Paternal age autism and other neurodevelopmental disorders due to older fathers can be prevented with education

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.
Labels: Herbert Meltzer Vanderbuilt University

AN EXCELLENT ARTICLE - EVERYONE WHO CARES ABOUT AUTISM SHOULD READ IT THOROUGHLY

February, 2009 in Biology | 0 comments | Post a comment

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



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.

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.


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.

February, 2009 in Biology | 0 comments | Post a comment

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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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.

January 26, 2009 Low Oxygen = Cancer or Autism

January 26, 2009
Low Oxygen = Cancer or Autism?
By Kent Heckenlively, Esq.

In 1931 the Nobel Prize was awarded to German scientist Otto Warburg for his theory that cancer started from injury to the mitochondria, the cell’s energy power plant, creating a low oxygen environment in the cell.

http://www.typepad.com/services/trackback/6a00d8357f3f2969e2010536e32cc9970b

Paternal Ages Above and below 35 are associated with a different risk of schizophrenia

Paternal Age Above 35

Paternal Ages Above and below 35 are associated with a different risk of schizophrenia
concerned heart View Delete
1: Eur Psychiatry. 2006 Dec 1; [Epub ahead of print] Links
Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl M, Gorwood P.
INSERM U675, 16 rue Henri Huchard 75018 Paris, France; AP-HP (Paris VII), C.H.U Louis Mourier, Service de psychiatrie du Professeur Ades, 178 rue des Renouillers, 92701 Colombes Cedex, France.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win((R))) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.
Labels: older age of fatherhood, paternal age 35, Philip Gorwood, public health, schizophrenia

When Will Young People Planning Their Lives Learn that The Best Years to Father Babies are between 25-30

The scientists in all fields agree that there is a genetic male biological clock for the health of the child. For over 50 years there have been research papers and studies showing the urgency of acknowledging this biological reality. When will this become common knowledge? When will people change their behavior and the rates of autism and schizophrenia, and bipolar come down? There are many other mysterious disorders such as type 1 diabetes, MS, and cancers caused by older paternal age at conception. For the studies read the blog thoroughly.

MS Type 1 Diabetes, Prostate Cancer, Breast Cancer, Autism, Schizophrenia, Bipolar etc. all increase with advancing paternal age

Request the word file by leaving your e mail address in the comments sections and find out what you risk for your child by late parenthood.

Men also have a biological clock

Health NewsView archive | RSS Feed Men also have a biological clock
Published: Jan. 21, 2009 at 4:04 PM
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.

The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome.

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.

Autism and Schizophrenia and As Fathers Age on a Populations level

Schizophrenia Risk and the Paternal Germ Line
By Dolores Malaspina


Dolores Malaspina
Paternal age at conception is a robust risk factor for schizophrenia. Possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The predisposing genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the

fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.

Seminal findings
We initially examined the relationship between paternal age and the risk for schizophrenia because it is well established that paternal age is the major source of de novo mutations in the human population, and most schizophrenia cases have no family history of psychosis. In 2001, we demonstrated a monotonic increase in the risk of schizophrenia as paternal age advanced in the rich database of the Jerusalem Perinatal Cohort. Compared with the offspring of fathers aged 20-24 years, in well-controlled analyses, each decade of paternal age multiplied the risk for schizophrenia by 1.4 (95 percent confidence interval: 1.2-1.7), so that the relative risk (RR) for offspring of fathers aged 45+ was 3.0 (1.6-5.5), with 1/46 of these offspring developing schizophrenia. There were no comparable maternal age effects (Malaspina et al., 2001).

Epidemiological evidence
This finding has now been replicated in numerous cohorts from diverse populations (Sipos et al., 2004; El-Saadi et al., 2004; Zammit et al., 2003; Byrne et al., 2003; Dalman and Allenbeck, 2002; Brown et al., 2002; Tsuchiya et al., 2005). By and large, each study shows a tripling of the risk for schizophrenia for the offspring of the oldest group of fathers, in comparison to the risk in a reference group of younger fathers. There is also a "dosage effect" of increasing paternal age; risk is roughly doubled for the offspring of men in their forties and is tripled for paternal age >50 years. These studies are methodologically sound, and most of them have employed prospective exposure data and validated psychiatric diagnoses. Together they demonstrate that the paternal age effect is not explained by other factors, including family history, maternal age, parental education and social ability, family social integration, social class, birth order, birth weight, and birth complications. Furthermore, the paternal age effect is specific for schizophrenia versus other adult onset psychiatric disorders. This is not the case for any other known schizophrenia risk factor, including many of the putative susceptibility genes (Craddock et al., 2006).

There have been no failures to replicate the paternal age effect, nor its approximate magnitude, in any adequately powered study. The data support the hypothesis that paternal age increases schizophrenia risk through a de novo genetic mechanism. The remarkable uniformity of the results across different cultures lends further coherence to the conclusion that this robust relationship is likely to reflect an innate human biological phenomenon that progresses over aging in the male germ line, which is independent of regional environmental, infectious, or other routes.

Indeed, the consistency of these data is unparalleled in schizophrenia research, with the exception of the increase in risk to the relatives of schizophrenia probands (i.e., 10 percent for a sibling). Yet, while having an affected first-degree relative confers a relatively higher risk for illness than having a father >50 years (~10 percent versus ~2 percent), paternal age explains a far greater portion of the population attributable risk for schizophrenia. This is because a family history is infrequent among schizophrenia cases, whereas paternal age explained 26.6 percent of the schizophrenia cases in our Jerusalem cohort. If we had only considered the risk in the cases with paternal age >30 years, our risk would be equivalent to that reported by Sipos et al. (2004) in the Swedish study (15.5 percent). When paternal ages >25 years are considered, the calculated risk is much higher. Although the increment in risk for fathers age 26 through 30 years is small (~14 percent), this group is very large, which accounts for the magnitude of their contribution to the overall risk. The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent.

