Why are we not told about the paternal age effect in Alzheimer's., cancers, MS. hemophilia, autism.schizophrenia diabetes?

Why are the wealthy corporate monied families in America funding the research at genome labs?

Alex asked: Are genetic disease and disorders caused by older paternal age and will there never be cures or for Alzheimer’s, diabetes, MS, hemophilia, autism, schizophrenia,cancers because in non-familial cases they are basic degradations of the human genome caused by genetic copy number variations?

Male Biological Clock Autism, Schizophrenia, Bipolar Alzheimer's etc in offspring

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

Advanced paternal age

Advanced paternal age
In recent years, several high-quality studies have confirmed an association between advanced paternal age and increased risk of schizophrenia.22-24 The association between paternal age and schizophrenia has been repeatedly shown to be present in those with no family history of the disorder, but not in those with a positive family history. This finding raises the possibility that accumulation of de-novo mutations in paternal sperm with ageing contributes to the risk of schizophrenia. The strengthened evidence linking advanced paternal age and schizophrenia has influenced a range of aetiological theories of schizophrenia. For example, the persistence of schizophrenia in the population in spite of reduced fertility could be explained by the transgenerational accumulation of paternally-derived mutations. Paternal exposure to micronutritional deficiencies such as folate could further amplify copy-error mutations in the male germ cell lines. Finally, it is also feasible that epigenetic processes (eg, chromatin folding, methylation of CpG bases) could be compromised in the sperm of older fathers, and that these mechanisms may contribute to the increased risk of schizophrenia in the offspring of older
fathers.

Med J Aust. 2009 Feb 16;190(4):S7-S9.
Links
New directions in the epidemiology of schizophrenia.
McGrath JJ, Susser ES.
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia. john_mcgrath@qcmhr.uq.edu.au.
New primary data and systematic reviews have prompted the review of some long-held views about the epidemiology of schizophrenia. The incidence and prevalence of schizophrenia show prominent variation between locations. Males are more likely to develop schizophrenia than females (1.4 : 1). Migrant status, urban birth or residence, and advanced paternal age are associated with an increased risk of developing schizophrenia. Prenatal infection and nutrition are associated with an increased risk of schizophrenia. Individuals with schizophrenia have a 2-3-fold increased mortality risk compared with the general population. This differential mortality gap may have worsened in recent decades. Epidemiology is good for generating candidate exposures but poor at proving them. Cross-disciplinary projects between epidemiology and neuroscience may help us understand the pathways leading to schizophrenia.
PMID: 19220176 [PubMed - as supplied by publisher]
Related Articles
ReviewSchizophrenia: a concise overview of incidence, prevalence, and mortality. [Epidemiol Rev. 2008]
ReviewUrban birth and risk of schizophrenia: a worrying example of epidemiology where the data are stronger than the hypotheses. [Epidemiol Psichiatr Soc. 2006]
ReviewPrevention of suicide and attempted suicide in Denmark. Epidemiological studies of suicide and intervention studies in selected risk groups. [Dan Med Bull. 2007]
ReviewA systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? [Arch Gen Psychiatry. 2007]
Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism. [Schizophr Bull. 2008]
» See Reviews... » See All...

By the time the father is over 45, his risk of having a child who will develop schizophrenia is nine times higher than that of a 20-year-old father

