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February, 2009 in Biology |

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


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

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

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

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

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

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



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.

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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.

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

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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Men also have a biological clock

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

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

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

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

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

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

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

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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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Working Dad: An Unauthorized Guide to Parenting

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« A third of parents clueless about children's development | Main

Lots of evidence that men have their own biological clocks
I stumbled across another article that says there is "abundent evidence" men have their own biological clocks.

Advanced daddy age increases the risk of spontaneous abortion, autism and other disorders in offspring, the journal Geriatrics reports in Older men are having children, but the reality of a male biological clock makes this trend worrisome.

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.
...
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. -- Geriatrics, 1/15/08.



Plus, "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."

The article summarizes a lot of the existing research, including

On autism:

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.



On schizophrenia:

Men older than 40 were more than twice as likely to have a child with schizophrenia as men in their 20s.

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

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


|

Pages | 1 | 2 | 3 | 4





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








Pages | 1 | 2 | 3 | 4





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

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

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




Email|Print|
Share
• Del.icio.us
• Digg
• Reddit
• Facebook
|Save|License |Discuss On Sermo




Pages | 1 | 2 | 3 | 4





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

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




Email|Print|
Share
• Del.icio.us
• Digg
• Reddit
• Facebook
|Save|License |Discuss On Sermo




Pages | 1 | 2 | 3 | 4





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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http://geriatrics.modernmedicine.com/geriatrics/article/articleDetail.jsp?id=575098&sk=&date=&pageID=2

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I have a file of research on the male biological clock I can send if you leave your e-mail address in the comments section. It has many articles and epidemiological studies.

Male biological clock possibly linked to autism, other disorders

Focus on Reproductive Biology
Focus issue: November 2008 Volume 14, No 11

Nature Medicine 14, 1170 (2008)
doi:10.1038/nm1108-1170a


Male biological clock possibly linked to autism, other disorders
Charlotte Schubert1

Washington, DC


Introduction
Istockphoto

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."