Biological plausibility
We used several approaches to examine the biological plausibility of paternal age as a risk factor for schizophrenia. First, we established a translational animal model using inbred mice. Previously it had been reported that the offspring of aged male rodents had less spontaneous activity and worse learning capacity than those of mature rodents, despite having no noticeable physical anomalies (Auroux et al., 1983). Our model carefully compared behavioral performance between the progeny of 18-24-month-old sires with that of 4-month-old sires. We replicated Auroux's findings, demonstrating significantly decreased learning in an active avoidance test, less exploration in the open field, and a number of other behavioral decrements in the offspring of older sires (Bradley-Moore et al., 2002).

Next, we examined if parental age was related to intelligence in healthy adolescents. We reasoned that if de novo genetic changes can cause schizophrenia, there might be effects of later paternal age on cognitive function, since cognitive problems are intertwined with core aspects of schizophrenia. For this study, we cross-linked data from the Jerusalem birth cohort with the neuropsychological data from the Israeli draft board (Malaspina et al., 2005a). We found that maternal and paternal age had independent effects on IQ scores, each accounting for ~2 percent of the total variance. Older paternal age was exclusively associated with a decrement in nonverbal (performance) intelligence IQ, without effects on verbal ability, suggestive of a specific effect on cognitive processing. In controlled analyses, maternal age showed an inverted U-shaped association with both verbal and performance IQ, suggestive of a generalized effect.

Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age.

A variant of schizophrenia
A persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980).

It is possible that the genetic events that occur in the paternal germ line are affecting the same genes that influence the risk in familial cases. However, there is evidence that this is not the case. First, a number of the loci linked to familial schizophrenia are also associated with bipolar disorder (Craddock et al., 2006), whereas advancing paternal age is specific for schizophrenia (Malaspina et al., 2001). Next, a few genetic studies that separately examined familial and sporadic cases found that the "at-risk haplotypes" linked to familial schizophrenia were unassociated with sporadic cases, including dystrobrevin-binding protein (Van Den Bogaert et al., 2003) and neuregulin (Williams et al., 2003). Segregating sporadic cases from the analyses actually strengthened the magnitude of the genetic association in the familial cases, consistent with etiological heterogeneity between familial and sporadic groups.

Finally, the phenotype of cases with no family history and later paternal age are distinct from familial cases in many studies. For example, only sporadic cases showed a significant improvement in negative symptoms between a "medication-free" and an "antipsychotic treatment" condition (Malaspina et al., 2000), and sporadic cases have significantly more disruptions in their smooth pursuit eye movement quality than familial cases (Malaspina et al., 1998). A recent study also showed differences between the groups in resting regional cerebral blood flow (rCBF) patterns, in comparison with healthy subjects. The sporadic group of cases had greater hypofrontality, with increased medial temporal lobe activity (frontotemporal imbalance), while the familial group evidenced left lateralized temperoparietal hypoperfusion along with widespread rCBF changes in cortico-striato-thalamo-cortical regions (Malaspina et al., 2005b). Other data linking paternal age with frontal pathology in schizophrenia include a proton magnetic resonance spectroscopy study that demonstrated a significant association between prefrontal cortex neuronal integrity (NAA) and paternal age in sporadic cases only, with no significant NAA decrement in the familial schizophrenia group (Kegeles et al., 2005). These findings support the hypothesis that schizophrenia subgroups may have distinct neural underpinnings and that the important changes in some sporadic (paternal germ line) cases may particularly impact on prefrontal cortical functioning.

Genetic mechanism
Several genetic mechanisms might explain the relationship between paternal age and the risk for schizophrenia (see Malaspina, 2001). It could be due to de novo point mutations arising in one or several schizophrenia susceptibility loci. Paternal age is known to be the principal source of new mutations in mammals, likely explained by the constant cell replication cycles that occur in spermatogenesis (James Crow, 2000). Following puberty, spermatogonia undergo some 23 divisions per year. At ages 20 and 40, a man's germ cell precursors will have undergone about 200 and 660 such divisions, respectively. During a man's life, the spermatogonia are vulnerable to DNA damage, and mutations may accumulate in clones of spermatogonia as men age. In contrast, the numbers of such divisions in female germ cells is usually 24, all but the last occurring during fetal life.

Trinucleotide repeat expansions could also underlie the paternal age effect. Repeat expansions have been demonstrated in several neuropsychiatric disorders, including myotonic dystrophy, fragile X syndrome, spinocerebellar ataxias, and Huntington disease. The sex of the transmitting parent is frequently a major factor influencing anticipation, with many disorders showing greater trinucleotide repeat expansion with paternal inheritance (Lindblad and Schalling, 1999; Schols et al., 2004; Duyao et al., 1993). Larger numbers of repeat expansions could be related to chance molecular events during the many cell divisions that occur during spermatogenesis.

