6 Fold Increase in Autism for Offspring of Men Over 40

Older parents, epigenomics and psychiatric illness

Older parents, epigenomics and psychiatric illness
2008-11-11 — Dave Bath
Nature’s British Journal of Pharmacology has (for free!) an editorial that is getting my nose twitching, and pushes me to speed up a Balneus post that has been brewing for a while. The growing literature on the diseases of children caused by advanced parental age suggests that the societal pattern of people building their careers before having children needs to be reviewed by social policy makers.


"Epigenetic biomarkers in psychiatric disorders" British Journal of Pharmacology (2008) 155, 795–796; doi:10.1038/bjp.2008.254; published online 23 June 2008 (also as PDF is yet another paper stressing the importance of epigenetics in pathogenesis, and introduces a new word, "epigenomics" that relates to testing and markers.

Basically, the older the person (male or female) when conceiving a child, the more likely something epigenetic has gone awry and will cause problems.

Another relatively recent paper highlighted the relationship between advanced parental age and schizophrenia: "Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia" Schizophrenia Bulletin doi:10.1093/schbul/sbm093 (advance publication 2007-08-21) contains the following:

In 2001, Malaspina et al showed that the incidence of schizophrenia increased progressively with increasing paternal age, the risk being 2-fold and 3-fold for offspring of fathers aged 45–49 and 50 or more years, compared with those of fathers aged less than 25 years.

It’s not just schizophrenia: autism, cognitive and learning difficulties, longevity … the list gets longer every year.

It’s a far cry from what we were taught at uni in the seventies: that old ova stuck in meiosis for 40 years accumulated damage (leading to increased incidence of trisomy 21 or Down’s Syndrome), but because spermatogenesis was continuous, older males didn’t cause such problems.

This raises questions about how social policy affects societal health perhaps more serious than the "diabesity" epidemic, as obesity is more easily treated than something caused at the time of conception (even before).

The easy recommendation is for ladies: ignore the flattery and bank balances of older men!

For males, it’s worthwhile trying to settle down earlier, do the parenting bit with your career on hold.

For politicians, this means that education patterns and work/life balance policies need some attention - unless we want each generation of teenagers to be nuttier than than the previous one.

Someone in Canberra should be crunching the numbers between the census details on parental age and epidemiology, taking into account greater diagnostic capabilities across the years.
I’m much relieved that at 48, my grandson is approaching 2, not only because of this research, but because I’ve got just enough energy to keep up with him for a couple of days (I stay with my daughter and grandson every second weekend on average). I’d be much less fun for him if my joints were any creakier!


Posted in Biology and Health, Politics, Society.

The male biological clock is ticking: a review of the literature

http://www.ncbi.nlm.nih.gov/pubmed/18711662?dopt=AbstractPlus

Sao Paulo Med J. 2008 May;126(3):197-201.
The male biological clock is ticking: a review of the literature.Pasqualotto FF, Borges Júnior E, Pasqualotto EB.
Association Institute Sapientiae, Universidade de Caxias do Sul, São Paulo, Brazil.

The term biological clock is usually used by physicians and psychologists to refer to the declining fertility, increasing risk of fetal birth defects and alterations to hormone levels experienced by women as they age. Female fecundity declines slowly after the age of 30 years and more rapidly after 40 and is considered the main limiting factor in treating infertility. However, there are several scientific reports, chapters in books and review articles suggesting that men may also have a biological clock. The aim of our study was to conduct a review of the literature, based on the Medical Literature Analysis and Retrieval System Online (Medline), to evaluate the male biological clock. After adjustments for other factors, the data demonstrate that the likelihood that a fertile couple will take more than 12 months to conceive nearly doubles from 8% when the man is < 25 years old to 15% when he is > 35 years old. Thus, paternal age is a further factor to be taken into account when deciding on the prognosis for infertile couples. Also, increasing male age is associated with a significant decline in fertility (five times longer to achieve pregnancy at the age of 45 years). Patients and their physicians therefore need to understand the effects of the male biological clock on sexual and reproductive health, in that it leads to erectile dysfunction and male infertility, as well as its potential implications for important medical conditions such as diabetes and cardiovascular diseases.

