In addition to "mutational errors involved in spermatogenisis that occur with increasing frequency as men age", dysregulation of imprinting processes

on autosomal and X chromosomes are probably involved in the increase in rates of schizophrenia and autism found in the offspring of older men. The older the age of the father, the more neurodevelopmental disorders in offspring at a population level.

From the paper cited below: "The causal mechanism underlying the well-established relation between advancing paternal age and schizophrenia is hypothesized to involve mutational errors during spermatogenesis that occur with increasing frequency as males age. Point mutations are well known to increase with advancing paternal age while other errors such as altered copy number in repeat DNA and chromosome breakage have in some cases also been associated with advancing paternal age."

Drs. Malaspina, Perrin and Brown state that some cases of COPY NUMBER VARIATION OR ALTERED COPY NUMBER IN REPEAT DNA INCREASE WITH PATERNAL AGE IN CONTRAST TO THOSE GENETICIST WHO SAY THAT THERE IS NO EVIDENCE THAT CNVs INCREASE WITH INCREASING PATERNAL AGE.




Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia
Mary C. Perrin2, Alan S. Brown3,4 and Dolores Malaspina1,2 2 Department of Psychiatry, School of Medicine, New York University, New York, NY3 New York State Psychiatric Institute, New York, NY4 Department of Psychiatry, Columbia University, New York, NY
1 To whom correspondence should be addressed; tel: 212-263-6214, fax: 212-263-5717, e-mail: Dolores.Malaspina@NYUMC.ORG
'//-->
.

"Imprinting errors could increase the risk of schizophrenia through multiple pathways including direct effects on the expression of genes involved in neuropsychiatric pathology or indirectly through imprinting errors in genes related to the normal functioning of the placenta. "


THE MALE BIOLOGICAL CLOCK ADVANCING PATERNAL AGE = NEW GENETIC DISORDERS AND DISEASES IN OFFSPRING!




Cynthia R. Daniel from Rutgers also pointed out the sperm DNA and imprinting errors that are due to increasing paternal age according to a great deal of public research. Her concerns were not included in the following press release:



Sperm Damage From Toxins Can Affect Children, Grandchildren
ScienceDaily (Feb. 21, 2008) — The consequence of maternal exposure to a variety of potentially toxic agents during pregnancy remains the prime focus of concern in scientific endeavors and in society at large.



However, there is now mounting evidence that paternal exposure can also adversely affect fetal and postnatal development of offspring and that this imprint can be expressed in subsequent generations.

Scientists are addressing the evidence for male-mediated influences on reproductive success and postnatal development and its implications at a symposium.*

"This symposium will present evidence from both animal and epidemiological studies which demonstrates that paternal exposure to a variety of potential toxins can adversely impact fetal development, produce a wide spectrum of deficits in offspring and be expressed in subsequent generations," said Gladys Friedler, PhD, an emerita associate professor of psychiatry at Boston University School of Medicine and organizer of the session.

"The goal of this symposium is to heighten awareness of the significant effect of the male parent in reproductive success and postnatal development as well as to stimulate research on male-mediated effects," added Friedler.

Friedler, who is considered a pioneer in the field, will introduce the symposium with a review of studies which indicate that male exposure to a variety of potential toxins including both recreational and therapeutic drugs, as well as workplace and other exposures can adversely alter reproductive outcome.

The reported impact on offspring outcome includes low birth weight; increase in childhood cancers; developmental, behavioral, endocrine abnormalities and cross-generational effects.

*The multidisciplinary symposium, sponsored by the American Association for the Advancement of Science is entitled The Father and Fetus Revisited. Also participating in this symposium are Matthew D. Anway from the University of Idaho, Moscow, who will present his studies: "Epigenetic Transgenerational Reproductive Disease." Political scientist Cynthia R. Daniels, from Rutgers University, New Brunswick, New Jersey, will discuss "Cultural Politics and the Father-Fetal Connection."

The offspring and offspring of the offspring suffer from the Ticking of the Male Biological Clock

Harry Fisch said as far as the connection between older paternal age and devastating genetic disorders, where you look you find it! The main predictor for non-familial autism is PATERNAL AGE.