Later paternal age might confer a risk for schizophrenia if it was associated with errors in the "imprinting" patterns of paternally inherited alleles. Imprinting is a form of gene regulation in which gene expression in the offspring depends on whether the allele was inherited from the male or female parent. Imprinted genes that are only expressed if paternally inherited alleles are reciprocally silenced at the maternal allele, and vice versa. Imprinting occurs during gametogenesis after the methylation patterns from the previous generation are "erased" and new parent of origin specific methylation patterns are established. Errors in erasure or reestablishment of these imprint patterns may lead to defective gene expression profiles in the offspring. The enzymes responsible for methylating DNA are the DNA methyltransferases, or DNMTs. These enzymes methylate cytosine residues in CpG dinucleotides, usually in the promoter region of genes, typically to reduce the expression of the mRNA. The methylation may become inefficient for a variety of reasons; one possibility is reduced DNA methylation activity in spermatogenesis, since DNMT levels diminish as paternal age increases (Benoit and Trasler, 1994; La Salle et al., 2004). Another possible mechanism is that this declining DNMT activity could be epigenetically transmitted to the offspring of older fathers. There are a number of different DNMTs that differ in whether they initiate or sustain methylation, and which are active at different ages and in different tissues.

Human imprinted genes have a critical role in the growth of the placenta, fetus, and central nervous system, in behavioral development, and in adult body size. It is an appealing hypothesis that loss of normal imprinting of genes critical to neurodevelopment may play a role in schizophrenia. Indeed, one of the most consistently identified molecular abnormalities in schizophrenia has been theorized to result from abnormal epigenetic mechanisms (Veldic et al., 2004), that is, the reduced GABA and reelin expression in prefrontal GABAergic interneurons. An overexpression of DNMT in these GABAergic interneurons, hypermethylating the reelin and GAD67 promoter regions, might be responsible for reducing their mRNA transcripts and expression levels. These decrements could functionally impair the role of GABAergic interneurons in regulating the activity and firing of pyramidal neurons, thereby causing cognitive dysfunction. Later paternal age could be related to the abnormal regulation or expression of DNMT activity in specific cells.

Conclusion
These findings suggest exciting new directions for research into the etiology of schizophrenia. If there is a unitary etiopathology for paternal age-related schizophrenia, then it is likely to be the most common form of the condition in the population and in treatment settings, since genetic linkage and association studies indicate that familial cases are likely to demonstrate significant allelic heterogeneity and varying epistatic effects. Schizophrenia is commonly considered to result from the interplay between genetic susceptibility and environmental exposures, particularly those that occur during fetal development and in adolescence. The data linking paternal age to the risk for schizophrenia indicate that we should expand this event horizon to consider the effects of environmental exposures over the lifespan of the father. The mutational stigmata of an exposure may remain in a spermatogonial cell, and be manifest in the clones of spermatozoa that it will subsequently generate over a man's reproductive life.

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Malaspina D. Paternal factors and schizophrenia risk: de novo mutations and imprinting. Schizophr Bull. 2001;27(3):379-93. Review. Abstract

Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, Yale S, Goetz D, Goetz R, Harlap S, Gorman J. Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet. 2002 Apr 8;114(3):299-303. Abstract

Malaspina D, Harkavy-Friedman J, Corcoran C, Mujica-Parodi L, Printz D, Gorman JM, Van Heertum R. Resting neural activity distinguishes subgroups of schizophrenia patients. Biol Psychiatry. 2005 (a) Dec 15;56(12):931-7. Abstract

Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, Wolitzky R, Rabinowitz J, Susser E, Knobler HY. Paternal age and intelligence: implications for age-related genomic changes in male germ cells. Psychiatr Genet. 2005 (b) Jun;15(2):117-25. Abstract

Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap, Rabinowitz J, Shulman L, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E: Advancing paternal age and Autism. Archives of General Psychiatry.

Schols L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004 May;3(5):291-304. Abstract

Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA, Gunnell D. Paternal age and schizophrenia: a population based cohort study. BMJ. 2004 Nov 6;329(7474):1070. Epub 2004 Oct 22. Abstract

Tsuchiya KJ, Takagai S, Kawai M, Matsumoto H, Nakamura K, Minabe Y, Mori N, Takei N. Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophr Res. 2005 Jul 15;76(2-3):337-42. Epub 2005 Apr 21. Abstract

Van Den Bogaert A, Schumacher J, Schulze TG, Otte AC, Ohlraun S, Kovalenko S, Becker T, Freudenberg J, Jonsson EG, Mattila-Evenden M, Sedvall GC, Czerski PM, Kapelski P, Hauser J, Maier W, Rietschel M, Propping P, Nothen MM, Cichon S. The DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history of the disease. Am J Hum Genet. 2003 Dec;73(6):1438-43. Abstract

Veldic M, Caruncho HJ, Liu WS, Davis J, Satta R, Grayson DR, Guidotti A, Costa E. DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):348-53. Abstract

Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S, O'Donovan MC, Owen MJ. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry. 2003 May;8(5):485-7. Abstract

Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, Lewis G. Paternal age and risk for schizophrenia. Br J Psychiatry. 2003 Nov;183:405-8. Abstract

Male biological clock possibly linked to autism, other disorders

Male biological clock possibly linked to autism, other disorders
at：2009-01-19 00:19:20 Click: 4
Nature Medicine 14, 1170 (2008)
doi:10.1038/nm1108-1170a

http://www.coboto.com/index.php/article/sports/2009-01-19/4727.html
Male biological clock possibly linked to autism, other disorders
Charlotte Schubert1

Washington, DC




Time for fatherhood: Aging affects sperm
Over the last few years, epidemiological evidence has suggested that as men age their odds of having a child with autism, schizophrenia or bipolar disorder might increase. The findings—along with more recent genetic data—have led researchers to ask whether the mutations that accumulate in sperm DNA with age might underlie this observed association.

