Men have biological clock too, claim researchers

Men have biological clock too, claim researchers
Biological clocks are found in men as well as women, according to new research that found male fertility begins to decline when they reach their mid-30s.

By Ben Leach
Last Updated: 7:50PM GMT 26 Oct 2008

Scientists said men who wait until their 40s before starting a family face a greater chance of their partner having a miscarriage, because of the poorer quality of their sperm.

"Drops in fertility from the age of 35 have been traditionally thought of as a fact-of-life for women but our study shows the same is true for men," said Dr Mark Bowman, the director of a Sydney IVF clinic which carried out tests on 3,324 men over four years.

Their sperm DNA was tested to assess its "reproductive potential". The study showed that from the age of 35, the proportion of damaged sperm increased.

Dr Bowman added: "This means that even if a man produces the average of 40 million sperm per ejaculation, many of those sperm will not be able to fertilise an egg normally. He will have a lower fertility potential and be less likely to father a child."

The study is further evidence that men have a biological clock.

Earlier this year a study of more than 20,000 couples seeking fertility help found that middle-aged men are almost a third less likely to conceive with their partner than males under 35.

Doctors have long warned that too many young women are putting off starting a family until their late thirties or early forties, by which time their fertility levels have started to fall.

But the example of older celebrity fathers, including Sir Paul McCartney and Rod Stewart, may have encouraged many men to believe that they can postpone having children for much longer than women.

The research at the Eylau Centre for Assisted Reproduction in Paris found that the older a prospective father, the less chance that their partner would become pregnant. The study involved a form of fertility treatment, where the sperm is "washed'' before being inseminated into the woman. This helps the sperm to survive for longer.

For men between 30 and 35 the successful pregnancy rate was 13.6 per cent. But that fell to 9.3 per cent if the man was older than 45, a decrease of almost a third

The findings also showed that men over 35 were 75 per cent more likely to have their partner suffer a miscarriage. Although lower than the miscarriage rate for older mothers, which was more than twice that of younger mothers, the researchers still described it as significant.

They believe there could be a number of reasons behind the findings, including that the DNA of sperm decays over time.

First-born children of older parents were three times more likely to develop autism than later children of younger parents, researchers found.

First-born children of older parents are more likely to be autistic
A major US study has provided the strongest evidence yet that older mothers and fathers are more likely to have a child with autism.

By Roger Dobson
Last Updated: 7:48PM BST 25 Oct 2008

First-born children of older parents were three times more likely to develop autism than later children of younger parents, researchers found.

"The results provide the most compelling evidence to date that autism risk increases with both maternal and paternal age, and decreases with birth order," according to the research team, whose study was funded by the US Centers for Disease Control and Prevention.

The findings could help to provide an explanation for the recent increase in the number of children diagnosed with autism, which has coincided with a trend towards parents having children at an older age, and to smaller family sizes.

The researchers say in their paper, reported in the American Journal of Epidemiology: "The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism."

In the study, the researchers examined records of 240,000 children born in 1994, and identified 1,251 as having autism. After taking into account a range of factors, both maternal and paternal age were found to be independently associated with autism.

For mothers aged 35 or over, the risk of having an autistic child was 30 per cent higher than for mothers aged 25 to 29. Mothers under 20 had a 30 per cent lower risk than those aged 35 to 29. Fathers aged 40 or over had a 40 per cent higher risk of having an autistic child than fathers aged 25 to 29.

Many western countries have seen a trend for women to have their first child later in life, while the decline in average family size means that a higher proportion of today's children are first-born.

There is no clear explanation for why parental age increases the risk of having an autistic child. The researchers speculate that older fathers could be more likely to pass on gene mutations, while older mothers may be more prone to age-related chromasome changes or pregnancy complications. Older parents are also more likely to have undergone fertility treatment.

Another theory is that older parents may be more aware of developmental abnormalities, and therefore more likely to seek treatment and have their child diagnosed with disorders such as autism.