Dolores Malaspina has studied paternal age and genetic neurocognitive disorders extensively and does not state this lightly:

Though more research is needed, Malaspina says it’s possible that — just like women — the prime time for becoming a dad is one's 20s and early 30s.
“Men," she says, "your biological clocks are ticking, too.”

If you want healthy children and grandchildren plan to have children earlier in life rather than after your very early 30s.

Sperm donors are limited to men under 35 or under 30 in cryobanks that know about the gene DNA deterioration in older men.

Read on if you want to know more about the Male Biological Clock Advancing Paternal Age and Genetic Disorders

What is the truth about autism and schizophrenia and other genetic disorders such as type 1 diabetes?

"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."




"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.

The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.7 This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose8 in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children. In the 1960s, an excess of schizophrenia in last-born children was also reported."



Clinical Psychology and Psychiatry Blogspot

A good chunk of studies have accumulated over the past few years (e.g., 1, 2, 3, 4, 5) that show a strong link between increasing paternal (father’s) age and risk of schizophrenia in children.
One researcher has described the link as follows:



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

Wow – one quarter of the risk for schizophrenia explained by paternal age? I’ll admit that these types of studies are not my area of expertise, but from my review of some of these studies, I’m willing to buy that paternal age is a significant risk. These findings have indeed been replicated on numerous occasions.


One of the main researchers in the area, Dolores Malaspina (quoted above), has said that findings such as this should not discourage parents from having children at whatever age they choose. I am not in agreement – older parents should be made aware of the risk and make an informed decision.


Why the effect? Here’s what seems to be a decent explanation…


"Every cell division makes a copy of DNA," [researcher] Gavrilova says. "And the same thing happens with the next division and this final copy is of less quality. This can introduce a slight risk of error in the genetic material of the new sperm. You can call it a kind of copy error.

The longer a man ages, the greater the chance of sperm mutations that could lead to schizophrenia or other problems in offspring.

There is also research linking autism to older fathers. It appears that such information is not widely known. I was certainly not familiar with it until recently. Consider the trends in Western societies – fathers having children at older ages is likely leading to a decent sized increase in rates of schizophrenia, autism, and perhaps other problems as well. While this is excellent news if one is in the antipsychotic business, is this really good news for everyone else?


Shouldn't this information be more widely discussed?........................

"Scientists have linked paternal age to genetic diseases since the 1950s......"






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

A MAJOR INFLUENCE ON NEW MUTATIONS IN THE HUMAN GENE POOL IS RELATED TO THE ADVANCING AGE OF FATHERS

"As a major influence on new mutations in the human gene pool is related to the advancing age of fathers, Dr. Malaspina first examined the relationship of schizophrenia and paternal age. Data showed a strong escalation in schizophrenia risk as the age of the father increased, accounting for over a quarter of the schizophrenia cases. Another of her studies found that fathers of sporadic schizophrenia cases were 5 years older than familial case fathers. If sporadic schizophrenia can originate from new mutations, then neurodevelopmental genes are reasonable candidates. Her study will examine if patients with sporadic schizophrenia, particularly those with fathers older than 35 at birth, show features found in other neurodevelopmental diseases that correlate with paternal age, such as craniofacial abnormalities, nonspecific cognitive deficits and delayed developmental milestones. However, if genes that arise from mutations are inherited by later generations, then some familial cases with a similar illness would not have a paternal age effect. Dr. Malaspina plans to define the clinical profile in sporadic patients associated with paternal age through group comparisons and cluster analysis. If the study is successful, this illness pattern may be useful in gene identification for schizophrenia."


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

$15,000,000 NARSAD WHY DON'T YOU ANNOUNCE TO THE PUBLIC THAT AT LEAST 33% OF AUTISM AND SCHIZOPHRENIA IS CAUSED BY OLDER FATHERS HAVING BABIES??

Interviewed by Norman Sussman Primary Psychiatry
"The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.7 This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose8 in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children...."
..............................................................................