"If this paternal age effect has something to do with mutations, then that opens up all sorts of interesting and sort of scary possibilities," says Jonathan Sebat, a human geneticist at Cold Spring Harbor Laboratory in New York State. He says it is conceivable that the trend of delaying fatherhood might contribute to an increased incidence of mutations in the population that can give rise to neuropsychiatric disorders.

In a study of more than 100,000 people, along with records about their parents' ages, Avi Reichenberg at King's College London and his colleagues found that 33 out of every 10,000 offspring of men 40 years or older had autism spectrum disorder—a 475% increase compared to offspring of men younger than 30, who fathered afflicted children at a rate of 6 per 10,000 (Arch. Gen. Psychiatry 63, 1026–1032; 2006). This association is now being tested in a larger study, says Reichenberg. A study this September showed a similar but less pronounced association of parental age with bipolar disorder (Arch. Gen. Psychiatry 65, 1034–1040; 2008).

Spontaneous mutations can arise in both sperm and eggs. As women age, for example, they have an increased risk of delivering a child with Down's syndrome and other disorders caused by large-scale chromosome problems in eggs, such as trisomy. But unlike eggs, sperm arise from stem cells that continuously divide—about 840 times by the time a man is 50 years old (Cytogenet. Genome Res. 111, 213–228; 2005). The theory is that the chances of mutations increase with each round of DNA replication—a process that could underlie estimates that the mutation rate in males is about five times that in females (Nature 416, 624–626; 2002).

"Any mutation you can think of occurs more frequently in the sperm of older men," says Sebat.

Meanwhile, recent genetic surveys of people with autism and other neuropsychiatric disorders have bolstered this controversial—and still tenuous—hypothesis. The DNA studies have suggested that 'spontaneous' mutations contribute to schizophrenia and autism. This type of mutation can arise in the sperm or egg of the parents.

Sebat and his colleagues, for instance, looked at spontaneous deletions and duplications measuring about 100,000 DNA base pairs and longer—a length that often contain dozens of genes—in the genome of people with of autism spectrum disorders (Science 316, 445–449; 2007). Such spontaneous mutations occurred in only 1% of unaffected people, but they occurred in about 10% of subjects with sporadic forms of the disorder, meaning they had no family history. The researchers' methods only pick up a fraction of mutations, so the effect of sporadic mutations is probably substantially larger, says Sebat.

Similar studies this year have shown that people with nonfamilial forms of schizophrenia also have a higher rate of spontaneous duplications and deletions, and Sebat says his unpublished data show a similar association in bipolar disorder.

But whether the mutations that arise spontaneously in neuropsychiatric disorders come mainly from mom or dad is still unclear, as is their association with parental age. Sebat says larger studies underway should help clarify these questions.

And researchers caution that they have very little idea how the disrupted genes in eggs and sperm might potentially give rise to neuropsychiatric disease. "It is not established, and it can put a class of individuals in a negative light," says Rita Cantor, a human geneticist at the University of California, Los Angeles.

Moreover, other, even more tenuous explanations could underlie the parental age effect—such as the idea that fathers who delay parenthood somehow have genes that affect their social behavior and make their offspring more prone to neuropsychiatric disorders. Says Cantor, "I think it's a delicate subject."

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

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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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Lots of evidence that men have their own biological clock

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Lots of evidence that men have their own biological clock

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

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

Feature Article
Publish date: Jan 15, 2009By: Harry Fisch, MDSource: Geriatrics

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 )
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.

Paternal Age and Risk of Schizophrenia in Adult Offspring

Am J Psychiatry 159:1528-1533, September 2002
© 2002 American Psychiatric Association --------------------------------------------------------------------------------

Article

Paternal Age and Risk of Schizophrenia in Adult Offspring
Alan S. Brown, M.D., Catherine A. Schaefer, Ph.D., Richard J. Wyatt, M.D., Melissa D. Begg, Sc.D., Raymond Goetz, Ph.D., Michaeline A. Bresnahan, Ph.D., Jill Harkavy-Friedman, Ph.D., Jack M. Gorman, M.D., Dolores Malaspina, M.D., and Ezra S. Susser, M.D., Dr.P.H.


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OBJECTIVE: The study examined the relation between paternal age at the time of birth and risk of schizophrenia in the adult offspring. METHOD: Data from the birth cohort of the Prenatal Determinants of Schizophrenia study were used in this study. Virtually all members of this birth cohort had prospective information about paternal age at the time of the offspring’s birth. Subjects with schizophrenia and other schizophrenia spectrum disorders (N=71) among members of this birth cohort were previously ascertained. In separate analyses, paternal age was modeled as a continuous variable and as a categorical variable, and its relation with the risk of adult schizophrenia and other schizophrenia spectrum disorders and with the risk of schizophrenia separately were examined. RESULTS: There was a marginally significant, monotonic association between advancing paternal age and risk of adult schizophrenia and schizophrenia spectrum disorders. The association held after the analysis controlled for the effects of maternal age and other potential confounders. Similar results were observed when only subjects with schizophrenia were included in the analysis. CONCLUSIONS: Advanced paternal age at the time of birth of the offspring may be a risk factor for adult schizophrenia.



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We sought to investigate whether older paternal age at the time of birth is associated with schizophrenia and other schizophrenia spectrum disorders among the offspring. Several lines of evidence support a relation between older paternal age and schizophrenia spectrum disorders. First, most previous studies that examined this relationship have demonstrated positive associations (1–5), although these studies have been criticized for methodologic limitations. Most recently, Malaspina et al. (1), in a large Israeli birth cohort, demonstrated a robust and "dose-related" effect of paternal age on risk of schizophrenia and related disorders, a finding that was unaltered after adjusting for maternal age.