Firstborn children are also more prone to suffer from other childhood disorders, including type I diabetes. One possible explanation is the so-called "hygiene hypothesis", which suggests that firstborns are exposed to fewer infections from other children early in childhood and as a result are more likely to develop autoimmune diseases.

Advanced Parental Age and the Risk of Autism Spectrum Disorder.

Am J Epidemiol. 2008 Oct 21. [Epub ahead of print]
Advanced Parental Age and the Risk of Autism Spectrum Disorder.Durkin MS, Maenner MJ, Newschaffer CJ, Lee LC, Cunniff CM, Daniels JL, Kirby RS, Leavitt L, Miller L, Zahorodny W, Schieve LA.
This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort included 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent's age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age >/=35 vs. 25-29 years = 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age >/=40 years vs. 25-29 years = 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20-34 years and fathers aged <40 years (odds ratio = 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology.

The report said there was significant DNA damage to sperm in samples from men over the age of 35.

Men have their own biological clock
Published by Times of the Internet at 3:34 am under Top News

SYDNEY, Oct. 22 (UPI) —


An Australian study suggests men have a biological clock that signals a drop in fertility after the age of 35.



Researchers at Sydney IVF said sperm and DNA samples from more than 3,000 men shows DNA fragmentation of sperm increased with age, the Australian Broadcasting Corp. reported Wednesday.



The report said there was significant DNA damage to sperm in samples from men over the age of 35.



They cannot take fertility absolutely for granted, there is also an impact of male age on fertility, Mark Bowman of Sydney IVF said.



Copyright 2008 by United Press International
All Rights Reserved.

The results indicate that advanced paternal age at conception has negative long-term effects on reproductive fitness and longevity of offspring

Biol Reprod. 2008 Oct 15. [Epub ahead of print]
Links
Delayed Fatherhood in Mice Decreases Reproductive Fitness and Longevity of Offspring.
García-Palomares S, Navarro S, Pertusa JF, Hermenegildo C, García-Pérez MA, Rausell F, Cano A, Tarín JJ.
This study aims to analyze, in mice, the long-term effects of delayed fatherhood on reproductive fitness and longevity of offspring. Hybrid parental-generation (F0) males, at the age of 12, 70, 100, and 120 weeks, were individually housed with a randomly-selected 12 week-old hybrid female. The reproductive fitness of first-generation (F1) females was tested from the age of 25 weeks until the end of their reproductive life. In F1 males, the testing period ranged from the age of 52 weeks until death. Breeding F1 females from the 120-week group displayed interbirth intervals longer than females from the 12-, 70- and 100-week groups. Furthermore, F2 pups begotten by F1 studs exhibited weaning weights lower than pups from the 12- and 70-week groups. Offspring from the 120-week group exhibited shorter survival times associated with lower incidence of tumorigenesis and higher loss of body weight when approaching death when compared to F1 offspring from younger age groups. The results indicate that advanced paternal age at conception has negative long-term effects on reproductive fitness and longevity of offspring in the mouse model.
PMID: 18923156 [PubMed - as supplied by publisher]

Long-term effects of delayed fatherhood in mice on postnatal development and behavioral traits of offspring1

