abnormalities leading to miscarriage or disease in their children. A retrospective multi-center European study revealed that the effects of advanced paternal age and maternal age are cumulative. If both partners are advanced in age, the risk of spontaneous abortion is higher.

Mechanisms behind biological clock effects

The precise genetic and physiological malfunctions underlying the observed links between advanced paternal age and congenital abnormalities remain uncertain although clues have been discovered in recent years. Studies in the murine model, for example, have shown that changes in testicular architecture affect semen quality. At 18 months (defined as "older" in a mouse), several age-related changes occur, including increased number of vacuoles in germ cells and thinning of the seminiferous epithelium. At the age of 30 months, seminiferous epithelia with scant spermatocytes were identified. Overall, total sperm production was significantly reduced and mutation frequency was significantly increased in "older" mice.14

Such changes in testicular architecture, as well as changes in the germinal epithelium, prostatic epithelium, and a host of genetic alterations, undoubtedly underlie the well-documented declines in human semen parameters observed over the years. The literature (11 of 16 published studies) clearly shows, for example, a decrease in semen volume with advanced age. In 2 studies, which adjusted for the confounder of abstinence duration, a decrease in semen volume of 0.15-0.5% was reported for each increase in year of age.15 The semen volume of men aged 50 or older was decreased by 20-30% when compared with men younger than age 30. An association between advanced paternal age and decreased sperm motility is also apparent. In a review of 19 studies, 13 found a decrease in sperm motility with increasing age. Five studies adjusted for the duration of abstinence—a key potential confounder—and found statistically significant declines. A comparison of men age 50 or older to men younger than 30, revealed a 3% to 37% decline in motility.

Abnormal sperm morphology is also tied to advanced paternal age. In 14 studies reviewed, 9 studies found decreases in the percentage of normal sperm with advancing age with the rates of decline ranging from 0.2% per year to 0.9% per year of age when controlling for confounders of duration of abstinence and year of birth.16

The male biological clock also "ticks" at the level of genes. The genetic integrity of sperm has been shown in several studies to decline with age. For example, age is associated with declines in the number of Leydig and Sertoli cells, as well as with an increase in arrested division of germ cells. There also seems to be an increasing failure of the body's ability to "weed out" genetically inferior sperm cells via the mechanism of apoptosis. Spermatozoa are continuously produced and undergo lifelong replication, meiosis, and spermatogenesis. An essential aspect of spermatogenesis that ensures selection of normal DNA is the process of apoptosis of sperm with damaged DNA. Since the rate of genetic abnormalities (such as double-strand breaks) during spermatogenesis increases as men age, the rate of apoptosis should rise as well. This, however, does not seem to be the case, for reasons that remain unknown, which results in higher levels of genetically damaged sperm in older men.

Oxidative stress may also play a role in the observed rise in the frequency of numerical and structural aberrations in sperm chromosomes with increasing paternal age. Spermatozoa have low concentrations of antioxidant scavenging enzymes, which makes them particularly susceptible to DNA damage from reactive oxygen species. A recent study found that seminal reactive oxygen species levels are significantly elevated in men older than 40 years of age.17

Aneuploidy errors in germ cell lines also occur at higher rates with advancing paternal age. The aneuploidy error of trisomy 21, for example, is responsible for Down syndrome. The rate of many autosomal dominant disorders such as Apert syndrome, achrondroplasia, osteogenesis imperfecta, progeria, Marfan syndrome, Waardenburg syndrome, and thanatophoric dysplasia increases with advanced paternal age. Apert syndrome, for example, is the result of an autosomal dominant mutation on chromosome 10, mutating fibroblast growth factor receptor 2 (FGFR2). With increasing paternal age, the incidence of sporadic Apert syndrome increases exponentially, resulting in part from an increased frequency of FGFR2 mutations in the sperm of older men.

The role of medications and comorbidities

The effects of the male biological clock can be exacerbated by both medications and comorbidities. Pharmacologically mediated fertility declines and/or sexual dysfunction has been demonstrated for antihypertensive drugs, antidepressants, and hormonal agents. Seminal emission can be blocked by alpha blocker medications, which are used to treat many symptoms of the lower urinary tract. Gonadotropin-releasing hormone agonists, which are used for prostate cancer treatment, can directly affect sperm production and testosterone levels. High doses of anabolic steroids, sometimes used for enhancement of performance and muscle enlargement, cause reduction of sperm production, which may be permanent. Erectile dysfunction, ejaculatory disorders, and decreased libido can be caused by the 5-alpha reductase inhibitors.

Sexual function and reproductive function can substantially decline in males treated for prostate cancer. Treatments such as radiotherapy, surgery or hormones, alone or in combination, can result in these dysfunctions in treated men of any age, though the severity of effects increases with age. A report found that ultrasound-guided needle biopsy of the prostate was associated with some abnormal semen parameters.18 Since prostate biopsy is more common in men 50 or older, this can be an issue for older would-be fathers.

Conclusions

The fact that men and women are waiting longer to have children, and that advances in reproductive technology are allowing older men and women to consider having children, carries a generally unrecognized public health risk in the form of increased infertility and risk for birth defects and other reproductive problems. CDC birth statistics show the average maternal age rose from 21.4 years of age in 1974 to 25.1 years of age in 2003. Paternal age is rising as well.