A second reason for examining paternal age in relation to schizophrenia is that older age of the father at the time of birth has been associated with several congenital disorders (6–10). The etiology of these associations is believed to involve new, autosomal dominant mutations in the male germ cell line. If a disruption of fetal development plays a role in the pathogenesis of schizophrenia, then new mutations secondary to advanced paternal age may operate to increase the risk of this disorder by adversely affecting brain development.

In the present investigation, we used data from the birth cohort of the Prenatal Determinants of Schizophrenia study (11) to address the relation of paternal age to schizophrenia. We hypothesized that the risk of schizophrenia would increase with advancing paternal age.

The Prenatal Determinants of Schizophrenia study had several design advantages that permitted us to address significant limitations of previous studies. First, most prior studies relied on exposure data from a variety of sources, some of questionable reliability. In contrast, the Prenatal Determinants of Schizophrenia study offered prospectively acquired data on paternal age from a direct interview, serving to diminish the likelihood of exposure misclassification. Second, most prior studies relied on case series to identify patients for study; the present investigation addressed this limitation by employing a cohort design that included continuous follow-up for ascertainment of cases of schizophrenia. These first two features help to minimize selection bias, as well as biases arising from the use of prevalent rather than incident cases of schizophrenia spectrum disorders. Third, previous investigations generally relied on chart diagnoses of schizophrenia spectrum disorders by older and less reliable diagnostic systems, or on hospital registry data; in our study, most cases were identified by means of face-to-face standardized research interviews and consensus procedures that used modern diagnostic criteria. Fourth, most prior studies did not control for maternal age, and nearly all failed to adjust for other confounders; the comprehensive data set of our study permitted us to control for these factors. Finally, unlike previous studies, our study assessed and confirmed biological paternity of the offspring in the majority of subjects.



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Subjects
The subjects for the present investigation consisted of the birth cohort of the Prenatal Determinants of Schizophrenia study. The design of this study has been described in full by Susser et al. (11) and will therefore be only briefly summarized here. The Prenatal Determinants of Schizophrenia study is a continuous follow-up of schizophrenia in the Child Health and Development Study cohort. The Child Health and Development Study recruited nearly all pregnant women in Alameda County, California, who received prenatal care from the Kaiser Foundation Health Plan, a large prepaid health care plan. The 19,044 live births to these women from 1959–1967 constituted the Child Health and Development Study cohort. The members of the Kaiser Foundation Health Plan were racially, educationally, and occupationally diverse, although there was some underrepresentation of the extremes of income (12).

Kaiser Foundation Health Plan maintained records of all psychiatric and medical care received by members; beginning in 1981, the records were computerized. These records were used to ascertain potential cases of schizophrenia spectrum disorders. Accordingly, the Prenatal Determinants of Schizophrenia study cohort consists of the subsample of 12,094 subjects who were born into the Child Health and Development Study cohort and were members of the Kaiser Foundation Health Plan from January 1, 1981, through the last date for case ascertainment in the Prenatal Determinants of Schizophrenia study, which was December 31, 1997. The youngest cohort members were aged 14 to 30 years, and the oldest cohort members were aged 22 to 38 years during this period. The median follow-up time among comparison subjects was 30 years.

Data Collection
At the time of the enrollment of pregnancies in the Child Health and Development Study, each mother was administered an interview that included questions on parental birth dates. Data on parental age were recorded only for gravidas that were married, which included virtually the entire sample. Parental ages on the birth dates of their offspring were calculated in years.

Ascertainment and Diagnosis
Ascertainment
The protocol for ascertainment and diagnosis of cases of schizophrenia spectrum disorders is fully described elsewhere (11). Briefly, schizophrenia spectrum disorders included the following disorders: schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorder not otherwise specified, and schizotypal personality disorder (13, 14). Ascertainment and diagnosis were accomplished by a three-step procedure. First, all individuals in the cohort treated for psychiatric disorders during Kaiser Foundation Health Plan membership were ascertained by means of the Kaiser Foundation Health Plan computerized inpatient and outpatient registries and a registry of outpatient pharmacy use. The inpatient registry, which began in 1981, included all psychiatric hospitalizations of Kaiser Foundation Health Plan members. The outpatient registry was also introduced in 1981 and included all outpatient contacts for psychiatric care. Supplementary data were provided by the Kaiser Foundation Health Plan outpatient pharmacy registry in order to ascertain cohort members prescribed antipsychotic medications; this registry commenced in 1992.

Second, subjects ascertained by these case registries were screened to identify potential cases of schizophrenia spectrum disorders. Subjects ascertained by means if the inpatient registry were initially screened by using ICD-9 diagnoses 295–299, followed by a review of medical and psychiatric records of all subjects with these diagnoses by two experienced psychiatric diagnosticians. For subjects in the outpatient registry, any subject with an ICD-9 diagnosis of 295–299 was considered to potentially have a schizophrenia spectrum disorder. In addition, all individuals prescribed antipsychotics were considered to potentially have a schizophrenia spectrum disorder. All of the subjects who potentially had these disorders (N=183) were targeted for a face-to-face diagnostic assessment. Among these, 13 were deceased by the time of data collection.

Contact for interview
The remaining 170 potential subjects with schizophrenia spectrum disorders were contacted for a diagnostic interview by using addresses and telephone numbers in Kaiser Foundation Health Plan files or other sources of data, including telephone directories and department of motor vehicle records. Among the 170, 146 (86%) were contacted.