Age of the Father and the Health of Future Generations

Age of the Father and the Health of Future Generations

THE AGE OF THE FATHER AND THE HEALTH OF FUTURE GENERATIONS

THE AGE OF THE FATHER AND THE
HEALTH OF FUTURE GENERATIONS
Word Count: 903
　
Leslie B. Raschka M.D., Associate Professor (retired),
Department of Psychiatry, University of Toronto
Address: 27 Edgecombe ave, Toronto, Ontario, Canada
M5N 2Xl, Tel. (416) 783-6938
2
Abstract
Purpose: To assess the role of paternal age in the origin of genetic illness in future generations.
Data Sources: All reference data originated in English language international scientific literature and findings of original research conducted by myself.
Study Selection: Original articles published between 1938 and 1998 were selected according to the stated purpose. One article was written by myself.
Data Extraction: The present paper deals with 4 subtopics: andrology, genetics, pathology, and psychiatry.
Results: Nine articles reporting on 1399 patients described the deterioration of the quality of semen related to ageing. Five articles reported an increased mutation rate in the male germ cells as compared to the female germ cell. Twenty-four articles reported on 1230 patients and related studies described paternal age effect on increased mutation rate causing genetic illness. Eight articles reporting on 10,347 patients described increased prevalence of mental illness as related to older paternal age.
Conclusions: The age of the father is an important determinant of the health of future generations. Children conceived by fathers older than 34 years of age are at increased risk for genetic illness due to recent mutation in the male germ cell.
3The genetic illness of a child could originate in a mutation related to the age of the father or to a mutation in the spermatogenesis caused by ageing in previous generations. The ageing process in the male is an important, probably the most important, cause of genetic illness in human populations.
　Key Words: Age of the father, mutation, genetic illness
4 Demographic changes taking place in the 20th Century have directed attention to all possible determinants of the health of future generations. The relationship between maternal age and Down Syndrome is a currently recognized scientific fact. The study of the reproductive efficiency of the male is also relevant to the health of future generations. Most children are born healthy regardless of paternal age; however, the age of the father is a determinant of ill health for a significant minority in future generations.
　
5 Andrology
Ageing in the male is expressed in a progressive decline both in the quality and quantity of the sperm (1). Changes include a decrease in motility (2), decreased vitality and an increased percentage of malformed sperm (3, 4, 5, 6, 7). The deterioration associated with ageing can be noticed first in men between the ages of 35 to 40 years (8, 9).
　
6 Genetics
The mutation rate is higher in the male than in the female germ cell (10, 11, 12, 13, 14). While the ageing male germ cell is especially sensitive to mutation (15) there is a significant difference in mutation, rates among different genes. There is evidence that mutation frequencies for a number of different genes causing illness increase with advancing paternal age. The rate of increase differs among different genes (16); not all genes are subject to the paternal age effect. Almost all new mutations were reported to occur in the male germ cell; however, paternal age effect is not equally pronounced in all mutations (12). It is operant in recent germline mutations. Inherited illnesses such as hemophilia A have their origins in mutations in earlier generations where, for example, increased maternal grandparental age was found and new germline mutation related to increased paternal age transmitted to future generations can result in hereditary illness. In the development of illness, more than one gene can be involved. The phenotypic expression can be influenced by modifying genes. The importance of mutations for the health of future generations was born out by the Bulletin of the World Health Organization 1986 (17), which states that about 1% of children will be born with a serious genetic disease and another 1% will develop a serious genetic illness later in life.
7 Pathology
The relationship between increased paternal age and pathological conditions of known genetic origin was reported for achondroplasia in nineteen publications (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34); for Apert Syndrome in sixteen publications (15, 19, 20, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35); on Marfan Syndrome in thirteen publications (15, 20, 21, 22, 23, 25, 26, 27, 30, 31, 32, 33, 34); on osteogenesis imperfecta in five publications (16, 19, 24, 25, 29); on basal cell naevus syndrome in three publications (22, 26, 32); in Waardenburg Syndrome in five publications (22, 26, 31, 32, 33); on Crouzon Syndrome in seven publications (22, 26, 28, 31, 32, 33, 35); on oculo-denta; digital syndrome in four publications (22, 26, 31, 32); on thanatophoric dysplasia in three publications (28, 29, 35); on Pfeiffer Syndrome in three publications (28, 32, 35); on tuberous sclerosis in three publications (31, 33, 36); on multiple endocrine neoplasm in three publications (32, 34, 37); on myositis ossificans in nine publications (15, 19, 21, 22, 24, 30, 31, 32, 33); and on Treacher Collins disease, four publications (22, 26, 31, 33). All of these illnesses are transmitted in an autosomal dominant fashion. Increased risk for X-linked conditions associated with increased maternal grand-parental age is known to exist regarding classical hemophilia and was reported in nine publications (15, 17, 23, 25, 26 31, 32, 34, 38). This is also true for Lesch-Nyhan syndrome, reported in five publications (10, 17, 27, 31, 38). The mutation is transmitted to the child through carrier mothers.
8Psychiatry
Mutations occurring in the course of gametogenesis in the male and the association of psychosis was described in one article (39). Older maternal and paternal age in schizophrenia was reported in four articles (39, 40, 41, 42). My own study involving 574 patients has shown that the increased age of the father is a causative factor in a sub-group of the schizophrenic population (43). Two other articles, reporting on 662 and 8000 patients respectively, confirmed my conclusions, as well as indicating that increased maternal age was secondary to increased paternal age (41, 42). Three articles reporting on 1081 patients described increased paternal age in Alzheimer’s disease (44, 45, 46).
　
9 Discussion
All genetic illnesses have their origin in a distant or recent mutation. Paternal age is an important determinant of mutation frequency in new germ cell mutation, causing both autosomal dominant and X-linked recessive illnesses. The role of other mutagenic factors is not the subject of this study. The results of my own research are supported by other information which indicates that the leading cause of genetic illness present in human populations is the ageing process in the male. Conceiving children by men younger than 35 years of age would prevent many genetic illnesses in future generations.
　
10 Bibliography
1. Johnson L, Nguyen H B, Petty C S, et al. Quantification of Human Spermatogenesis: Germ Cell Degeneration during Spermatocytogenesis and Meiosis in Testes from Younger and Older Adult Men. Biol Reprod 1987; 37: 739.
2. Nieschlag E, Lammers U, Freischem C W, et al. Reproductive Functions in Young Fathers and Grandfathers. J Clin Endocrinol Metab 1982; 55: 676.
3. Holstein A F. Spermatid Differentiation In Man During Senescence. In. : Andre J, ed. Proceedings of the Fourth International Symposium on Spermatology; 1982 June; The Hague. Martinus Nijhoff, 1983: 15-18.
4. Homonnai Z T, Fainman N, David M P, et al. Semen Quality and Sex Hormone Pattern of 39 Middle Aged Men. Andrologia 1982; 14(2): 164.
5. Bacetti B, Renieri T, Selmi M G, et al. Sperm Structure and Function in 70 Year Old Humans. In: Andre J, ed. Proceedings of the Fourth International Symposium on Spermatology; 1982 June; The Hague. Martinus Nijhoff, 1983: 19-23.
6. Spira A, Ducot B. Variations physiologiques du spermatogramme. Ann Biol Clin (Paris) 1985; 43: 55.
7. Sternbach H. Age-Associated Testosterone Decline in Men: Clinical Issues for Psychiatry. Am J Psychiatry 1998; 155: 1310.
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8. Bishop M W H. Aging and Reproduction in the Male. J Reprod Fert 1970; (Suppl. 12): 65.
9. Schwartz D, Mayaux MJ, Spira A, et al. Semen characteristics as a function of age in 833 fertile men. Fertil Steril, 1983; 39: 530.
10. Vogel F. Editorial. A probable sex difference in some mutation rates. Am J Hum Genet, 1977; 29: 312.
11. Haldene J B S. The Mutation Rate of the Gene for Haemophilia and it’s Segregation Ratios in Males and Females. Ann Hum Genet 1947; 13: 261.
12. Vogel F, Motulsky AG. Human Genetics, Problems and Approaches. Berlin: Heidelberg: New York: Springer Verlag, 1979; 282.
13. Crow J F, Denniston C. Mutation in Human Populations. In: Harris H, Hirschhorn K, eds. Advances in Human Genetics. New York: London: Plenum Press, 1985; 14: 59-123.
14. Shimmin L C, Chang B H, Li W. Male-driven evolution of DNA sequences. Nature 1993; 362: 745.
15. Vogel F, Rathenberg R. Spontanious Mutation in Man. In: Harris H, Hirschhorn K, eds. Advances in Human Genetics. New York: London: Plenum Press, 1975; 5: 223-318. 12