The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. This article has demonstrated a host of potential reproductive problems among older men. Semen parameters as well as semen genetic integrity decline with age, which leads to an increased risk for spontaneous abortion as well as genetic abnormalities in offspring. The decreasing apoptotic rate and increase in reactive oxygen species among the rapidly replicating spermatogonia are possible mechanisms behind an amplification of errors in germ cell lines of older men. Such errors may account for the observed increases in Down syndrome, schizophrenia, and autosomal dominant disorders in children born to older fathers.

Future research may elucidate in greater detail the etiology and manifestation of the male biological clock in older men. Novel methods to reverse or slow the clock may be discovered by improved understanding of the cellular and biochemical mechanisms of gonadal aging. This research may diminish potential adverse genetic consequences in offspring and increase the chances that older couples will have a healthy child.

References

1. Fisch H, Hyun G, Golden R, et al. The influence of paternal age on Down syndrome. J Urol. 2003:169(6):2275-2278.

2. Eskenazi B, Wyrobek AJ, Sloter E, et al. The association of age and semen quality in healthy men. Hum Reprod. 2003;18(2):447-454.

3. Lewis BH, Legato M, Fisch H. Medical implications of the male biological clock. JAMA. 2006;296(19):2369-2371.

4. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589-598.

5. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350(5):482-492.

6. Travison TG, Araujo AB, O'Donnell AB, et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007;92(1):196-202.

7. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731.

8. Imamoto T, Suzuki H, Yano M, et al. The role of testosterone in the pathogenesis of prostate cancer. Int J Urol. 2008;15(6):472-480.

9. Ford WC, North K, Taylor H, et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. Hum Reprod. 2000;15(8):1703-1708.

10. Mathieu C, Ecochard R, Bied V. Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age. Hum Reprod. 1995;10(5):1090-1097.

11. Reichenberg A, Gross R, Weiser M, et al. Advancing Paternal Age and Autism. Arch Gen Psychiatry. 2006;63(9):1026-1032.

12. Malaspina D, Harlap S, Fennig S, et al. Advancing Paternal Age and the Risk of Schizophrenia. Arch Gen Psychiatry. 2001;58(4):361-367.

13. de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage: results of a multicentre European study. Hum Reprod. 2002;17(6):1649-1656.

14. Walter CA, Intano GW, McCarrey JR, et al. Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc Natl Acad Sci. 1998;95(17):10015-10019.

15. Andolz P, Bielsa MA, Vila J. Evolution of semen quality in North-eastern Spain: a study in 22,759 infertile men over a 36 year period. Hum Reprod. 1999;14(3):731-735.

16. Auger J, Kunstmann JM, Czyglik F, et al. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995;332(5):281-285.

17. Cocuzza M, Athayde KS, Agarwal A, et al. Age-related increase of reactive oxygen species in neat semen in healthy fertile men. Urology. 2008;71(3):490-494.

18. Manoharan M, Ayyathurai R, Nieder AM, Soloway MS. Hemospermia following transrectal ultrasound-guided prostate biopsy: a prospective study. Prostate Cancer Prostatic Dis. 2007;10(3):283-287.

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Being Born Small, Early Raises Autism Risk

2009-01-16T08:14:00.000-08:00

Thursday, January 15, 2009
Being Born Small, Early Raises Autism Risk

Children who are born underweight or early have more than double the risk of developing autism, new research shows.

The study, by researchers at the U.S. Centers for Disease Control and Prevention, helps tease out the mysterious underpinnings of this disorder but is unlikely to translate into benefits for patients anytime soon.

"This gives us more clues about autism, which we desperately need, but it's not anything clinicians can use right away," said Dr. Cindy Molloy, an autism researcher and clinical assistant professor of pediatrics at the Center for Epidemiology and Biostatistics at Cincinnati Children's Hospital.

The results do reinforce the importance of monitoring children who are born underweight or early for behavioral problems so they can be treated, said study author Diana Schendel, lead health scientist at the CDC's National Center on Birth Defects and Developmental Disabilities.

So-called "autism-spectrum disorders" are a group of developmental disorders characterized by social and communication problems. According to the National Institute for Neurological Disorders and Stroke, some three to six children out of every 1,000 will have autism, while males are four times more likely to develop the disorder than girls.

Previous studies have indicated that low birth weight and being born premature are important risk factors for developmental problems generally in children. But the association between these factors and autism is less clear.

A Canadian study published earlier this year did find that premature infants who were born at a very low birth weight -- about 3.3 pounds -- were more likely to screen positive on tests of autistic behaviors, but the findings were considered preliminary.

The investigators on the current study looked at 565 children with autism born in metropolitan Atlanta between 1986 and 1993, and compared them to a set of children without autism, as well as to children with other developmental disabilities, such as mental retardation, cerebral palsy, hearing loss or vision problems.

Overall, low birth weight was associated with a twofold increased risk for autism, but the risk was higher for girls than for boys.

For all low-birth-weight children, the risk for autism accompanied by other developmental problems, such as mental retardation, was higher than the risk of developing autism alone.