Risk may increase, for example, with the age at which parents conceive a child. Although this is not the same type of genetic risk as the one just discussed, the cause of the increased risk is nevertheless genetic. Until recently, most attention focused on mothers over 40, who are known to be at higher risk of having children with diseases such as Down’s syndrome. It now appears, however, that it is not older mothers who are more likely to have offspring who become schizophrenic but rather older fathers. Regardless of whether they have a family history of schizophrenia, older fathers confer an increased risk of schizophrenia on their offspring. In fact, the risk to the offspring goes up steadily with the age of the father after age 24, independent of the age of the mother. By the time the father is over 45, his risk of having a child who will develop schizophrenia is nine times higher than that of a 20-year-old father. The most likely reason is that men are constantly developing new sperm. Because the precursors to sperm— spermatocytes—divide every 16 days, by the time a man is 55 years old, almost 1,000 cell divisions have taken place. The opportunity for a copying error in the sperm in which a mutation spreads through the generations of sperm by copying itself is, therefore, relatively high.
The contribution of a father’s increased age could explain a good number of the observations associated with schizophrenia. For instance, although schizophrenia clearly runs in families, it does not do so in a manner consistent with the classical genetics of Gregor Mendel. It can, for instance, appear in families where it has not been seen before. The risk attached to older fathers may be more apparent today. Probably a certain number of older men have always produced children, but having a large pool of older fathers healthy enough to have children in substantial numbers is a new phenomenon.

Picture Emerging on Genetic Risks of IVF

Picture Emerging on Genetic Risks of IVF


Published: February 16, 2009
(Page 2 of 2)
That prompted Dr. Feinberg and Dr. DeBaun to investigate the prevalence of IVF and related methods in the pregnancies that resulted in children with Beckwith-Wiedemann syndrome. Their conclusion, and the conclusion from at least half a dozen other large studies, was that there were about 10 times more parents who had used IVF or related methods than would be expected.
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Related
Health Guide: In Vitro Fertilization IVF
Another disorder caused by abnormal gene expression, Angelman syndrome, also is suspected of being linked to IVF. It involves severe mental retardation, motor defects, an inability to speak and a cheerful disposition. The disorders are rare. Beckwith-Wiedemann occurs just once in 13,000 children, and Angelman occurs about once in every 10,000 children.
Why, researchers ask, would growing embryos in petri dishes elicit changes in gene expression? And if there are changes, could they alter the laboratory conditions so those gene expression changes do not occur?
One place to look might be the broth, known as the culture medium, in which embryos grow. From the start of IVF, scientists knew that the composition of the broth affected how quickly embryos grew, Dr. Rawlins said. And they knew that embryos, both animal and human, grew much more slowly in the lab than they did in the body.
One thing the culture medium provides is chemicals that can be used to add methyl groups to genes. The presence, or absence, of the methyl groups can control whether genes are active or not, a process known as epigenetics. Epigenetic changes not only cause rare disorders like Beckwith-Wiedemann syndrome but also are associated with low-birth-weight babies and an increased risk of a variety of cancers. That does not mean that growing embryos in petri dishes will have such effects, but it does raise questions about what is known about the procedure.
Dr. George Daley, a researcher at Harvard Medical School studying human embryonic stem cells, said the questions also extended to those cells, which are taken from human embryos and grown in petri dishes. He has seen epigenetic changes in stem cells but is not sure what they mean.
“My major concern is that we don’t have enough information, or the tools to measure epigenetic stability,” he said. “It may or may not be relevant to the safety of the cells, though I suspect it is.”
But figuring out what, if anything, in the culture medium might adversely affect embryo growth and development may not be easy, Dr. Feinberg said.
Dr. Ginsburg said the Society for Assisted Reproductive Technology discussed whether to ask IVF centers to report what media they were using to grow their embryos. But, she said, “programs use multiple media, and it is very common for programs to switch from one media to another.”
If mouse embryos are even close to reflecting what can happen with humans, then there is no question that gene expression can be altered by growing embryos in a laboratory, Dr. Schultz says.
He and several others spent years asking whether there were gene expression changes in mouse embryos that are grown in the laboratory — there are — and whether they could see behavioral changes in the animals. They did.
For example, the investigators gave mice a test that required remembering the location of a platform hidden by opaque water. The IVF mice had no trouble learning where the platform was, but were more likely to forget what they had learned, Dr. Schultz found.
In another test, which measured a fear response when mice are in the open, IVF mice lacked the normal caution and fear that non-IVF mice are born with.
“They are changes,” Dr. Schultz said, of the test results. “And the only difference is that they were cultured,” meaning that the mice started out as embryos in a petri dish.
Along with the behavioral changes were changes in the methylation of genes — epigenetic changes, Dr. Schultz reports. “I am suspicious that manipulation and culturing of embryos is a contributing factor,” he adds.
But following babies born after IVF or intracytoplasmic sperm injection is not easy. And if problems emerge from epigenetic changes, they may not be apparent until adulthood or middle or old age.
“When you send questionnaires, the tendency is for the couple who may have had a problem or who think they have a problem to answer that questionnaire,” said Dr. Zev Rosenwaks, director of the Center for Reproductive Medicine and Infertility at New York Weill Cornell Center. Those who do not respond tend to be parents whose children seem fine, skewing the data.
Dr. Rosenwaks’s group largely paid for its own studies. They conclude, he said, that “even if there was a slight increase in abnormalities, the rate was not much higher than in the general population.”
Others, like Dr. Alistair Sutcliffe of University College London, say the field is crying out for more information on the risks.
“I talk on this topic worldwide,” he said. “My talks over time are based on the known literature. And I have gradually become slightly less optimistic about the things that are known about the health of the children” born after IVF and related procedures.
“Obviously, more knowledge is required,” Dr. Sutcliffe said. “The perfect study hasn’t been done.”