NARSAD: The Mental Health Research Association Announces 245 New Research Grants To Established And Early-Career Investigators

23 May 2007 - 12:00 PDT



NARSAD: The Mental Health Research Association announces the awarding of 23 Distinguished Investigator grants and 222 Young Investigator grants for 2007. The awards, which represent more than 15 million dollars in new grantmaking, will be used to support brain and behavioral research that offers the potential of breakthrough findings on serious mental illnesses.
-----------------------------------------------------------------------------------
Dolores M. Malaspina, M.D. 2001 Independent Investigator 2001



Dolores Malaspina, M.D., M.S.P.H. (Independent Investigator 2001) of New York State Psychiatric Institute, will examine the novel hypothesis that new genetic mutations can cause schizophrenia, and will attempt to define the clinical profile (phenotype) of this type of schizophrenia, known as sporadic schizophrenia (the birth of an affected individual into an unaffected family). This type of schizophrenia has previously been thought to originate from environmental factors that either act independently or interact with latent genes. Dr. Malaspina has conducted two preliminary studies which support the new mutations hypothesis. As a major influence on new mutations in the human gene pool is related to the advancing age of fathers, Dr. Malaspina first examined the relationship of schizophrenia and paternal age. Data showed a strong escalation in schizophrenia risk as the age of the father increased, accounting for over a quarter of the schizophrenia cases. Another of her studies found that fathers of sporadic schizophrenia cases were 5 years older than familial case fathers. If sporadic schizophrenia can originate from new mutations, then neurodevelopmental genes are reasonable candidates. Her study will examine if patients with sporadic schizophrenia, particularly those with fathers older than 35 at birth, show features found in other neurodevelopmental diseases that correlate with paternal age, such as craniofacial abnormalities, nonspecific cognitive deficits and delayed developmental milestones. However, if genes that arise from mutations are inherited by later generations, then some familial cases with a similar illness would not have a paternal age effect. Dr. Malaspina plans to define the clinical profile in sporadic patients associated with paternal age through group comparisons and cluster analysis.

IS ANYONE TRYING TO PREVENT MORE CASES OF AUTISM AND SCHIZOPHRENIA?

TAKEN FROM THE ALLIANCE FOR HUMAN RESEARCH PROTECTION BLOG


What are many psychiatrists interested in? Are they interested in the public knowing the robust, dramatic connection between advancing paternal age and autism/the childhood schizophrenia type and schizophrenia? No they are not.

Dolores Malaspina, This interview took place on April 26, 2006, and was conducted by Norman Sussman, MD.




"The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.7 This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose8 in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children. In the 1960s, an excess of schizophrenia in last-born children was also reported..."





Thomas Wassink is an associate professor of psychiatry.

Is he interested in preventing autism through publicizing the link between paternal age with mutations in sperm and autism? NO. Wassink says they did further study to narrow down the gene mutation. Wassink says, "At some point in the embryonic development of the father, an abnormality occurred or a mutation arose in his primordial sperm cell."


He says the finding could eventually help with treatments for autism.

Wassink says it may indicate different types of medications to try in treating autism. He is an associate professor of psychiatry, and says this study does not show any link to an earlier study that indicated that the chances for autism increased with the age of the father. Wassink says age is not a factor in this finding." not showing any link to an earlier study that indicated that the chances for autism increased with the age of the father. Wassink says age is not a factor in this finding, but he says nothing about the age of this father. When asked he and other psychiatrists on the study will not reveal the age of the father. One Dr. said:

"Because the mutation is identical in the two siblings, it is likely that it occurred during germ-line development and so paternal age is unlikely to be relevant." UNLIKELY

"The reason is that the deletion is identical in the two siblings. For two identical deletions to occur in different sperm by chance is so unlikely as to be almost inconceivable. The deletion had to come from a progenitor sperm cell, and is unlikely to be related to the paternal age effect reported in autism." Thanks for the interest,







De novo point mutations in such genes could explain the advanced paternal age association that has been reported for autism13. There is no evidence, however, that the risk of a de novo CNV is related to the age of either parent. Arthur L. Beaudet


Dolores Malaspina, M.D.
New Point Mutations in Humans Are Introduced Through The Male Line" This Has Been Known Since the 1950s", "What is Intriguing is why society chooses
to ignore this"

Dolores Malaspina, M.D.

Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4.


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.

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) 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.



Philip Gorwood

Philip Gorwood

DOLORES MALASPINA INVESTIGATES CAN DE NOVO MUTATIONS CAUSE SCHIZOPHRENIA

Dolores Malaspina, M.D., M.S.P.H. (Independent Investigator 2001) of New York State Psychiatric Institute, will examine the novel hypothesis that new genetic mutations can cause schizophrenia, and will attempt to define the clinical profile (phenotype) of this type of schizophrenia, known as sporadic schizophrenia (the birth of an affected individual into an unaffected family). This type of schizophrenia has previously been thought to originate from environmental factors that either act independently or interact with latent genes. Dr. Malaspina has conducted two preliminary studies which support the new mutations hypothesis. As a major influence on new mutations in the human gene pool is related to the advancing age of fathers, Dr. Malaspina first examined the relationship of schizophrenia and paternal age. Data showed a strong escalation in schizophrenia risk as the age of the father increased, accounting for over a quarter of the schizophrenia cases. Another of her studies found that fathers of sporadic schizophrenia cases were 5 years older than familial case fathers. If sporadic schizophrenia can originate from new mutations, then neurodevelopmental genes are reasonable candidates. Her study will examine if patients with sporadic schizophrenia, particularly those with fathers older than 35 at birth, show features found in other neurodevelopmental diseases that correlate with paternal age, such as craniofacial abnormalities, nonspecific cognitive deficits and delayed developmental milestones. However, if genes that arise from mutations are inherited by later generations, then some familial cases with a similar illness would not have a paternal age effect. Dr. Malaspina plans to define the clinical profile in sporadic patients associated with paternal age through group comparisons and cluster analysis. If the study is successful, this illness pattern may be useful in gene identification for schizophrenia.

"New Point Mutations in Humans Are Introduced Through The Male Line" This Has Been Known Since the 1950s", "What is Intriguing is why society chooses

TO IGNORE THIS" said Malaspina.


But now it is becoming increasingly clear that the biological clock ticks
for men as well as women, as researchers turn up evidence that as would-be
fathers get older, they have an increased chance of passing on genetic
defects to their children.

"New point mutations in humans are introduced through the male line," says
Dolores Malaspina, MD, professor of clinical psychiatry at Columbia
University and the New York State Psychiatric Institute. Furthermore, she
adds, the number of mutations in sperm increases as men age.

"This has been known since the 50s," said Malaspina. "What is intriguing is
why society chooses to ignore this."




CULTURAL RESISTANCE
There are many reason why paternal contribution to birth defects has a low
profile. James F. Crow, PhD, emeritus professor of genetics and medical
genetics at the University of Wisconsin in Madison, mentions that most of
these defects occur at low levels, on the order of 1 in tens of thousands.
In contrast, the odds of having a child with Down syndrome are about 1 in
350 when the mother is age 35 years and 1 in 100 at age 40 years. However,
some scientists hint that society may not be ready to hear that older men,
like older women, run the risk of passing on birth defects.

But the risk of having a child who later develops schizophrenia, Malaspina
notes, is about 1 in 110 when the father is age 40-similar to a 40-year-old
woman's risk of having a child with Down syndrome.

Malaspina says she believes her findings met resistance because of a
reluctance by men to accept that fathering children later in life poses
increased health risks to their children.

"Despite the fact that our paper received excellent reviews it was rejected
by two medical journals," she said, noting that the study results now have
been replicated five times with similar results. "And these biases really
hold us back from scientific advances."






from an article by Paul D. Thacker:

Biological Clock Ticks for Men, Too
Genetic Defects Linked to Sperm of Older Fathers
Paul D. Thacker

JAMA. 2004;291:1683-1685.