There was also double the risk for developing autism in babies born prematurely, although this was primarily due to a more than fivefold increased risk in girls born early.

"This was one of the first studies that had a large enough sample to look at girls," Molloy said. "They really were able to tease out what is different about boys and girls."

Even so, the elevated risk for autism seen in low-birth-weight and preterm babies was much lower than that linked with cerebral palsy, mental retardation, hearing loss or vision impairment.

"It's not yet clear why being small or being born too soon could lead to these problems but, Schendel said, "[these factors] could be a marker for an impaired fetus, one that has a neurological problem which is retarding its growth. On the other hand, being small or being born too soon may be related to factors that could harm the neurological development of the fetus such as infection during pregnancy."

The findings support the idea that there are different kinds of autism and different mechanisms underlying those cases, Molloy said.

Older men are having children, but the reality of a male biological clock makes this trend worrisome

2009-01-15T20:46:00.000-08:00

Older men are having children, but the reality of a male biological clock makes this trend worrisome
Feature Article
Publish date: Jan 15, 2009
By: Harry Fisch, MD
Source: Geriatrics

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Dr Fisch is Professor of Clinical Urology, Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York City.
Disclosure: The author states that he has no financial relationship with any manufacturers in this area of medicine.
ABSTRACT

Couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. The age-related changes associated with the male biological clock affect sperm quality, fertility, hormone levels, libido, erectile function, and a host of non-reproductive physiological issues. This article focuses on the potentially adverse effects of the male biological clock on fertility in older men. Advanced paternal age increases the risk for spontaneous abortion as well as genetic abnormalities in offspring due to multiple factors, including DNA damage from abnormal apoptosis and reactive oxygen species. Increased paternal age is also associated with a decrease in semen volume, percentage of normal sperm, and sperm motility. Older men considering parenthood should have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response. Older men should also be counseled regarding the effects of paternal age on spermatogenesis and pregnancy.
Fisch H. The aging male and his biological clock. Geriatrics. 2009;64(1):14-17.
Keywords: apoptosis, hypogonadism, male biological clock, male infertility, paternal age, spermatogenesis, testosterone
The phrase "biological clock" commonly refers to the declining fertility, increasing risk for fetal birth defects, and altered hormone levels experienced by women as they age. Abundant scientific evidence suggests that men also have a biological clock.1,2 The hormonal and physiological effects of the male clock are linked with testosterone and fertility declines, as well as pregnancy loss and an increased risk of birth defects.3 In this article, we review the effects of the male biological clock, and the association between advanced paternal age and decreased spermatogenesis, pregnancy rates, and birth outcomes.
Male testosterone levels (both total and free) decline roughly 1% per year after age 30.4 The rate of decline in one study4 was not significantly different between healthy men and those with chronic illnesses or multiple comorbidities. This decline can shift men whose testosterone levels are in the low end of the normal spectrum to levels considered below-normal, or hypogonadal (testosterone <325 ng/mL) as they age. An estimated 2 to 4 million men in the United States fall in this category, either from age-related declines, illness, injury, or congenital conditions.5 The population of hypogonadal men is increasing due both to the aging of the general population and unknown factors that appear to be suppressing the average levels of testosterone in more recent birth cohorts.6 The increasing prevalence of abnormally low testosterone levels in elderly men was demonstrated in the Baltimore Longitudinal Study on Aging, which determined that hypogonadal testosterone levels were present in approximately 20% of men over 60, 30% over 70, and 50% over 80 years of age.7
Sub-normal testosterone levels are associated not only with decrements in fertility and sexual response, but also a wide range of other health problems such as declines in muscle mass/strength, energy levels, and cognitive function, as well as increased incidence of weight gain (particularly central adiposity), type 2 diabetes, the metabolic syndrome, and cardiovascular disease. Testosterone replacement therapy to address the wide range of health problems related to hypogonadism is becoming increasingly popular. Delivery via gels or transdermal patches can result in physiologically normal levels of testosterone, which is preferable to the spiky levels obtained via testosterone injections. Oral formulations are under development but none have progressed beyond the clinical trial phase. Fears that testosterone replacement therapy may promote the growth of prostate carcinomas has abated in light of findings from several studies that find no such link.8

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Declining fertility and increasing birth defects
It has long been recognized that female fertility declines with age and, obviously, ceases with menopause. Only relatively recently, however, has it been proven that male fertility also declines with age—often significantly so—and that semen quality and the related risk for birth defects is also sensitive to aging. Studies demonstrate that men older than age 35 are twice as likely to be infertile (defined as the inability to initiate a pregnancy within 12 months) as men younger than 25 years.9 Among couples undergoing fertility treatments with intra-uterine insemination, the amount of time necessary to achieve a pregnancy rises significantly with the age of the male. Further, after controlling for maternal age, couples in which the male is older than 35 have a 50% lower pregnancy rate compared with couples in which men are 30 or younger.10
The risk of birth defects is also now known to be related to paternal age. A significant association has been found between advancing paternal age and the risk of autism spectrum disorder (ASD) in children.11 Offspring of men 40 years or older were 5.75 times more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age.