Long-term effects of delayed fatherhood in mice on postnatal
development and behavioral traits of offspring1
Short title: Long-term effects of paternal age on offspring
Summary sentence: Delayed fatherhood has long-term effects on preweaning development,
spontaneous motor activity and passive-avoidance learning capacity of offspring in the mouse
model
Key words: delayed fatherhood long-term effects offspring
Silvia García-Palomares3, José F. Pertusa3, José Miñarro4, Miguel A. García-Pérez5,6,
Carlos Hermenegildo5,7, Francisco Rausell3, Antonio Cano8 and Juan J. Tarín2,3
1Supported by grant BFI2003-04761 from “Ministerio de Ciencia y Tecnología”, cofinanced by
the “Fondo Europeo de Desarrollo Regional (FEDER); grant ISCIII2006-PI0405 from “Instituto
de Salud Carlos III, Fondo de Investigación Sanitaria, Ministerio de Sanidad y Consumo”,
cofinanced by the FEDER; and grants GV2004-B-206 and AE/2007/001 from “Generalitat
Valenciana, Conselleria d’Émpresa, Universitat i Ciencia”.
2Correspondence: Juan J. Tarín, Department of Functional Biology and Physical Anthropology,
Faculty of Biological Sciences, University of Valencia, Dr. Moliner 50, 46100 Burjassot,
Valencia, Spain; Tel. 34-96-354 3221; E-mail: tarinjj@uv.es
3Department of Functional Biology and Physical Anthropology, Faculty of Biological Sciences,
University of Valencia, Burjassot, 46100 Valencia, Spain
BOR Papers in Press. Published on October 15, 2008 as DOI:10.1095/biolreprod.108.072066
Copyright 2008 by The Society for the Study of Reproduction.
García-Palomares et al.
2
2
4Department of Psychobiology, Faculty of Psychology, University of Valencia, 46071 Valencia,
Spain
5Research Unit, Hospital Clínico de Valencia, 46010 Valencia, Spain
6Department of Genetics, University of Valencia, 46100 Valencia, Spain
7Department of Physiology, University of Valencia, 46010 Valencia, Spain
8Department of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of
Valencia, 46010 Valencia, Spain
García-Palomares et al.
3
3
ABSTRACT
This study aims to analyze, in mice, the long-term effects of delayed fatherhood on
postnatal development, spontaneous motor activity and learning 5 capacity of offspring. Hybrid
parental-generation (F0) males, at the age of 12, 70, 100 and 120 weeks, were individually housed
with a randomly-selected 12 week-old hybrid female. The resulting first-generation (F1)
offspring were tested for several developmental and behavioral variables. Cumulative percentage
of F1 pups that attained immediate righting in the 120-week group was lower than that found in
10 the 12-, 70- and 100-week groups. Furthermore, the postnatal day of attaining immediate
righting was higher in pups from the 120-week group when compared to pups from the other age
groups. At the age of 20 weeks, F1 offspring from the 120-week group displayed lower counts of
motor activity than offspring from the 12-, 70- and 100-week groups. One week later, a higher
percentage of offspring from the 100- and 120- groups entered the dark compartment during the
15 retention trial of the passive avoidance test when compared to offspring from the 12-week group.
Offspring from the 120-week group exhibited also lower step-through latency in the retention
trial than offspring from the 12-, 70- and 100-week groups. These results show that advanced
paternal age at conception has long-term effects on preweaning development, spontaneous motor
activity and reduced passive-avoidance learning capacity of mouse offspring.
20
García-Palomares et al.
4
4
INTRODUCTION
The present trend of couples from most Western countries to pursue educational and
professional goals before conceiving is increasingly forcing them 25 to postpone parenthood until
the mid-thirties or even beyond [1], i.e. the latter part of a woman’s childbearing years.
Furthermore, the wish of parenthood in a new partnership is increasing due to the changing
patterns of marriage and divorce that are taking place in the Western society. Although male
reproductive functions do not cease at middle age such as it occurs in women, it is known that