Again this Important Paper Perils of the Being the Offspring of an Older Dad

Perils of the Being the Offspring of an Older Dad
at：2009-02-17 08:56:45 Click: 15
Reprint E-Mail Post Republish More> January 15, 2009 Older men are having children, but the reality of a male biological clock makes this trend worrisome By Harry Fisch, MDFeature 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. © 2009 Advanstar Communications Inc.. Permission granted for up to 5 copies. All rights reserved. You may forward this article or get additional permissions by typing http://license.icopyright.net/3.7452?icx_id=575098 into any web browser. Advanstar Communications Inc. and Geriatrics logos are registered trademarks of Advanstar

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

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

Gender equality: Aging egg and sperm are both problematic

Gender equality: Aging egg and sperm are both problematic


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

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

Global: Older men are having children, but the reality of a male biological clock
Date Posted: Sunday 08-Feb-2009
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.
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Genetic Diseases related to Advanced Paternal Age

Genetic Diseases related to Advanced Paternal Age

,


Table II. Long-term effects of paternal ageing on offspring from table on page 2373 of Long –term effects of delayed parenthood by J.J. Tarin, J. Brines, and A. Cano

Dominant disorders
Wilms tumour, thanatophoric dysplasia, retinitis pigmentosa, osteogenisis imperfecta type IIA, acrodysostosis, achondroplasia, Apert’s disease, fibrodysplasia ossificans progressiva, aniridia, bilateral retinoblastoma, multiple exostoses, Marfan’s, Lesch-Nyan’s, Pfeiffer’s, Wardenburg’s, Treacher-Collins, Soto’s, and Crouzon’s syndromes, basel cell nevus, cleidocranial dysostosis, polyposis coli, oculodentodigital syndrome, Costello syndrome , progeria, Recklinghausen’s neurofibromatosis, tuberous sclerosis and renal polycystic kidney disease.

X-linked recessive diseases
Haemophilia A and Duchenne’s muscular dystrophy

Non-cytogenetic congential defects
Congential cataracts, reduction defects of the upper limb, nasal aplasia, pulmonic and urethtal stenosis, perauricular cyst, cleft palate,1 neural tube defects

Athetoid /dystonic cerebral palsy and congenital hemiplegia

Psychotic disorders

Decreased learning capacity and/or mental retardation




Moreover, (i) the activities of antioxidant enzymes within the seminal plasma and spermatozoa from older men may be reduced and so spermatozoa may be more vulnerable to mutational changes than spermatozoa from younger men; and (ii) late spermatids, and immature and mature spermatozoa do not have a DNA repair system.