Another study finds a link between paternal age and a higher risk of fathering a child with schizophrenia.12 Men older than 40 were more than twice as likely to have a child with schizophrenia as men in their 20s. A similar influence of paternal age on the risk of having a child with Down syndrome has been reported by several research teams,1 with paternal age a factor in half the cases of Down syndrome when maternal age exceeded 35 years. Other investigators have found that the rate of miscarriages increases with rising paternal age when maternal age was older than 35.13 Thus, there is convincing evidence for an effect of paternal age alone, as well as a combined effect of advancing paternal and maternal age, on increased risks of genetic abnormalities leading to miscarriage or disease in their children. A retrospective multi-center European study revealed that the effects of advanced paternal age and maternal age are cumulative. If both partners are advanced in age, the risk of spontaneous abortion is higher.
Mechanisms behind biological clock effects
The precise genetic and physiological malfunctions underlying the observed links between advanced paternal age and congenital abnormalities remain uncertain although clues have been discovered in recent years. Studies in the murine model, for example, have shown that changes in testicular architecture affect semen quality. At 18 months (defined as "older" in a mouse), several age-related changes occur, including increased number of vacuoles in germ cells and thinning of the seminiferous epithelium. At the age of 30 months, seminiferous epithelia with scant spermatocytes were identified. Overall, total sperm production was significantly reduced and mutation frequency was significantly increased in "older" mice.14
Such changes in testicular architecture, as well as changes in the germinal epithelium, prostatic epithelium, and a host of genetic alterations, undoubtedly underlie the well-documented declines in human semen parameters observed over the years. The literature (11 of 16 published studies) clearly shows, for example, a decrease in semen volume with advanced age. In 2 studies, which adjusted for the confounder of abstinence duration, a decrease in semen volume of 0.15-0.5% was reported for each increase in year of age.15 The semen volume of men aged 50 or older was decreased by 20-30% when compared with men younger than age 30. An association between advanced paternal age and decreased sperm motility is also apparent. In a review of 19 studies, 13 found a decrease in sperm motility with increasing age. Five studies adjusted for the duration of abstinence—a key potential confounder—and found statistically significant declines. A comparison of men age 50 or older to men younger than 30, revealed a 3% to 37% decline in motility.
Abnormal sperm morphology is also tied to advanced paternal age. In 14 studies reviewed, 9 studies found decreases in the percentage of normal sperm with advancing age with the rates of decline ranging from 0.2% per year to 0.9% per year of age when controlling for confounders of duration of abstinence and year of birth.16

Older men are having children, but the reality of a male biological clock makes this trend worrisomeFeature Article
Publish date: Jan 15, 2009
By: Harry Fisch, MD
Source: Geriatrics

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The male biological clock also "ticks" at the level of genes. The genetic integrity of sperm has been shown in several studies to decline with age. For example, age is associated with declines in the number of Leydig and Sertoli cells, as well as with an increase in arrested division of germ cells. There also seems to be an increasing failure of the body's ability to "weed out" genetically inferior sperm cells via the mechanism of apoptosis. Spermatozoa are continuously produced and undergo lifelong replication, meiosis, and spermatogenesis. An essential aspect of spermatogenesis that ensures selection of normal DNA is the process of apoptosis of sperm with damaged DNA. Since the rate of genetic abnormalities (such as double-strand breaks) during spermatogenesis increases as men age, the rate of apoptosis should rise as well. This, however, does not seem to be the case, for reasons that remain unknown, which results in higher levels of genetically damaged sperm in older men.
Oxidative stress may also play a role in the observed rise in the frequency of numerical and structural aberrations in sperm chromosomes with increasing paternal age. Spermatozoa have low concentrations of antioxidant scavenging enzymes, which makes them particularly susceptible to DNA damage from reactive oxygen species. A recent study found that seminal reactive oxygen species levels are significantly elevated in men older than 40 years of age.17
Aneuploidy errors in germ cell lines also occur at higher rates with advancing paternal age. The aneuploidy error of trisomy 21, for example, is responsible for Down syndrome. The rate of many autosomal dominant disorders such as Apert syndrome, achrondroplasia, osteogenesis imperfecta, progeria, Marfan syndrome, Waardenburg syndrome, and thanatophoric dysplasia increases with advanced paternal age. Apert syndrome, for example, is the result of an autosomal dominant mutation on chromosome 10, mutating fibroblast growth factor receptor 2 (FGFR2). With increasing paternal age, the incidence of sporadic Apert syndrome increases exponentially, resulting in part from an increased frequency of FGFR2 mutations in the sperm of older men.