30 men > 40 years contribute to reduced fertility and fecundity of a couple [2]. In addition, delayed
fatherhood is associated with increased risks of conceiving a child suffering from dominant or Xlinked
recessive diseases, non-cytogenetic congenital defects, athetoid/dystonic cerebral palsy,
cogenital hemiplegia, multiple sclerosis [3], schizophrenia [4-5], autism [6], epilepsy [7],
decreased learning capacity [8] and/or mental retardation of unknown etiology [2, 9-12].
35 Advanced paternal age has been also related with increased risks of spontaneous abortion [13-
14], fetal loss [13-15], preeclampsia [16], stillbirth [17], neonatal mortality [15] and childhood
cancers [10, 14, 18-19]. In contrast, there is no clear evidence for the existence of a negative
paternal effect on preterm delivery and incidence of low birth weight [2, 14].
The purpose of the present study is to analyze, in the mouse, the long-term effects of
40 delayed fatherhood on postnatal development and behavioral traits of offspring including
spontaneous motor activity and learning capacity using a passive avoidance behavior test.
García-Palomares et al.
5
5
MATERIALS AND METHODS
Mouse strain, housing and pairings of parental generation (F0) males
All the animal experiments performed in this study 45 were conducted in accordance with
the National Research Council’s (NRC) publication Guide for the Care and Use of Laboratory
Animals [20]. On postnatal day 21 (at weaning), 4 cohorts of 20, 20, 44 and 70 hybrid
(C57BL/6JIco female X CBA/JIco male) virgin F0 males (Criffa, Barcelona, Spain) were
randomly selected for the study. These mice were housed in groups of 10 in 35.5 x 23.5 x 18.5
50 cm plastic cages, fed a standard laboratory diet and tap water ad libitum and maintained on a
14L:10D photoperiod (lights-on at 0800 h) in a temperature-controlled room at 21 to 23ºC until
the age of 12, 70, 100 or 120 weeks. At this time, those males that were still alive (20, 20, 30 and
8, respectively) were individually housed in 26.5 x 20.5 x 13.5 cm plastic cages with a randomlyselected
12-week-old hybrid F0 female to produce a single litter of first-generation (F1) mice.
55
Birth and housing of F1 offspring
From day 10 after adding the F0 female to the cage, females were examined once a day for
physical evidence of pregnancy, i.e. the presence of a distended abdomen. When the researcher
(SGP) was assured a female was pregnant (20, 20, 20 and 5 females in the 12-, 70-, 100- and 120-
60 week group, respectively), the male was removed and the female allowed to give birth and breastfeed
her pups until weaning. Within the first 24 h after parturition, litter size and gender of F1
pups were recorded. Pups were sexed by means of the ano-genital distance, which is longer in
males; this was confirmed in later examinations during preweaning development. Pups were
weighed within the first 24 h after parturition, on postnatal days 3, 10 and 21 (at weaning) and
65 just before the onset of the developmental and behavior tests applied (see below). Each animal
was marked by labeling its skin with a silver nitrate-diamant fuchsin stain and water-proof feltGarcía-
Palomares et al.
6
6
tipped pen before weaning and by ear punching/cutting after weaning. At weaning, male and
female F1 offspring were separated and housed in groups of 10 in 35.5 x 23.5 x 18.5 cm plastic
cages with wood shavings as bedding. Bedding was changed weekly. Offspring were fed the
same diet and housed under the same light:dark cycle and temperature 70 conditions as their parents.
Righting reflex of F1 offspring
The righting reflex test was performed on postnatal days 3 to 10 between 0900 and 1030 h
in all F1 pups. The righting response was defined as the time it took a pup that had been placed
75 on its back to turn over to restore their normal prone position. An upper limit of 180 sec was set
for this test. This test of sensorimotor integration was performed daily until pups righted
themselves immediately (although mice took < 1 sec to right themselves, righting latencies in
these cases were recorded as zero) when placed on the supine position [21].
80 Spontaneous motor activity of F1 offspring