Diagnosis
Potential subjects with schizophrenia spectrum disorder were administered the Diagnostic Interview for Genetic Studies (15). All subjects provided written, informed consent before administration of the Diagnostic Interview for Genetic Studies. This instrument was administered by a clinician with a minimum of a master’s degree in a mental health-related field, trained to reliability. All psychiatric diagnoses were made with DSM-IV criteria by consensus of three psychiatrists on the basis of a review of the written Diagnostic Interview for Genetic Studies narrative, the medical records, and a discussion with the interviewer. Of the 146 contacted subjects, 107 (73%) completed the Diagnostic Interview for Genetic Studies. The 76 potential subjects with schizophrenia spectrum disorders who could not be interviewed were diagnosed by means of a chart review conducted by experienced psychiatric/psychologic clinicians fully trained in chart review diagnosis.

These procedures yielded a total of 71 subjects with schizophrenia spectrum disorders (for 44 subjects, the diagnosis was determined after the Diagnostic Interview for Genetic Studies; for 27 subjects, the diagnosis was made by chart review). The diagnostic breakdown was: 43 with schizophrenia, 17 with schizoaffective disorder, one with delusional disorder, five with schizotypal personality disorder, and five with other schizophrenia spectrum psychoses (subjects for whom a specific schizophrenia spectrum psychosis diagnosis could not be made).

Data Analysis
The analytic sample
The sample comprised 12,094 subjects who were Kaiser Foundation Health Plan members after December 31, 1980. Seventy-one subjects were ascertained to have a schizophrenia spectrum disorder, and 12,023 subjects were not so ascertained. Because many of the study analyses required data obtained from maternal interviews, those without maternal interview data were excluded, leaving 9,682 subjects. Since siblings represent nonindependent observations, only one sibling per family was included in the analyses. Toward this end, all siblings of subjects with schizophrenia spectrum disorders who did not themselves have a schizophrenia spectrum disorder were excluded from the analyses, and one sibling per family was selected at random from sets of siblings in which the proband did not have a schizophrenia spectrum disorder. Finally, the original group of 71 subjects with schizophrenia spectrum disorders included one set of two siblings from the same family. One of these siblings was excluded from the analytic sample. After these exclusions were applied, a total of 7,793 subjects—70 subjects with and 7,723 subjects without schizophrenia spectrum disorders—remained. For paternal age, data were missing for two subjects with and 82 subjects without schizophrenia spectrum disorders, leaving 68 subjects with and 7,641 subjects without schizophrenia spectrum disorders for the analysis.

Analytic strategy
To examine the association of paternal age at the time of birth and subsequent risk of schizophrenia spectrum disorders or schizophrenia, proportional hazards regression—a type of survival analysis—was used. This method accounts for varying duration of follow-up among subjects and permits adjustment for potential confounding variables. Essentially, proportional hazards regression models the relationship between an exposure and an outcome, where outcome is defined as the time from a well-defined starting point until the occurrence of the outcome of interest, or until the end of observation for subjects without the outcome. In this study, proportional hazards analysis was used to model the relationship between paternal age at the offspring’s birth and the occurrence of schizophrenia spectrum disorders in the offspring. The primary outcome was schizophrenia spectrum disorders; a second set of analyses was performed by using data from the subset of subjects with schizophrenia only. To calculate survival time for either outcome, date of birth was considered the starting point for follow-up. Actual age at onset of disorder was not available for many of the subjects. Age at first treatment or hospitalization for schizophrenia spectrum disorders was substituted for age at onset, since this was reliably ascertained for all subjects with a disorder. Subjects without a diagnosis of schizophrenia spectrum disorders were censored as of their last day of membership in the Kaiser Foundation Health Plan or at the end of study follow-up (Dec. 31, 1997).

The primary exposure variable was paternal age at the time of the offspring’s birth. We examined paternal age first as a continuous measure and then as a categorical measure (to allow for a general, nonlinear effect of paternal age on the logarithm of the rate of schizophrenia spectrum disorders). For the categorical analyses, paternal age was divided into four age categories: 15–24 years (considered to be the referent category), 25–34 years, 35–44 years, and 45 years. This scheme afforded natural groupings by decade of age, with the oldest category coinciding with the age for a marked increase in the rate of de novo mutations (16).

Covariates
Because the correlation between paternal age and maternal age is high, and maternal age has been associated with schizophrenia spectrum disorders in previous work (3, 5), a primary objective was to rule out confounding by maternal age of the relationship between schizophrenia spectrum disorder risk and paternal age. Like paternal age, maternal age was defined first as a continuous measure, then as a categorical measure. We categorized maternal age into two categories (<30 and 30), owing to sample size considerations.

Other covariates selected a priori to be potential confounders included paternal education, paternal race/ethnicity, and parity. Paternal education was defined categorically: less than high school, high school graduate (referent category), some college, or college graduate. Paternal race/ethnicity comprised three groups: white (referent category), black, and other. Parity was treated as a continuous measure. Among these other potential confounders, all were associated with either paternal age and with schizophrenia spectrum disorders, but none were associated with both variables. Thus, the main adjusted analysis included only maternal age as a covariate; however, in the interest of completeness, we also tested a model that included maternal age plus the three additional covariates.

Regression modeling
Proportional hazards regression (17, 18) was used to analyze the data. This method allowed comparison of the exposure and covariate measurements of each subject at his/her age of first treatment with the average measurements of the population at risk at that time. The population at risk consisted of all subjects who were still Kaiser Foundation Health Plan members and still at risk of failure (diagnosis of schizophrenia spectrum disorders) on the date at which the subject first received treatment. The output from a proportional hazards model includes estimated regression coefficients (interpreted as log rate ratios) and their standard errors for all predictor variables, from which estimated rate ratios, confidence intervals (CIs), and test statistics were generated.