The role of medications and comorbidities
The effects of the male biological clock can be exacerbated by both medications and comorbidities. Pharmacologically mediated fertility declines and/or sexual dysfunction has been demonstrated for antihypertensive drugs, antidepressants, and hormonal agents. Seminal emission can be blocked by alpha blocker medications, which are used to treat many symptoms of the lower urinary tract. Gonadotropin-releasing hormone agonists, which are used for prostate cancer treatment, can directly affect sperm production and testosterone levels. High doses of anabolic steroids, sometimes used for enhancement of performance and muscle enlargement, cause reduction of sperm production, which may be permanent. Erectile dysfunction, ejaculatory disorders, and decreased libido can be caused by the 5-alpha reductase inhibitors.
Sexual function and reproductive function can substantially decline in males treated for prostate cancer. Treatments such as radiotherapy, surgery or hormones, alone or in combination, can result in these dysfunctions in treated men of any age, though the severity of effects increases with age. A report found that ultrasound-guided needle biopsy of the prostate was associated with some abnormal semen parameters.18 Since prostate biopsy is more common in men 50 or older, this can be an issue for older would-be fathers.
Conclusions
The fact that men and women are waiting longer to have children, and that advances in reproductive technology are allowing older men and women to consider having children, carries a generally unrecognized public health risk in the form of increased infertility and risk for birth defects and other reproductive problems. CDC birth statistics show the average maternal age rose from 21.4 years of age in 1974 to 25.1 years of age in 2003. Paternal age is rising as well.
The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. This article has demonstrated a host of potential reproductive problems among older men. Semen parameters as well as semen genetic integrity decline with age, which leads to an increased risk for spontaneous abortion as well as genetic abnormalities in offspring. The decreasing apoptotic rate and increase in reactive oxygen species among the rapidly replicating spermatogonia are possible mechanisms behind an amplification of errors in germ cell lines of older men. Such errors may account for the observed increases in Down syndrome, schizophrenia, and autosomal dominant disorders in children born to older fathers.
Older men are having children, but the reality of a male biological clock makes this trend worrisomeFeature Article
Publish date: Jan 15, 2009
By: Harry Fisch, MD
Source: Geriatrics

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Future research may elucidate in greater detail the etiology and manifestation of the male biological clock in older men. Novel methods to reverse or slow the clock may be discovered by improved understanding of the cellular and biochemical mechanisms of gonadal aging. This research may diminish potential adverse genetic consequences in offspring and increase the chances that older couples will have a healthy child.
References
1. Fisch H, Hyun G, Golden R, et al. The influence of paternal age on Down syndrome. J Urol. 2003:169(6):2275-2278.

2. Eskenazi B, Wyrobek AJ, Sloter E, et al. The association of age and semen quality in healthy men. Hum Reprod. 2003;18(2):447-454.
3. Lewis BH, Legato M, Fisch H. Medical implications of the male biological clock. JAMA. 2006;296(19):2369-2371.
4. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589-598.
5. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350(5):482-492.
6. Travison TG, Araujo AB, O'Donnell AB, et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007;92(1):196-202.
7. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731.
8. Imamoto T, Suzuki H, Yano M, et al. The role of testosterone in the pathogenesis of prostate cancer. Int J Urol. 2008;15(6):472-480.
9. Ford WC, North K, Taylor H, et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. Hum Reprod. 2000;15(8):1703-1708.
10. Mathieu C, Ecochard R, Bied V. Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age. Hum Reprod. 1995;10(5):1090-1097.
11. Reichenberg A, Gross R, Weiser M, et al. Advancing Paternal Age and Autism. Arch Gen Psychiatry. 2006;63(9):1026-1032.
12. Malaspina D, Harlap S, Fennig S, et al. Advancing Paternal Age and the Risk of Schizophrenia. Arch Gen Psychiatry. 2001;58(4):361-367.
13. de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage: results of a multicentre European study. Hum Reprod. 2002;17(6):1649-1656.
14. Walter CA, Intano GW, McCarrey JR, et al. Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc Natl Acad Sci. 1998;95(17):10015-10019.
15. Andolz P, Bielsa MA, Vila J. Evolution of semen quality in North-eastern Spain: a study in 22,759 infertile men over a 36 year period. Hum Reprod. 1999;14(3):731-735.
16. Auger J, Kunstmann JM, Czyglik F, et al. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995;332(5):281-285.
17. Cocuzza M, Athayde KS, Agarwal A, et al. Age-related increase of reactive oxygen species in neat semen in healthy fertile men. Urology. 2008;71(3):490-494.
18. Manoharan M, Ayyathurai R, Nieder AM, Soloway MS. Hemospermia following transrectal ultrasound-guided prostate biopsy: a prospective study. Prostate Cancer Prostatic Dis. 2007;10(3):283-287.
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Study: Bipolar Disorder Linked to Older Dads

2008-12-31T08:31:00.000-08:00

Study: Bipolar Disorder Linked to Older Dads
at：2008-12-31 05:25:14 Click: 12
Schizophrenia, autism and now bipolar disorder are all linked with older fathers. Here is the Associated Press story by Lindsey Tanner that ran two days ago discussing the newest study.

CHICAGO (AP) — Children born to older fathers face a greater chance of developing bipolar disorder, according to one of the largest studies linking mental illness with advanced paternal age.

Previous research has connected schizophrenia and autism with older dads, and a Danish study published last year added bipolar disorder to the list. The new study led by researchers at Sweden's Karolinska Institute strengthens the evidence.

The leading theory is that older men's sperm may be more likely to develop mutations. Even so, the odds of a person becoming bipolar are so low that the study's authors said it shouldn't dissuade older men from becoming fathers.

Researchers analyzed Swedish national registry data from more than 80,000 people, including 13,428 with bipolar disorder who were born between 1932 and 1991.