At the age of 20 weeks (just 1 week before performing the passive avoidance behavior
test), the spontaneous motor activity of F1 offspring was measured in a computer-controlled
actimetre (Actisystem II, Panlab S.L., Barcelona, Spain). The actimetre consisted of four 35 x 35
cm sensory plates, which registered any activity of the animals through an electromagnetic
85 system, an interface, and a computer that allowed the acquisition and storage of data from the
sensory plates. Mice underwent a single motor-activity session between 0700 and 0900 h. In
each session, any motility of animals, resulting or not in a displacement was registered at
intervals of 5 min during a period of 60 min. After each session, the actimetre was cleaned with
water and the number of defecations scored as a measure of emotionality [21].
90
García-Palomares et al.
7
7
Passive avoidance behavior of F1 offspring
At the age of 21 weeks, F1 offspring were tested for passive avoidance behavior as
previously described [21]. This test was chosen because it fits the learning abilities of F1
offspring better than other tests such as the spatial-learning Morris water maze and the simplediscrimination-
learning Y-maze [21]. The experimental apparatus used 95 was a two-section box in
which the walls of one section were black and those of the other section white and illuminated
with a lamp (60 W). The two sections were separated by an automatic door. In the acquisition
trial, each mouse was placed in the illuminated compartment, facing the dark section with the
door closed. After 60 sec the door automatically opened and the time for a mouse to enter the
100 dark compartment was registered. As soon as the mouse entered the dark compartment, the door
automatically closed and an electrical foot-shock (0.3 mA) was delivered during a period of 5
sec. Immediately after this shock, the animal was returned to its home cage. In the retention
trial, which was performed exactly 24 h after the acquisition trial (between 0700 and 0900 h), the
mouse was again placed in the illuminated compartment, but no electrical shock was
105 administered if it entered the dark section. In both the acquisition and the retention trial, the time
to enter the dark compartment was recorded as step-through latency. The maximum step-through
latency allowed when the mouse did not enter the dark compartment in the retention trial was 300
sec.
110 Statistical analysis
Fixed-effects (models with only fixed effects, covariate and the residual term) designs of
ANOVA, mixed-effects (some effects are random and some are fixed) nested designs of
ANOVA, and repeated measures nested designs of ANOVA with two-way interactions between
variables were applied for comparisons of means. Nested designs were applied to control the
García-Palomares et al.
8
8
potential correlation among observations within a particular litter 115 (littermates) and avoid spurious
inflation of the sample size [22]. Several covariates were introduced in the statistical analyses to
control for possible confounders not included in the study design, e.g. day 3-10 body weight
(mean body weight of measures taken on postnatal days 3 and 10) and time at which mice
underwent the spontaneous motor activity session or the passive avoidance behavior test.
120 Kolmogorov-Smirnov one-sample test was used to check whether variables were normally
distributed. If the normality assumption was violated, logarithmic or square root (if variables
were metric), or arcsine square root (if data were percentages) transformation of the variable was
applied to induce normality. Bonferroni test (when the variances were assumed to be equal) or
Dunnett’s T3 test (when the variances were assumed to be unequal) were applied to perform post
125 hoc pairwise multiple comparisons between groups. Levene test was used to test the
homogeneity of variance for each dependent variable across all level combinations of the
between-subjects factors. Automated binomial logistic regression analysis with forward stepwise
variable selection was used to ascertain the effect of paternal