Regression modeling began by fitting paternal age as the only predictor of time until first treatment for schizophrenia spectrum disorders. Subsequent models adjusted for maternal age, and the other covariates were fitted to remove any potential confounding bias in the paternal age effect. When adjusting for maternal age, paternal age and maternal age were consistently defined, i.e., both were treated as categorical or both as continuous in any regression model.

For models with the continuous paternal age variable, the coefficient of paternal age represented the log of the ratio of the rate of schizophrenia spectrum disorders (or schizophrenia) corresponding to a 1-year increase in paternal age. Although the analysis was performed on a continuous variable, we have reported the results in terms of a 10-year increase in paternal age for ease of interpretation. For models that used the categorical paternal age variable, the coefficient for each indicator variable represents the log rate ratio for that category versus the referent category (15–24 years).



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Incidence of Schizophrenia Spectrum Disorders
In Table 1, we report the cumulative incidence of schizophrenia spectrum disorders by father’s age. A graded increase in the cumulative incidence of schizophrenia spectrum disorders (calculated by using the method of Kaplan and Meier for censored data [19]) is observed with advancing paternal age.


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TABLE 1



Paternal Age as a Continuous Variable
We first examined paternal age modeled as a continuous variable in relation to risk of schizophrenia spectrum disorders in adult offspring. The analysis revealed a strong trend toward an association between advancing paternal age and risk of adult schizophrenia spectrum disorders. The change in the rate ratio associated with each 10-year increase in paternal age in this unadjusted model is 1.35 (95% CI=0.99–1.83, z=1.93, p=0.053).

In the primary analysis, which adjusted for maternal age, there was a positive and significant association between paternal age and schizophrenia spectrum disorders. The adjusted rate ratio associated with each 10-year increase in paternal age was 1.86 (95% CI=1.20–2.87, z=2.79, p=0.005), indicating nearly twice the rate of adult schizophrenia spectrum disorders in children of men who were 10 years older at the child’s birth, holding all other factors constant. The rate ratio changed only slightly (rate ratio=1.71, 95% CI=0.96–3.07, z=1.82, p<0.07) when adjustment was made for maternal age, paternal education, paternal race/ethnicity, and parity.

Paternal Age as a Categorical Variable
Having demonstrated a positive association between risk of schizophrenia spectrum disorders and increasing paternal age on a continuous scale, we then examined the effect of paternal age on schizophrenia spectrum disorders risk using the aforementioned 10-year age categories. The unadjusted rate ratios for each of these categories, relative to the 15–24-year age group, are presented in Table 2. There was a steady, monotonic increase in the rate of schizophrenia spectrum disorders with advancing categories of paternal age. The monotonic increase in risk of schizophrenia spectrum disorders with advancing paternal age categories was similar when adjustment was made for maternal age only, and for maternal age, paternal education, paternal race, and parity.


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TABLE 2



Risk of Schizophrenia
We further examined whether the findings persisted when the outcome was restricted to schizophrenia. For the effect of paternal age, modeled as a continuous variable, on risk of schizophrenia, the unadjusted rate ratio for each 10-year increase in paternal age was 1.41 (95% CI=0.95–2.09, z=1.69, p<0.10). In the analysis adjusting for maternal age, the rate ratio was 1.89 (95% CI=1.08–3.32, z=2.22, p<0.03). Modeled as a categorical variable, paternal age showed a similar dose-related increase for risk of schizophrenia as that found for schizophrenia spectrum disorders (Table 2).



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In a prospective birth cohort study, we have demonstrated a relationship between increasing paternal age at the time of the offspring’s birth and the risk of adult schizophrenia spectrum disorders. This effect persisted after adjustment for maternal age, as well as other potential confounders.

Several previous studies have examined the relation between paternal age and schizophrenia. In the Israeli study by Malaspina et al. (1), the overall pattern and magnitude of the relationship between paternal age and schizophrenia and related disorders was similar to that found in the present investigation, with a relative risk of nearly threefold for paternal age >50 years. That study had many strengths, including a prospective cohort design and large number of subjects with schizophrenia and related disorders. Our study furthers this finding by incorporating several additional methodologic advantages. First, we recorded parental age by direct interview of the mother during pregnancy, rather than relying on varying sources of information, as was done in the earlier study (1). Second, diagnoses of schizophrenia spectrum disorders were made by using a directly administered, research-based diagnostic assessment complemented by psychiatric records, in contrast to the reliance on hospital registry diagnoses. This permitted us to demonstrate that the association was present for schizophrenia analyzed separately from other schizophrenia spectrum disorders. Third, biological paternity was confirmed in the vast majority of our subjects, and this measure also permitted us to create a data set of independent subjects for analysis. Fourth, our study offered continuous follow-up of the entire cohort, thereby permitting us to define precisely the population at risk at the time each case was first treated. Finally, the replication in a United States birth cohort of the results of the study by Malaspina et al. (1) adds to the generalizability of the findings.

Our findings are also consistent with those of other earlier studies. Hare and Moran (2), in England and Wales, demonstrated a significant increase of paternal age in cases of schizophrenia, a finding that persisted despite adjustment for maternal age. Significant increases in paternal age were also found in Ontario (3) and Sweden (4) and in a second study in England (5). However, two earlier studies failed to replicate the association between advanced paternal age and schizophrenia (20, 21). These earlier studies were limited, however, by the use of clinical case series to derive schizophrenia cases, retrospectively acquired data on paternal age, and no adjustment for potential confounders.