The risks started increasing around age 40 but were strongest among those 55 and older. Children born to these dads were 37 percent more likely to develop bipolar disorder than those born to men in their 20s.

They also faced more than double the risk of developing bipolar disorder before age 20. Scientists call that early onset disease, and while they have long known that bipolar disorder tends to run in families, early onset disease has been thought to be most strongly linked with genetics.

The age of the mothers didn't appear to be much of a factor.

The study, released Monday, appears in September's Archives of General Psychiatry.

While the findings don't explain what might cause some older men to have bipolar children, it "reinforces the notion that there's a strong biological component to this," said Dr. Harold Pincus, vice chair of psychiatry at Columbia University.

Bipolar disorder causes dramatic mood swings, from deep depression to manic highs. It affects more than 5 million Americans.

Lifetime risks for it have been estimated at roughly 1 percent to 4 percent. The study results suggest that having an older father might increase that slightly. The findings aren't definitive, but even if the link proves to be real, Pincus noted that still means most people with older fathers won't ever get bipolar disorder.

Factors involving mothers, including age and health, have long been thought to be most closely linked with birth defects and other abnormalities. But the new study adds to mounting evidence that paternal factors also play an important role, said New York University researcher Susan Harlap.

Sperm are produced throughout a man's lifetime, and scientists believe that as men age there is a greater chance for mutations that could contribute to disorders in their children.

Advanced paternal age also has been linked with birth defects, and some sperm banks have age limits for donors because of that.

While important for scientists, the study results shouldn't discourage older men from fathering children, said Emma Frans, the lead author.

She said the results suggest that similar mechanisms might contribute to risks for bipolar disorder, schizophrenia and autism. Each of these disorders is thought to have many causes including biologic and outside factors.

On the Net:
Archives: http://www.archgenpsychiatry.com
National Institutes of Health bipolar information: http://tinyurl.com/2wjbv7

Comments
Les at : 2008-12-31 08:25:35
Type 1 diabetes, MS, Alzheimer's, cerebral palsy, epilepsy, breast, prostate, leukemia, and early childhood cancer are among the many other disorders that rise in incidence with increasing paternal age. Some sperm US banks refuse sperm of a man past his 35th birthday to try an avoid paternal age related genetic disease. By the age of 33-35 men are rapidly accumulating mutations in their sperm making cells. http://how-old-is-too-old.blogspot.com/
Comment

The Age of Fathers Can Matter to Fertility and to the Genetic health of the child

2008-12-13T14:37:00.000-08:00

How new study about fertility risk for men over 35 woke me up to my own biological timebomb
By Nic Fleming
Last updated at 9:58 PM on 13th December 2008
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While I have always said I want children, I have rarely felt in a rush to do anything about it.
The joys of nappy changing, parents’ evenings and Center Parc holidays have yet to entice me, at the age of 37, to join the ranks of new fathers among my friends who are increasingly absent from trips to the football and nights in playing Grand Theft Auto on the Xbox.
But my state of responsibility-free bliss has been undermined by a study published in July by French researcher Dr Stephanie Belloc.
Decision time: Author Nic Fleming with his fiancee Linda Geddes

Analysing the records of 12,000 couples who attended her fertility clinic in Paris, she found that women whose husbands or boyfriends were aged 35 and above were more likely to have miscarriages than those with younger partners.
Her findings back up a study by Bristol University that found women with partners aged 35 and over were half as likely as those with men aged 24 and younger to conceive within a year.

Sir Paul McCartney, who became a father at 61, and John Humphrys, who did so at 56, are the exceptions, not the rule.
In another study, published two years ago, it was also found that the offspring of men aged 40 and over were nearly six times more likely to suffer from autism than those with fathers under 30.

Other research has found that men aged 50 and over are more likely to have children with Down’s syndrome, or who may develop schizophrenia.
‘I think a man who wants children who has reached 35 should get a move on,’ says Christopher Barratt, professor of reproductive medicine at the University of Dundee.

‘People say I’m not in the right relationship, I haven’t got enough money, or the car isn’t big enough.
‘In reality, you have never quite got what you want. It’s hard to beat biology, and increasingly we are seeing that applies to men as well.’
My fiancee Linda recently turned 30. She enjoys her job as a science journalist, and we have no immediate plans to start a family.

However, I’m starting to wonder whether it is my biological clock rather than hers we should keep track of, which explains how I came to make an appointment to have my semen analysed at Andrology Solutions private fertility clinic in London.
‘In the past it was only women who had maybe focused on their careers - and did not have a partner - who worried about leaving it too late to start a family,’ says Dr Sheryl Homa, the clinic’s scientific director, when I returned two weeks later for my results.
‘But now we’re seeing more men who want to have children but who are not in a relationship and are concerned that time is slipping by.’
Semen analysis involves measuring sperm count, motility - or how lively it is - and its morphology or shape.

Some research suggests older men have semen that contains less sperm, and that their sperm is more likely to be sluggish and abnormally shaped.