[mnchp-l] Genetic Defects Linked to Sperm of Older Fathers
McGillivray, Katrina katrina at beststart.org
Wed Apr 14 10:00:40 EDT 2004

Risk of Non-Familial Autism Is Often Related To the Age of the Father at a Child's Birth

Published on the EBD Blog

In order to access the links and the complete comment section please read this paper where it was originally published: THE EBD BLOG


cFathers’ Age as Contributor to Risk for Autism
Leslie FeldmanThe average age of fatherhood is increasing in the US and in Western Europe. Some research shows that offspring of older fathers are at increased risk for diseases and conditions (Bray et al., 2006). Some experts predict an upswing in cases of schizophrenia will accompany the increasing average paternal age. “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” (Malaspina et al., 2006). Approximately 25-33% of all cases of schizophrenia may be due to the father’s age at conception, according to Malaspina (2006). Malaspina sees a connection between advancing paternal age and neural functioning difficulties in people with autism and with schizophrenia. According to Tarin et al. (1998), there are well over 30 known conditions that the offspring of older fathers are more at risk for (see chart on paternal aging in the linked article).

The diagnosis of autism is increasing in the US and elsewhere (Centers for Disease Control, 2006). In a population study of 1990 through 1999, a total of 669,995 children, Atladóttir and colleagues (2007) reported increased diagnosese of autism, Torrette Syndrome, and hyperkinetic disorder. Is there a connection between increased cases of disorders such as autism and increased average paternal age? Psychiatrist Michael Craig Miller (2006), editor of the Harvard Mental Health Letter is convinced there is. Although a connection between the two would be corelational (not causal), the relationship encourages examination of the possibility that something related to paternal age (e.g. mutations in gametes) may contribute to the occurrence of autism. If there is a potential causal relationship, the new study by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network would provide a valuable opportunity to test the hypothesis.

Observations of a connection between advanced paternal age and difficulties for offspring go way back. Earlier research looking for a link between maternal age and autism also found the average paternal age (34) was much higher than the average age in the general population (Gillberg, 1980). Geneticist James F. Crow (1997) cites Wilhelm Weinberg (1862-1937) as noticing, during his 42 years of medical practice and helping 3,500 births, that the mutation rate might be a function of paternal age. Crow said, the evidence suggested that the greatest mutational health hazard in the population is fertile old men.

A study by Reichenberg et al. (2006) found a strong connection between cases of autism and advancing paternal age. Reichenberg and colleagues, who found more autism as paternal age increased, also found that the ratio of girls to boys in this cohort was 1:1, suggesting that this was a special subset of autism, maybe de novo rather than familial autism.

What might be the mechanism that produces higher rates of disorders among children of older fathers? The DNA in a 20 year-old male has been copied approximately100 times but in a 50 year-old father it has been copied over 800 times. Singh and colleagues (2003) studied differences in the sperm of older and younger men. Men over age 35 have sperm with lower motility and more highly damaged DNA in the form of double-strand breaks. The older group also had fewer apoptotic cells, an important discovery. (Apoptosis is form of cell death that protects the parent organism from problems or that permits differentiation, as in resorption of a tadpole’s tail.) A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage, as most other cells do. As a result, the only way to avoid passing DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age. Singh is quoted in Science Blog (Sullivan, 2002) as explaining that, “In older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated.”

Sources

The following list of sources is for works cited in this document or for other studies finding a connection between age of fathers at conception and various disorders. Access to some of the Web-based resources may be limited because of the policies of the publishers.

Atladóttir, H. O., Parner, E. T., Schendel, D., Dalsgaard, S., Thomsen, P. H., & Thorsen, P. (2007). Time trends in reported diagnoses of childhood neuropsychiatric disorders. Arch Pediatr Adolesc Med., 161, 193-198. Link

Brown et al. (2002): Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry, 159, 1528-1533. Link

Bray, I., Gunnell, D., & Smith, G. D. (2006). Advanced paternal age: How old is too old? Journal of Epidemiology and Community Health, 60, 851-853. Link

Burd et al., (1999). Prenatal and perinatal risk factors for autism. J. Perinatal. Med., 27, 441-450. Link

Byrne, M., Agerbo, E., Ewald, H., Easton, W. W., & Mortensen, P. D. (2003). Parental age and risk of schizophrenia, A case control study. Arch Gen Psychiatry, 60, 673-678. Link

Centers for Disease Control, (2006). How common are Autism Spectrum Disorders (ASD)? Link