posted by concerned heart at 8:37 PM | 0 comments
Labels: basal cell nevus, disease, Marfan's, neurofibromatosis, progeria, renal polycystic kidney


posted by concerned heart @ 11:20 PM 0 Comments

Saturday, January 13, 2007
Paternal Age Effect and Disorders Known in 1999

Table II. Long-term effects of paternal ageing on offspring from table on page 2373 of Long –term effects of delayed parenthood by J.J. Tarin, J. Brines, and A. Cano

Dominant disorders
Wilms tumour, thanatophoric dysplasia, retinitis pigmentosa, osteogenisis imperfecta type IIA, acrodysostosis, achondroplasia, Apert’s disease, fibrodysplasia ossificans progressiva, aniridia, bilateral retinoblastoma, multiple exostoses, Marfan’s, Lesch-Nyan’s, Pfeiffer’s, Wardenburg’s, Treacher-Collins, Soto’s, and Crouzon’s syndromes, basel cell nevus, cleidocranial dysostosis, polyposis coli, oculodentodigital syndrome, Costello syndrome , progeria, Recklinghausen’s neurofibromatosis, tuberous sclerosis and renal polycystic kidney disease.

X-linked recessive diseases
Haemophilia A and Duchenne’s muscular dystrophy

Non-cytogenetic congential defects
Congential cataracts, reduction defects of the upper limb, nasal aplasia, pulmonic and urethtal stenosis, perauricular cyst, cleft palate,1 neural tube defects

Athetoid /dystonic cerebral palsy and congenital hemiplegia

Psychotic disorders

Decreased learning capacity and/or mental retardation

Gene Mutation Tied to Majority of Cases of Mental Retardation

Gene Mutation Tied to Majority of Cases of Mental Retardation
Finding might lead to better diagnosis and drug treatments, study says
Posted February 4, 2009
By Steven Reinberg
HealthDay Reporter

WEDNESDAY, Feb. 4 (HealthDay News) -- Children who have the most common form of mental retardation -- called nonsyndromic mental retardation -- appear to have a genetic mutation that may contribute to the condition, new research finds.



What's unusual about the mutation is that it occurs during development of the child and is not passed on by the child's parents, the researchers said.

"Nonsyndromic mental retardation is a very common problem -- it involves about 3 percent of the population," said lead researcher Dr. Jacques L. Michaud, of the Center of Excellence in Neuromics at the University of Montreal in Canada. "It is the most common mental handicap in children."

Children and adults who have nonsyndromic mental retardation have no physical abnormality, they look like any other child or adult, but they nonetheless have the condition, Michaud said.

"We have good reason to think genes are the cause of this syndrome," he said.

The findings were published in the Feb. 5 issue of the New England Journal of Medicine.

For the study, Michaud and his colleagues zeroed in on the SYNGAP1 gene -- which produces a protein critical for learning and memory -- in 94 patients with nonsyndromic mental retardation. The researchers identified mutations in the gene in three children.

These are new mutations, Michaud said. "Mutations you find in the kids, but you don't find in the parents," he said. "The mutation arises in the development of the kid."

The mutations involve the brain, especially those areas that affect the development, function and connection between neurons, Michaud said.

The researchers then looked for the same mutations in 142 people with autism, 143 people with schizophrenia and 190 healthy people. None of these people had the mutations associated with nonsyndromic mental retardation, the researchers said.

One important aspect of this finding is that it explains the origins of nonsyndromic mental retardation, Michaud said. "For a lot of families, not having an explanation makes it difficult to accept the condition. Having an explanation helps them to better accept the condition," he said.

The finding should also reassure parents that the condition isn't inherited, he said.

Michaud thinks the finding may lead to the development of new methods to teach children with nonsyndromic mental retardation. And a long-term goal is to develop medications that would help these children, in much the same way that ADHD can be treated with drugs, he said.

Dr. Randi Hagerman, a professor of pediatrics and medical director of the M.I.N.D. Institute at the University of California, Davis, thinks the finding is important, because it could lead to better diagnosis and possibly treatment of the condition.

"This is an important paper, because it represents about 3 percent of nonsyndromic mental retardation," Hagerman said. "This suggests that more screening for this mutation should be done in the workup of patients," he said.

Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and

autism.

: Schizophr Bull. 2008 Nov;34(6):1042-6. Epub 2008 Sep 15. Links
Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism.Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, Shmushkevitch M, Caspi A, Malaspina D, Davidson M.
Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. mweiser@netvision.net.il

BACKGROUND: Evidence indicates an association between older parents at birth and increased risk for schizophrenia and autism. Patients with schizophrenia and autism and their first-degree relatives have impaired social functioning; hence, impaired social functioning is probably an intermediate phenotype of the illness. This study tested the hypothesis that advanced father's age at birth would be associated with poorer social functioning in the general population. To test this hypothesis, we examined the association between parental age at birth and the social functioning of their adolescent male offspring in a population-based study. METHODS: Subjects were 403486, 16- to 17-year-old Israeli-born male adolescents assessed by the Israeli Draft Board. The effect of parental age on social functioning was assessed in analyses controlling for cognitive functioning, the other parent's age, parental socioeconomic status, birth order, and year of draft board assessment. RESULTS: Compared with offspring of parents aged 25-29 years, the prevalence of poor social functioning was increased both in offspring of fathers younger than 20 years (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.08-1.49) and in offspring of fathers 45 years old (OR = 1.52, 95% CI = 1.43-1.61). Male adolescent children of mothers aged 40 years and above were 1.15 (95% CI = 1.07-1.24) times more likely to have poor social functioning. CONCLUSIONS: These modest associations between parental age and poor social functioning in the general population parallel the associations between parental age and risk for schizophrenia and autism and suggest that the risk pathways between advanced parental age and schizophrenia and autism might, at least partially, include mildly deleterious effects on social functioning.

Autism and Schizophrenia and As Fathers Age on a Populations level

Autism and Schizophrenia and As Fathers Age on a Populations level
at：2009-02-04 01:06:45 Click: 23
Schizophrenia Risk and the Paternal Germ Line
By Dolores Malaspina


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References:
Auroux M. Decrease of learning capacity in offspring with increasing paternal age in the rat. Teratology. 1983 Apr;27(2):141-8. Abstract

Benoit G, Trasler JM. Developmental expression of DNA methyltransferase messenger ribonucleic acid, protein, and enzyme activity in the mouse testis. Biol Reprod. 1994 50:1312-9. Abstract

Bradley-Moore M, Abner R, Edwards T, Lira J, Lira A, Mullen T, Paul S, Malaspina D, Brunner D, Gingrich JA. Modeling The Effect Of Advanced Paternal Age On Progeny Behavior In Mice. Developmental Psychobiology, abstract, 2002; (41)3, 230.

Breslow, N. E. and Day, N. E. (1980). The analysis of case-control data. In Statistical Methods in Cancer Research , Volume 1. Lyon: World Health Organization.

Brown AS, Schaefer CA, Wyatt RJ, Begg MD, Goetz R, Bresnahan MA, Harkavy-Friedman J, Gorman JM, Malaspina D, Susser ES. Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry. 2002 Sep;159(9):1528-33. Abstract

Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. Parental age and risk of schizophrenia: a case-control study. Arch Gen Psychiatry. 2003 Jul;60(7):673-8. Abstract

Crow JF (1997). The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci USA 94:8380-8386.

Craddock N, O'Donovan MC, Owen MJ. Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull. 2006 Jan;32(1):9-16. Abstract

Dalman C, Allebeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry. 2002 Sep;159(9):1591-2. Abstract

Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993 Aug;4(4):387-92. Abstract

El-Saadi O, Pedersen CB, McNeil TF, Saha S, Welham J, O'Callaghan E, Cantor-Graae E, Chant D, Mortensen PB, McGrath J. Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia.Schizophr Res. 2004 Apr 1;67(2-3):227-36. Abstract

Kegeles LS, Shungu DC, Mao X, Goetz R, Mikell CB, Abi-Dargham A, Laurelle M, Malaspina D. Relationship of age and paternal age to neuronal functional integrity in the prefrontal cortex in schizophrenia determined by proton magnetic resonance spectroscopy. Schizophrenia Bulletin, 31:443; 2005.