PMID: 18711662 [PubMed - as supplied by publisher]

AN Excellent Video A MUST SEE

Male Biological Clock

Prevent Your Child Needing Health Care for Chronic Disorders By Fathering Babies Earlier In Life

It has been disasterous for offspring of the many, many men who father older and older in the Western World and elsewhere. Why are first borns smarter? Did they even ask about paternal age? No, the study did ask about maternal age.





It’s Waning Men,
June 14, 2007
First Published: 00:48 IST(14/6/2007)
Last Updated: 03:16 IST(14/6/2007)






This Father’s Day (June 18) will be observed with a difference. So say the western media that have been running a series of articles to celebrate men as “elaborately engineered gamete vectors”. In fact, the focus seems to be more on the “elaborately engineered” gametes themselves: the sperm. And rightly, too, considering male sperm cells are specialised ones that are only formed after puberty. It is the ability to produce sperm that makes men — well, arguably — such an invaluable resource for the human species. As it is with the male in every other species.

It is curious that although sperm have been around since the beginning of time, we know so little about what is in them, and what makes them tick, er, swim. So scientists spend a lot of their waking hours trying to compare the structure and content of the proteins of sperm in various species, in order to understand their evolution and origin. For instance, the mutated DNA in the genes of the sperm of older fathers is believed to cause many genetic diseases. It is almost as if a man’s biological clock accelerates mutation in sperm cells in his early ’30s.

But perhaps there’s a more important reason to ponder the future of “man” this Father’s Day. Researchers recently successfully prompted embryonic stem cells (that could turn into any type of cell in the body) in mice to become sperm, which fertilised a mouse egg. Once this success is replicated in humans, it would be entirely possible to produce sperm without men. Not quite a man’s world, is it?

Men 40 and over are nearly six time more likely to have offspring with autism and other genetic defects, also schizophrenia rates are increased etc.

Scientific Evidence Points to Male Biological Clock
Symptoms Include Declining Fertility, Lowered Testosterone Levels and Increased Risk of Heart Disease, Diabetes and Genetic Abnormalities Such as Autism
NEW YORK (Nov 15, 2006)

It is well known that women have a "biological clock" associated with declining fertility, increasing risk for fetal birth defects, and altered hormone levels. Now an increasing body of scientific evidence points to the existence of a similar male biological clock, according to a retrospective review article by NewYork-Presbyterian Hospital and Columbia University Medical Center researchers published in the Nov. 15 Journal of the American Medical Association (JAMA). Conditions associated with the male phenomenon include declining fertility, lowered testosterone levels, diabetes, heart disease, depression, erectile dysfunction (ED) and an increased risk of fetal birth defects.

"Similar to women, aging is associated with declines in sex hormone levels in men. Testosterone decrease is not as steep or as sudden as that associated with estrogen declines during menopause in women, but its effects can be significant," says Dr. Harry Fisch, the study's senior author and director of the Male Reproductive Center and director of urologic microsurgery at NewYork-Presbyterian/Columbia, and professor of clinical urology at Columbia University College of Physicians and Surgeons. Dr. Fisch is also the author of The Male Biological Clock (Free Press), published earlier this year.

Low testosterone level (hypogonadism) affects between two million and four million American men. Symptoms include decreased muscle mass and bone mineral density; decreased libido and energy; obesity; insulin resistance; and mental and emotional problems. Other associated medical conditions and specific findings chronicled in Dr. Fisch's article include:

Male Infertility. Male infertility increases with the man's age. Men older than 35 are twice as likely to be infertile (defined as the inability to initiate a pregnancy within 12 months) compared to men younger than 25.

Birth Defects. As with advanced maternal age, advanced paternal age is associated with an increased incidence of birth defects due to decreased genetic quality of sperm. Men 40 and older are nearly six times more likely to have offspring with autism than men younger than 30, even after controlling for maternal age and other variables. Other defects associated with elevated paternal age include schizophrenia, Down syndrome and genetic abnormalities.

Type 2 Diabetes and Metabolic Syndrome. Both Type 2 diabetes and metabolic syndrome (which involves pre-diabetes symptoms as well as cardiovascular risk factors) are strongly associated with below-normal levels of testosterone. Of men aged 40 to 49 with Type 2 diabetes, 40 percent had decreased testosterone; the rate was nearly 55 percent among men in their 70s.