However, other studies have failed to detect these effects.
‘Even if semen quality declines with age, it would have to do so a lot before there’s an impact on the ability of a man to conceive,’ says Allan Pacey, a senior lecturer in andrology at Sheffield University.
Dr Homa said my count was high and motility was good. In most men, about 80 per cent of sperm cells have abnormalities that mean they have less chance of fertilising an egg.

I have a slightly higher number of such abnormalities.

No one knows why - it could be genetic or it could be down to diet. I am lucky as the effects are balanced out by my high count.
On average, 84 per cent of couples conceive naturally within a year if they have sex regularly without contraception.

National guidelines state that GPs should refer couples for tests, including semen analysis, after a year of unsuccessfully trying to conceive.

A man who is simply curious, such as me, has to pay about £75 for a test at a private clinic.
Some scientists believe higher levels of damage in sperm DNA could play an important role in undermining fertility in older men.

In the constant production of sperm cells, a single cell called a gametocyte divides into two, each ‘half’ becoming a new sperm.
During this process - meiosis --genetic material is divided and abnormalities can occur, rendering the new cells unviable.

The older men become, the more likely this is to occur.

Exposure to heat, chemotherapy treatment, radiation, genital tract inflammation, and smoking can also cause DNA damage-Some private clinics offer DNA damage tests, but scientists disagree on which tests are the more accurate and what level of damage triggers infertility.

At £300, such tests are thought to be helpful only in certain specific circumstances.
Men trying for a baby are advised to minimise alcohol intake. The evidence on caffeine is mixed but experts recommend those having more than three drinks of coffee, tea or cola a day should cut back.
There are also links between poor sperm quality and smoking, tight underwear, recreational drugs, anabolic steroids and hot baths.
Folate, one of the B vitamins, is important to women before and during pregnancy.

It is found in foods such as broccoli, sprouts, asparagus, peas and brown rice. It is also believed to be good for sperm quality.
Zinc, contained in meat, shellfish, dairy foods, bread and cereal products, is found in high concentrations in sperm and is needed to make the outer layer and tail of sperm.
I’m in a pensive mood as I leave the clinic clutching my results. I watch a group of young children playing in a park.
Discovering, from the results, that I am able to reproduce is a relief.

Maybe it’s time to eat more greens, throw out the games console and think about putting my fertility to use while I still can.

New study backs parent age-autism link

2008-12-12T16:59:00.000-08:00

New study backs parent age-autism link

Last Updated: 2008-12-12 9:12:21 -0400 (Reuters Health)

By Anne Harding

NEW YORK (Reuters Health) - Advanced parental age does indeed appear to boost autism risk in children, and the risk is seen with both mothers and fathers, new research shows.

"What we found was that actually it's both parents age, and when you control for one parent's age you still see the effect of the other parent's age, and vice versa," Dr. Maureen Durkin of the University of Wisconsin School of Medicine and Public Health in Madison, the lead researcher of the study reported in the American Journal of Epidemiology, told Reuters Health.

The findings may offer clues to understanding the causes of autism and why it's on the rise, but they shouldn't be used to guide family planning decisions, Durkin said. Even though the oldest child born to two older parents is three times as likely to be autistic than a middle or youngest child with younger parents, she explained, there's still a 97 percent chance that the higher-risk child will be perfectly fine. "The vast majority of children don't develop autism," she emphasized.

Several studies have suggested links between a father's age or the age of both parents and a child's likelihood of having autism. The current study included twice as many autism cases as any other research on this issue to date, which made it possible to tease out the effects of both maternal and paternal age.

The researchers looked at 253,347 children born in 1994 at 10 sites included in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. There were 1,251 children who met standard criteria for an autism spectrum disorder at age 8 for whom information on both parents' age was available.

Copy Number Variation and Schizophrenia (Paternal Age)

2008-12-12T09:27:00.000-08:00

Schizophrenia Bulletin Advance Access originally published online on November 5, 2008
Schizophrenia Bulletin 2009 35(1):9-12; doi:10.1093/schbul/sbn147

© The Author 2008. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Copy Number Variation and Schizophrenia
David St Clair1,2
2 Institute of Medical Sciences, University of Aberdeen

1 To whom correspondence should be addressed; David St Clair, Professor of Psychiatry, University of Aberdeen, Institute of Medical Science, Foresterhill, Aberdeen, AB25 2ZD, email: mmbl@bigpond.com

Over the last 12 months, a series of major articles have reported associations with schizophrenia of copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 22q12, and Neurexin 1 loci. These are rare high-penetrant mutations that increase risk not only of schizophrenia but also of a range of other psychiatric disorders including autism and mental retardation. In some cases, the same phenotype can occur irrespective of whether the copy number variant causes a deletion or duplication. Some of these mutations occur at very high rates in human populations, but because of reduced fecundity associated with major psychiatric disorders the overall frequency in the population remains low. These new findings raise fundamental clinical and scientific questions concerning classification of major neuropsychiatric disorders, modes of inheritance, diagnostics, and genetic counseling. Although the loci identified so far account for only a small proportion of cases, many more are likely to be discovered over the next few years. A major focus of research will be to identify the key, the genetic and environmental determinants of schizophrenia risk in carriers of these copy number variants, and to discover whether their rates of mutation are unstable or fixed.