16. Evans HJ. Mutation as a cause of genetic disease. Phil Trans R Soc Lond 1988; 319: 325.
17. Berg K, Bochkov N P, Coutelle C, et al. Bull WHO 1986; 64(2): 205.
18. Penrose L S. Parental Age and Mutation. The Lancet 1955; 2: 312.
19. Modell B, Kuliev A. Changing paternal age distribution and the human mutation rate in Europe. Hum Genet 1990; 86:198.
20. Murdoch J L, Walker B A, Hall J G, et al. Achondroplasia-a genetic and statistical survey. Ann Hum Genet 1970; 33: 227.
21. Rogers J G, Danks D M. Birth defects and the father. Med J Austr 1983; 2: 3.
22. Karp L E. Older Fathers and Genetic Mutations. Am J Med Genet 1980; 7: 405.
23. Tunte W. Human Mutations and Paternal Age. Hum Genet 1972; 16: 77.
24. Modell B, Kuliev A. Impact of public health on human genetics. Clin Genet 1989; 36: 286.
　
　
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25. Carothers A D, McAllion S J, Paterson C R. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986; 23: 227.
26. Jones K L, Smith D W, Sedgwick Harvey M A, et al. Older paternal age and fresh gene mutation: Data on additional disorders. J Ped 1975; 86: 84.
27. Hook EB. Paternal Age and Effects on Chromosomal and Specific Locus Mutations and on Other Genetic Outcomes in Offspring. In: Mastroianni L Jr, Paulsen C A, eds. Aging, Reproduction and the Climacteric. New York and London: Plenum Press, 1986: 117-145.
28. Wilkin D J, Szabo J K, Cameron R, et. al. Mutations in Fibroblast Growth -Factor Receptor 3 in Sporadic Cases of Achendroplansia Occur Exclusively on the Paternally Derived Chromosome. Am J Hum Genet 1998; 63: 711.
29. Orioli J M, Castilla E E, Scarano G, et. al. Effect of Paternal Age in Achondroplasia, Thanatophoric Dysplasia and Osteogenesis Imperfecta. Am J Med Genet 1995; 59: 209.
30. Erickson D, Cohen M M Jr., A Study of parental age effects on the occurrance of fresh mutations for the Apert syndrome. Ann Hum Genet 1974; 38: 89.