Erectile Dysfunction (ED)-Related Conditions. Broadly speaking, ED is strongly related to age-related biological changes and, hence, the male biological clock is also implicated in these other chronic, frequently progressive, and disruptive conditions:

Cardiovascular Disease. Prevalence of ED is significantly higher among patients being treated for heart disease and hypertension. Treatments for hypertension may contribute to erectile dysfunction, which may help explain the increased incidence of ED in these patients. However, the reverse relationship is also true: ED should be considered a marker for hypertension and other cardiovascular complications.

Depression. Depression may both contribute to and link erectile dysfunction and cardiovascular disease. Erectile dysfunction is associated with well-established negative psychological effects, primarily depression and anxiety. Furthermore, patients with ED who are depressed are more likely to develop cardiovascular disease.

Mortality. In one study, men with low testosterone had a mortality rate of 35 percent during the eight-year study period compared with a mortality rate of only 20 percent among men with normal testosterone levels. This trend persisted even after controlling for all reasonable variables in the study population.

The most common available treatment for hypogonadism is testosterone replacement therapy.

The study reports that prescription testosterone use in the United States has increased significantly in recent years with approximately 2.3 million prescriptions written in 2005; this represents a 50-percent increase from 2001 and a 210-precent increase from 1999. (In another ill-advised practice, testosterone therapy is prescribed "off label" for physical enhancement, such as for boosting muscle mass or "energy" in otherwise healthy men.)

"An improved understanding of the associated cellular and biochemical mechanisms of 'gonadal' aging is needed so that safe and effective ways to delay this process, or, in effect, 'rewind' the clock, might be possible," says Dr. Fisch.

The article's co-authors include Dr. Marianne Legato, founder and director of the Partnership for Gender Specific Medicine at NewYork-Presbyterian/Columbia and professor of clinical medicine at Columbia University College of Physicians and Surgeons; and Dr. Benjamin H. Lewis, cardiologist at NewYork-Presbyterian/Columbia and associate clinical professor of medicine at Columbia University College of Physicians and Surgeons.

For more information, patients may call (866) NYP-NEWS.

NewYork-Presbyterian Hospital
NewYork-Presbyterian Hospital – based in New York City – is the nation's largest not-for-profit, non-sectarian hospital, with 2,224 beds. It provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/Allen Pavilion and NewYork-Presbyterian Hospital/Westchester Division. One of the largest and most comprehensive health-care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. It ranks sixth on U.S.News & World Report's guide to "America's Best Hospitals," has the greatest number of physicians listed in New York magazine's "Best Doctors" issue, and is included among Solucient's top 15 major teaching hospitals. The Hospital has academic affiliations with two of the nation's leading medical colleges: Joan and Sanford I. Weill Medical College of Cornell University and Columbia University College of Physicians and Surgeons.

Columbia University Medical Center
Columbia University Medical Center provides international leadership in pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians and Surgeons, the College of Dental Medicine, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. For more information, visit www.cumc.columbia.edu.

Dr. Narendra P. Singh, Unversity of Washington

"One of the best markers we have of the male biological clock is an increase in DNA-damaged sperm. At age 25, only 5 percent of a man's sperm has DNA damage; by age 35, that percentage has grown to 20 percent. That's a fourfold increase in just ten years. As the percentage of damaged sperm increases, the odds of fertilization decrease." — Narendra Singh, associate professor in the Department of Bioengineering at the University of Washington, Seattle

In a study examing the sperm of 66 men aged 22-80. Dr.Narendra P Singh, Dr. Charles Mueller, and Dr. Richard Berger found....

The researchers found that men over age 35 had sperm with lower motility and more highly damaged DNA in the form of DNA double-strand breaks. The older group also had fewer apoptotic cells -- an important discovery, Singh said.

"A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage," he said. "Most other cells do."

As a result, the only way to avoid passing sperm DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age.

"So in older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated," Singh said. "That means some of that damage could be transmitted to the baby." More research is needed to determine just what the risks are......