Keywords: schizophrenia / genome / CNV

Paternal age: are the risks of infecundity and miscarriage higher when the man is aged 40 years or over?

2008-12-01T10:38:00.000-08:00

1: Rev Epidemiol Sante Publique. 2005 Nov;53 Spec No 2:2S47-55.Related Articles, Links
Paternal age: are the risks of infecundity and miscarriage higher when the man is aged 40 years or over?

De La Rochebrochard E, Thonneau P.

Unité Inserm-Ined 569, Hôpital de Bicêtre, 82, rue du Général-Leclerc, 94276 Le Kremlin-Bicêtre. roche@ined.fr

BACKGROUND: Maternal age of 35 years or over is a well-known risk factor for human reproduction that has been extensively investigated by demographers and epidemiologists. However, the possibility of a paternal age effect has rarely been considered. We carried out review of the literature to investigate the effect of paternal age on the risks of infecundity and miscarriage. METHODS: We carried out a MEDLINE search and checked the exhaustiveness of our reference list. RESULTS: We identified 19 articles analysing the effect of paternal age. Epidemiological studies provided evidence that paternal age older than 35-40 years affects infecundity. However, the few studies based on data from assisted reproductive techniques (especially IVF with ovum donation) do not confirm this finding. All studies analysing the effect of paternal age on the risk of miscarriage showed an increased risk in men aged 35-40 years or over. Other studies have shown some evidence for a paternal age effect on late foetal deaths. CONCLUSION: The risks of infecundity and miscarriage increase with paternal age. Two main hypotheses can be considered. First, these risks increase after the age of 35-40 years. However, a later paternal age effect (after 45-50 years) cannot be excluded. Second, due to the interaction of the ages of the two partners, the risks of infecundity and miscarriage may be higher when both partners are older (woman aged 35 years or over and man aged 40 years or over).

Publication Types:
Review

PMID: 16471144 [PubMed - indexed for MEDLINE]

Sperm 2. DNA damage is significantly related to age

2008-11-25T06:24:00.000-08:00

Sperm DNA Damage: Correlation To Severity Of Semen Abnormalities
Main Category: Fertility
Also Included In: Urology / Nephrology; Genetics
Article Date: 24 Nov 2008 - 1:00 PST

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SAN FRANCISCO, CA, USA (UroToday.com) - Evaluation of male fertility includes assessment of the standard semen parameters (SSP) and may include assessment of DNA damage. However, the relationship between DNA damage and SSP remains controversial. This study examined the the relationship of DNA damage to SSP in patients presenting for infertility evaluation.

The authors conducted an IRB approved retrospective review of semen samples from 2586 unselected non-azoospermic patients underwent computer-assisted semen analysis and flow cytometry based sperm DNA damage assessment expressed as the DNA Fragmentation Index (DFI). DFI was significantly negatively correlated to sperm concentration, motility, and normal morphology and positively correlated to age (P<0.001). DNA damage increased in relationship to the number of abnormalities in the SSP (P <0.001).

The authors concluded:

1. DNA damage is significantly related to standard parameters of semen analysis
2. DNA damage is significantly related to age
3. The degree of DNA damage increases with the number of abnormal parameters in a sample and is most severe in patients with oligo-astheno-teratospermia (OAT).

Editorial Comments:

The authors demonstrate the relationship between progressively more abnormal semen parameters and abnormal DFI. This is consistent with clinical observations and does not appear to demonstrate any incremental value to DFI assessment, in clinical practice, in the initial assessment of the infertile male.

Presented by S. I. Moskovtsev, J. Willis, and J. White, et al., at the 64th Annual Meeting of the American Society for Reproductive Medicine - November 8 - 12, 2008 - San Francisco, California

Reported by UroToday.com Contributing Editor Harris M. Nagler, MD

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Alzheimer's link to older fathers

2008-11-21T19:16:00.000-08:00

Alzheimer's link to older fathers
Independent, The (London), Sep 17, 1998 by Charles Arthur Technology Editor
E-mail Print Link CHILDREN BORN to fathers who are approaching middle age have a higher than average risk of developing Alzheimer's disease in later life, a study suggests.

A retrospective investigation of 206 people who have the degenerative illness, but no history of it occurring in the family, revealed a statistically significant link with the age of their father when they were born.

Some genes are known to contibute to the chance of developing Alzheimer's, but the new study, carried out by Lars Bertram at the Technical University of Munich, suggests that simply having an older father - average age 35.7 - can be a risk factor even in the absence of those genes. For those where there was a family history of Alzheimer's, the average age of the father was 31.3 years.

Though the sample is comparatively small, it is in line with the knowledge that ageing is associated with genetic damage to the sperm, which carry the father's genetic contribution to the child. That might eventually lead to Alzheimer's in the offspring. "There's an accumulation of environmental factors which somehow alter the genome of the father," Dr Bertram told New Scientist magazine.

Similar effects are already known to occur in women, where mothers over 35 have a far higher chance of giving birth to babies with Down's syndrome, which is caused by a genetic defect in the embryo. People with Down's syndrome are also more likely eventually to develop Alzheimer's.

Copyright 1998 Newspaper Publishing PLC
Provided by ProQuest Information and Learning Company. All rights Reserved.

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