Advanced Parental Age at Birth Is Associated With Poorer Social Functioning in Adolescent Males

© 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.


Advanced Parental Age at Birth Is Associated With Poorer Social Functioning in Adolescent Males: Shedding Light on a Core Symptom of Schizophrenia and Autism
Mark Weiser14, Abraham Reichenberg5, Nomi Werbeloff2, Karine Kleinhaus6, Gad Lubin3, Moti Shmushkevitch3, Asaf Caspi2,4, Dolores Malaspina7 and Michael Davidson2,4
2 Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel
3 IDF, Division of Mental Health, Israel
4 Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel
5 Institute of Psychiatry, London, UK
6 Department of Psychiatry, Colombia University, NY
7 Department of Psychiatry, New York University, NY

1 To whom correspondence should be addressed; tel: +972-52-666-6575, fax: +972-3-6358599, e-mail: mweiser@netvision.net.il.

Background: Evidence indicates an association between older parents at birth and increased risk for schizophrenia and autism. Patients with schizophrenia and autism and their first-degree relatives have impaired social functioning; hence, impaired social functioning is probably an intermediate phenotype of the illness. This study tested the hypothesis that advanced father's age at birth would be associated with poorer social functioning in the general population. To test this hypothesis, we examined the association between parental age at birth and the social functioning of their adolescent male offspring in a population-based study. Methods: Subjects were 403 486, 16- to 17-year-old Israeli-born male adolescents assessed by the Israeli Draft Board. The effect of parental age on social functioning was assessed in analyses controlling for cognitive functioning, the other parent's age, parental socioeconomic status, birth order, and year of draft board assessment. Results: Compared with offspring of parents aged 25–29 years, the prevalence of poor social functioning was increased both in offspring of fathers younger than 20 years (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.08–1.49) and in offspring of fathers 45 years old (OR = 1.52, 95% CI = 1.43–1.61). Male adolescent children of mothers aged 40 years and above were 1.15 (95% CI = 1.07–1.24) times more likely to have poor social functioning. Conclusions: These modest associations between parental age and poor social functioning in the general population parallel the associations between parental age and risk for schizophrenia and autism and suggest that the risk pathways between advanced parental age and schizophrenia and autism might, at least partially, include mildly deleterious effects on social functioning.


Keywords: schizophrenia / social functioning / parental age


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Overlap Found Between Autism, Schizophrenia-Spectrum Disorders

Psychiatr News October 3, 2008
Volume 43, Number 19, page 20
© 2008 American Psychiatric Association



Articles by Arehart-Treichel, J.




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

Clinical & Research News


Overlap Found Between Autism, Schizophrenia-Spectrum Disorders
Joan Arehart-Treichel
Some patients may have traits of both autism and schizophrenia because the autism-spectrum and schizophrenia-spectrum disorders share some of the same susceptibility genes.

Although autism and schizophrenia are now generally recognized as two separate illnesses, there is reason to believe that autistic traits and schizophrenia traits co-occur in some individuals.

For instance, some children with autism disorder have been found to develop schizophrenia later in life, the negative symptoms of schizophrenia have been found to co-vary with autistic traits in certain schizophrenia subjects, and a link between autistic traits and schizophrenia traits was found in a sample of college students.

Now certain individuals with schizotypal personality disorder—considered the mildest schizophrenia-spectrum illness—have been found to possess an unusual preponderance of autistic traits. The results of the study, which was led by Michelle Esterberg, M.P.H., of Emory University, were published in the September Schizophrenia Research.

The study included 121 adolescent subjects—35 with schizotypal personality disorder; 38 with other types of personality disorders (antisocial, avoidant, borderline, narcissistic, obsessive-compulsive, paranoid, or schizoid); and 48 with no personality disorders. The subjects were evaluated for various autistic characteristics, and the results for each group were then compared.

The schizotypal group scored significantly higher than the other two groups on a number of autistic traits. They included being socially anxious, having no close friends, using a limited number of facial expressions, not showing affection, being unaware of social cues, having circumscribed or unusual interests, and being resistant to change. Furthermore, the schizotypal group scored especially high on deficits in the social-functioning domain.

"The present findings indicate significant ... overlap between autism-spectrum and schizophrenia-spectrum disorders," Esterberg and her colleagues concluded.

Why might autistic traits and schizophrenia traits coexist in certain persons? Esterberg and her group suspect that it is because the autism-spectrum disorders and the schizophrenia-spectrum disorders share some of the same susceptibility genes or because some of the susceptibility genes contributing to each spectrum are occasionally inherited together.

For instance, individuals who lack genes on a particular stretch of chromosome 22—called the 22q11 chromosomal deletion—are known to be at heightened risk for both the autistic-spectrum and schizophrenia-spectrum disorders, they pointed out, suggesting that some genes located in this stretch are complicit in both disorders (Psychiatric News, September 19).

But one point they are quite sure about, as are many other investigators, is that autism and schizophrenia are not identical illnesses. One reason is because 10 of their schizotypal subjects, as well as two other subjects from the "other personality disorder" category, developed schizophrenia during a three-year follow-up period. Yet the researchers could find no link between having autistic traits and subsequently developing schizophrenia.

The study was funded by the National Institute of Mental Health.

An abstract of "Childhood and Current Autistic Features in Adolescents With Schizotypal Personality Disorder" can be accessed at by clicking on "Browse A-Z," "S," and then "Schizophrenia Research."