La Salle S, Mertineit C, Taketo T, Moens PB, Bestor TH, Trasler JM. Windows for sex-specific methylation marked by DNA methyltransferase expression profiles in mouse germ cells. Dev Biol. 2004 268:403-15. Abstract

Lindblad K, Schalling M. Expanded repeat sequences and disease. Semin Neurol. 1999;19(3):289-99. Abstract

Malaspina D, Friedman JH, Kaufmann C, Bruder G, Amador X, Strauss D, Clark S, Yale S, Lukens E, Thorning H, Goetz R, Gorman J. Psychobiological heterogeneity of familial and sporadic schizophrenia. Biol Psychiatry. 1998 Apr 1;43(7):489-96. Abstract

Malaspina D, Goetz RR, Yale S, Berman A, Friedman JH, Tremeau F, Printz D, Amador X, Johnson J, Brown A, Gorman JM. Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome. Am J Psychiatry. 2000 Jun;157(6):994-1003. Abstract

Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001 Apr;58(4):361-7. Abstract

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

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

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

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

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

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

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

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

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

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

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

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

Is Older Paternal Age a Cause of these Mistakes

Scientists show extra copies of a gene carry extra risk
February 4th, 2009 in Medicine & Health / Genetics
Is more of a good thing better? A gene known as LIS1 is crucial for ensuring the proper placement of neurons in the developing brain. When an LIS1 gene is missing, brains fail to develop the characteristic folds; babies with lissencephaly or 'smooth brain' are born severely mentally retarded. But new research by Prof. Orly Reiner of the Institute's Molecular Genetics Department, which recently appeared in Nature Genetics, shows that having extra LIS1 genes can cause problems as well.

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Reiner was the first to discover LIS1's tie to lissencephaly, in 1993. Their latest study shows that it works by helping to determine polarity in the cell - how the various organelles are arranged inside the cell as well as where it connects to neighboring cells. Neurons alter their polarity several times during development, especially when they take on an elongated shape and migrate to new locations in the brain.

But what if, rather than too little, the body has too much LIS1? One of the surprises to come out of the recent spate of post-human-genome research is the number of genes that can be repeated or deleted in an individual's genome. Most extra copies of genes may be no more harmful than a computer backup disk, but scientists have been finding that some repeats can cause disease.

Research associate Dr. Tamar Sapir and lab technician Talia Levy, working in Reiner's lab, developed a mouse model in which additional LIS1 protein was produced in the brain. The scientists found that the brains of these mice were a bit smaller than average. On closer inspection, they discovered a range of subtle changes in cell polarity and movement: Nuclei within the proliferating zone tended to move faster, but with less control; rates of cell death were higher; and various factors in the cell became more disordered.

Reiner then asked whether their findings might apply to humans. Together with Jim Lupski and Drs. Weimin Bi and Oleg A. Shchelochkov of Baylor College of Medicine in Houston, Texas, they searched through blood samples using a technique that matches a patient's DNA with control DNA to identify additions or deletions in its sequence. They identified seven individuals with extra copies of either LIS1 or adjacent genes that are also involved in brain development. All suffered developmental abnormalities. Two of the patients - children with a second LIS1 gene - had previously been diagnosed with failure to thrive and delayed development, and were found to have small brain sizes. A third, who had three copies of the gene, was mentally retarded and suffered from bone deformation as well.

Reiner: 'Several brain diseases, including schizophrenia, epilepsy and autism, have been linked to faulty neuron migration, and recent research has hinted that some of these may involve variations in gene number. Our study is the first to demonstrate the effects of the duplication of a single gene in a mouse model and tie it to a new 'copy number variation' human disease.'

For the scientific paper, please see: http://www.nature.com/ng/journal/v41/n2/pdf/ng.302.pdf

Source: Weizmann Institute of Science