Centers for Disease Control. (2002). Prevalence of the Autism Spectrum Disorders (ASDs) in multiple areas of the United States, 2000 and 2002. Atlanta, GA: Author. Link

Crow, J. F. (1997). The high spontaneous mutation rate: Is it a health risk? Proc. Natl. Acad. Sci. USA, 94, 8380-8386. Link

Dalman, C., & Allebeck, D. (2002). Paternal age and schizophrenia: Further support for an association. Am J Psychiatry, 159, 1591-1592. Link

Gillberg, C. (1980). Maternal age and infantile autism. J. Autism and Developmental Disorders, 10, 293-297. Link

Lauritsen M. B., Pedersen, C. B., & Mortensen, P. B. (2005) Effect of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J. Child Psychology and Psychiatry, 46, 963-971. Link

Miller, M. C. (2006) A new key to Autism. Aetna IntelliHealth, September 25. Link

Malaspina, D., et al. (2001): Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry, 58, 361-367. Link

Malaspina, D. (2006). In session with Dolores Malaspina, MD, MSPH: Impact of childhood trauma on psychiatric illness (interview by N. Sussman). Primary Psychiatry, 13(7), 33-36. Link

Malaspina, D. (2006). Schizophrenia risk and the paternal germ line. Schizophrenia Research Forum. Link

Rasmussen, F. (2006) Paternal age, size at birth, size in young adulthood&mdashrisk factors for schizophrenia. Eur Journal of Endocrinology, 155 Suppl 1:S65-69. Link

Reichenburg, A., Gross, R., Weiser, M. Bresnahan, M., Silverman, J. Harlap, S., et al. (2006). Advancing paternal age and autism. Arch Gen Psychiatry, 63, 1026-1032. Link

Singh, N. P., Muller, C. H., & Burger, R. E. (2003). Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertility and Sterility, 80, 1420-1430. Link

Sipos, A., Rasmussen, R., Harrison, G., Tynelius, P., Lews, G., Leon, D. A., et al. (2004). Paternal age and schizophrenia: A population based cohort study. BMJ, 329, 1070. Link

Sullivan, B. J. (2002). Research reveals a cellular basis for a male biological clock. Science Blog, 2002-11-25 22:31. Link

Tarin, J. J., Brines, J., & Cano, A. (1998). Long-term effects of delayed parenthood. Human Reproduction, 13, 2371-2376. Link

Tsuchiya, K. J., Takagai, S., Kawai, M., Matsumoto, H., Nakamura, K., Minabe, Y., et al. (2005). Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophrenia Research, 76, 337-342. Link

Wohl, M. & Gorwood, P. (2006). Paternal ages below or above 35 are associated with a different risk for schizophrenia in offspring. Eur. Psychiatry, Dec 1 [Epub ahead of print]. Link

Zammit, S., Allebeck, P., Dalman, C., Lundgerg, I., Hemming, T., Owen, M. J., et al. (2003). Paternal age and risk for schizophrenia. Br. J. Psychiatry, 183, 405-408. Link

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Pingback by EBDblog » Paternal age–more — 21 February 2007 @ 3:08 pm

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5601a1.htm

February 9, 2007 / 56(SS01);1-11

Prevalence of Autism Spectrum Disorders — Autism and Developmental Disabilities Monitoring Network, Six Sites, United States, 2000

Corresponding author: Catherine Rice, PhD, Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, CDC, 1600 Clifton Road, N.E., MS E-86, Atlanta, GA 30333. Telephone: 404-498-3860; Fax: 404-498-3550; E-mail: crice@cdc.gov.

http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5601a1.htm

Comment by Leslie Feldman — 21 February 2007 @ 7:36 pm

Dr. Narendra P.Singh suggested that I elaborate about what happens when the DNA in the primitive sperm making cells divides hundreds and hundreds of times as men age.

I will try.

Mutations arise with each cell division and the mutation rate increases with age. There are base substitutions and deletions and other copying errors. In a man of 45 there have been 770 cell divisions ancestral to a sperm. See James F. Crow’s paper, “The high spontaneous mutation rate: Is it a health risk? in the sources section of the paper.

Comment by Leslie Feldman — 22 February 2007 @ 7:38 pm








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