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2. Bordson B L, Leonardo VS. The appropriate upper age limit for semen donors: a review of the genetic effects of paternal age. Fertil Steril 1991; 56: 397.
1. Sankaranarayanan K. Ionizing radiation and genetic risks IX. Estimates of the frequencies of mendelian diseases and spontaneous mutation rates in human populations: a 1998 perspective. Mutat Res 1998; 411: 129.
2. Friedman J M. Genetic Disease in the Offspring of Older Fathers. Obstet Gynecol 1981; 57: 745.
3. Carlson K M, Bracamontes J, Jackson C E, et al. Parent-of-Origin Effects in Multiple Endocrine Neoplasia Type 2B. Am J Hum Genet 1994; 55: 1076.
4. Moloney D M, Slaney S F, Oldridge M, et al. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet 1996; 13: 48.
5. Osborne J P, Fryer A, Webb D. Epidemiology of Tuberous Sclerosis. Ann NY Acad Sci 1991; 615: 125.
6. Schuffenecker I, Ginet N, Goldgan D, et al. Prevalence and Parental Origin of De Novo RET Mutations in Multiple Endocrine Neoplasia Type 2A and Familial Medullary Thyroid Carcinoma. Am J Hum Genet 1997; 60: 233.
　
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7. Crow J F. How Much Do We Know About Spontaneous Human Mutation Rates? Environ Mol Mutagen 1993; 21: 122.
8. Crow T J. Editorial. Mutation and psychosis: A suggested explanation of seasonality of birth. Psychol Med 1987; 17: 821.
9. Gordon A. The Incidence of Psychotic Disorders in Individuals Whose Parents Married at an Advanced Age. Med Records 1938; 148: 109.
10. Kinnell H G. Parental Age in Schizophrenia. Br J Psychiatry 1983; 142: 204.
11. Hare E H, Moran PAP. Raised Parental Age in Psychiatric Patients: Evidence for the Constitutional Hypothesis. Br J Psychiatry 1979; 134: 169.
12. Raschka L B. Parental Age and Schizophrenia. Magyar Andrologia-Hungarian Andrology 1998/2; III: 47.
13. Bertram L, Busch R, Spiegl M, et al. Paternal age is a risk factor for Alzheimer disease in the absence of a major gene. Neurogenetics 1998; 1: 277.
14. Whalley L J, Thomas B M, Starr J M. Epidemiology of Presenile Alzheimer’s Disease in Scotland (1974-88). 11. Exposures to Possible Risk Factors. Br J Psychiatry 1995; 167: 732.
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3. Urikami K, Adachi Y, Takahashi K. A Community-Based Study of Parental Age in Alzheimer-Type Dementia in Western Japan. Arch Neurol 1988; 45: 375.
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Labels: Age of the father and the Health of Future Generations Leslie B. Raschka


posted by concerned heart @ 8:37 PM 0 Comments

Tuesday, April 24, 2007
Leslie B.Raschka REALLY TRIED TO GET PEOPLE TO KNOW AND PUBLICIZE THIS RISK HE WAS TRYING TO GET THE WORLD HEALTH ORGANIZATION TO ANNOUNCE IT

this letter was published a year before Dr. Raschka's death. He sounded like a broken record trying to mention paternal age.