Potential Explanations
We discuss three potential explanations for the observed relation between advancing paternal age and risk of schizophrenia spectrum disorders.

De novo mutations
Advanced paternal age has been associated with major congenital malformation syndromes and isolated birth defects, including Apert’s syndrome (8), craniosynostosis (22), situs inversus (6), syndactyly (10), cleft lip and/or palate (9, 23), hydrocephalus (9), and neural tube defects (7). Several of these disorders are known to be caused by autosomal dominant mutations.

The most widely accepted proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose (24). After puberty, spermatocytes divide every 16 days; by age 35, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations resulting from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes, and these mutations accumulate with advancing paternal age. For the male germ cell line, the mutations are believed to largely consist of single base substitutions (25).

New mutations may also explain associations between advanced paternal age and some adult-onset disorders, including sporadic Alzheimer’s disease (26) and cancers of the prostate (27) and the nervous system (28). It has been similarly hypothesized that de novo point mutations play a role in the etiology of schizophrenia (29). If such mutations in the male germ cell line are responsible for the paternal age association with schizophrenia, then this provides one explanation for how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction. Excessively mutable single nucleotides in genes critical for brain development or function, such as the fibroblast growth factor receptor 3 gene, may be involved (30, 31).

Parental constitutional factors
Conceivably, parental constitutional factors, such as schizophrenia spectrum disorders in either of the parents, may also explain the association between increased paternal age and schizophrenia. Previous studies of schizophrenia have demonstrated reduced marriage rates and delayed age at marriage (32–35), which may be more prevalent in men than women, and decreased fertility and fecundity (34–38), although the latter two findings are disputed (37). Although studies have generally shown only a 5%–6% morbid risk of schizophrenia spectrum disorders in the parents of subjects with these disorders (39), others have shown substantially higher risks (40). It is also possible that the older fathers were more likely to have heritable traits of schizophrenia without meeting diagnostic criteria.

Environmental deprivation
Conceivably, the children of older fathers may undergo higher levels of psychosocial stresses, such as physical illness in the father and/or loss of the father in childhood. In our study, however, it is likely that only a minority of the fathers for whom the age effect on schizophrenia risk was strongest (i.e., those aged >44 years at the time of birth) would have developed serious physical illnesses when their offspring were passing through childhood. There is also no solid evidence that loss of a parent during childhood increases the risk for schizophrenia (41).

Limitations
There are several limitations of the present study. First, currently there is insufficient information to delineate the relative contributions of biological, genetic, and psychosocial factors to our findings. Data on schizophrenia spectrum disorder diagnoses among the parents and on factors reflecting genetic predisposition to this disorder, including the age of marriage, are necessary to address the hypothesis that confounding by genetic vulnerability to schizophrenia spectrum disorders may explain our finding. This possibility can be at least partially addressed by obtaining data on schizophrenia spectrum disorder diagnoses in relatives of our cohort members, although genetically mediated traits that do not meet the threshold criteria for schizophrenia might prove difficult to assess. Second, because the size of the study group was modest, we were unable to examine the paternal age categories as finely as was done in the study by Malaspina et al. (1), which included a substantially larger number of subjects. Nonetheless, our results are consistent with those of that study. Third, while the ascertainment for schizophrenia was good, it is likely that a number of cases of schizotypal personality disorder were missed, because only treated cases were ascertained and patients with schizotypal personality disorder are less likely to have been treated. Finally, given the high correlation between paternal and maternal age, it is conceivable that our findings could be explained by factors associated with a greater deviation in ages between the father and mother. However, Malaspina et al. (1) found a robust effect of paternal age on risk of schizophrenia spectrum disorders after excluding offspring in which the difference between paternal and maternal age was greater than 10 years. Additional research will be necessary to disentangle the effects of paternal age and parental age difference on schizophrenia risk.



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We have demonstrated a significant, dose-dependent association between advancing paternal age and risk of schizophrenia and other schizophrenia spectrum disorders in a prospective birth cohort study with several methodologic advantages compared with previous work. The findings persisted after adjustment for maternal age and were present when schizophrenia was examined separately from schizophrenia spectrum disorders. De novo mutations in the male germ cell line may be responsible, at least in part, for the observed association. While further work is necessary to confirm this interpretation, our study nonetheless provides further evidence that advanced paternal age is a risk factor for schizophrenia spectrum disorders. If the de novo mutation hypothesis can be confirmed by future studies, this discovery may lead to the identification of candidate genes for this disorder.




Footnotes


Received July 12, 2001; revision received April 22, 2002; accepted April 24, 2002. From the Department of Psychiatry, College of Physicians and Surgeons of Columbia University; and the Department of Epidemiology of Brain Disorders, New York State Psychiatric Institute. Address reprint requests to Dr. Brown, New York State Psychiatric Institute, 1051 Riverside Dr., Unit 2, New York, NY 10032; asb11@coumbia.edu (e-mail). Supported by NIMH grants MH-01206 (Dr. Brown), MH-53147 (Dr. Susser), MH-50727 and MH-59342 (Dr. Gorman), and MH-59114 and MH-01699 (Dr. Malaspina); a Young Investigator Award (Dr. Brown) and an Independent Investigator Award (Dr. Susser) from the National Alliance for Research on Schizophrenia and Depression; the Theodore and Vada Stanley Foundation (Dr. Susser); and the Lieber Center for Schizophrenia Research at Columbia University (Dr. Gorman).The authors thank Bea van den Berg, M.D., Barbara Cohn, Ph.D., and Ralph Vogel, Ph.D., for their contributions to this work.Dr. Wyatt died in June, 2002.



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