Dr. Nancy Snyderman and The Male Biological Clock on the Today Show

http://allday.msnbc.msn.com/archive/2007/03/13/88225.aspx
caught up with Dr. Nancy after her segment on the male biological clock this morning. I asked her what the one take-away point should be from the segment, and she said quite simply: "There is one." That is, there IS a male biological clock, and it's something that everyone should take into account when family planning and deciding to have children. The female biological clock often receives the attention because it's a clear and simple fact -- women cannot have children after a certain age. However, men can still reproduce at any age, and that's the reason that the male risk factors often drop off the radar screen.

Some of the statistics are quite alarming, however. Of the nearly 6 million fertility problems in the US each year, roughly 40% of them are attributed to the man. Of all the babies born with Down Syndrome to women over the age of 35, HALF of them are actually sperm-related. (Source for both statistics: Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center.) There are other studies out there that are still being discussed, with possible links between the male biological clock and diseases such as autism and schizophrenia.

And both men and women should be aware of the male biological risk factors, rather than solely focusing on the woman's age. She was emphatic about this story, and wants as many people to listen up as possible. WATCH VIDEO.

Dr. Emily Senay on the Early Show

Evidence Of Male Biological Clock Mounts
Senay: More Studies Show Men's Ability To Father Healthy Kids Diminishes With Age
NEW YORK, March 5, 2007


Senay observed that the notion of a male biological clock isn't as new as many people think.

A leading researcher in the field says basic knowledge of age-related changes in men's sperm goes back to the 1950s. She says it's intriguing that society chooses to ignore this information.

Senay herself told Smith, "I think there's a resistance, if you will, or even a measure of denial."

The NY Times science section On the male biological clock

Older fathers appear to raise risks of genetic disorders

By Roni Rabin Published: February 28, 2007





When it comes to fertility and the prospect of having normal babies, it has always been assumed that men have no biological clock — that unlike women, they can have it all, at any age.

But mounting evidence is raising questions about that assumption, suggesting that as men get older, they face an increased risk of fathering children with abnormalities. Several recent studies are starting to persuade many doctors that men should not be too cavalier about postponing marriage and children.

Until now, the problems known to occur more often with advanced paternal age were so rare they received scant public attention. The newer studies were alarming because they found higher rates of more common conditions — including autism and schizophrenia — in offspring born to men in their middle and late 40s. A number of studies also suggest that male fertility may diminish with age.

Ageless Fatherhood? Maybe Not--- a very good article

KATHLEEN DOHENY
c. 2007 HealthDay News
Distributed by The New York Times Syndicate
This is the first of four recent article or TV spots on this vitally important topic.
Here are some extensive excerpts:


.............."Several studies have found that older fathers risk having children with medical problems, including Down syndrome. Fisch and his colleagues evaluated more than 3,400 cases of Down syndrome, finding that if the woman and the man were both over age 35 at the time of conception, the father's age played a role in prevalence of the disorder. This effect was most pronounced when the woman was over 40, the researchers found. And, in those cases, the incidence of Down syndrome was about 50 percent attributable to the sperm, the researchers said. The study was published in 2003 in The Journal of Urology.

In another study, Dr. Avraham Reichenberg, of Mount Sinai School of Medicine in New York City, found that advanced age for fathers is associated with an increased risk of autism. His team gathered data on the age of fathers of more than 318,000 people born in Israel during the 1980s. The researchers found that the chances of having a child with autism or a related disorder were about six times greater if the father was 40 or older, compared to men 29 or younger. The findings were published in the September 2006 issue of The Archives of General Psychiatry.

Still another study found that the risk of schizophrenia in children was tied to older age of the father. In the study, which included about 90,000 people, the researchers discovered that children whose fathers were 50 or older when they were born were nearly three times more likely to have the disorder than those born to younger fathers. That study was published in 2001 in The Archives of General Psychiatry.

Another study, published in 2002 in Human Reproduction, found a higher risk of miscarriage in mothers 35 and older and fathers 40 and older.

And, in 2004, The Journal of the American Medical Association reported that 20 different disorders in children, ranging from schizophrenia to skeletal disorders, have been linked to the advanced age of the father......................

Orignally published February 27, 2007