Journal of Psychiatry
November 2002


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La revue canadienne
de psychiatrie
2002 novembre


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Letters to the Editor
(PDF)


Paternal Age as a Risk Factor



Letters to the Editor

Paternal Age as a Risk Factor
Dear Editor:

Recent research reports have focused attention on the association between advanced paternal age and increased risk of schizophrenia in offspring (1,2). In addition to schizophrenia, numerous genetic illnesses are reported to have the same association with increased paternal age (3). An increased mutation rate related to increased paternal age has been documented in the male gametogenesis (4). Most of these illnesses are autosomal-dominant disorders (5). Two x-linked recessive illnesses—hemophilia A and Lesch-Nyhan disease—have been frequently found with increased maternal grandpaternal age (6–8). It is proposed that the origin of schizophrenia can in some cases be related to a mutation in the gametogenesis of the father that is related to aging. It is further proposed that, as with hemophilia A and Lesch-Nyhan disease, the mutated gene or genes in some cases of schizophrenia and other genetic illnesses can be transmitted to future generations. In such cases, the illness could be expressed in a distant relative far removed in time from the original mutational event. Further genetic research on germline mutations related to paternal age is needed to establish the significance of paternal age as a risk factor.

References
1. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, and others. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001;58:361–7.

2. Raschka LB. Parental age and schizophrenia. Magyar Andrologia [Hungarian Andrology] 1998;111:47–50.

3. Tarin JJ, Brines J, Cano A. Long-term effects of delayed parenthood. Hum Reprod 1998;13:2371–6.

4. Crow JF. How much do we know about spontaneious human mutation rates? Environ Mol Mutagen 1993;21:122–9.

5. Carothers AD, McAllion SJ, Paterson CR. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986;23:227–30.

6. Rimoin DL. Mutation in man. In: Emery AEH, Rimoin DA, editors. Principles and practice of medical genetics. Edinburgh (UK): Churchill Livingstone; 1983. p 32–3.

7. Crow JF. The high spontaneious mutation rate: is it a risk? Proc Natl Acad Sic USA 1997;94:8380–6.

8. Prevention of avoidable mutational disease: memorandum from a WHO meeting. Bull World Health Organ 1986;64:205–16.

Leslie B Raschka, MD, FRCPC
Toronto, Ontario
Labels: prevention of avoidable mutational disease, Schizophrenia


posted by concerned heart @ 7:00 PM 0 Comments

LESLIE B. RASCHKA M.D. TRIED TO WARN OTHERS ABOUT THE PATERNAL AGE EFFECT BEFORE DR. MALASPINA'S 2001 PAPER

Abstract
Purpose: To assess the role of paternal age in the origin of genetic illness in future generations.
Data Sources: All reference data originated in English language international scientific literature and findings of original research conducted by myself.
Study Selection: Original articles published between 1938 and 1998 were selected according to the stated purpose. One article was written by myself.
Data Extraction: The present paper deals with 4 subtopics: andrology, genetics, pathology, and psychiatry.
Results: Nine articles reporting on 1399 patients described the deterioration of the quality of semen related to ageing. Five articles reported an increased mutation rate in the male germ cells as compared to the female germ cell. Twenty-four articles reported on 1230 patients and related studies described paternal age effect on increased mutation rate causing genetic illness. Eight articles reporting on 10,347 patients described increased prevalence of mental illness as related to older paternal age.


Conclusions: The age of the father is an important determinant of the health of future generations. Children conceived by fathers older than 34 years of age are at increased risk for genetic illness due to recent mutation in the male germ cell.
3The genetic illness of a child could originate in a mutation related to the age of the father or to a mutation in the spermatogenesis caused by ageing in previous generations. The ageing process in the male is an important, probably the most important, cause of genetic illness in human populations.
Labels: children conceived by older fathers are at increased risk of genetic illness due to a recent mutation in the male germ line, Leslie B. Raschka, M.D.