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Biological clock ticks for men, too, studies say

The Baltimore Sun

A flurry of new genetic and epidemiological studies is chipping away at a prized male myth: Sperm, it turns out, don't age as well as some men imagine.

At least 20 exceedingly rare but potentially devastating genetic disorders, including dwarfism and other skeletal deformities, have now been linked to older fathers. Men who have families later in life also have a higher risk of fathering children with schizophrenia, studies show.

And in the latest reality check, researchers reported last week that men over 40 are nearly six times as likely to have an autistic child as those under 30.

"The conventional wisdom is clearly inaccurate: Men have as important a biological clock as women for having healthy babies," says Dr. Dolores Malaspina of Columbia University, one of several researchers of this "paternal age" effect.

Despite the gloomy statistics, scientists stress that the vast majority of children born to men of all ages are healthy, and that the deterioration of sperm over time isn't nearly as precipitous as that of a woman's eggs. Down syndrome, for example, occurs in fewer than 1 in 1,000 births to women under 30. At 35, the risk jumps to 1 in 400. By 50, it's 1 in 6.

"In this regard, God was sexist," says Terry Hassold of Washington State University, an authority on chromosome defects in human sex cells. "There's no question that females have a much higher risk of chromosomal aberrations as they age."

But it's also clear that more men are putting off first-time parenthood - or, in some cases, fathering new broods with younger spouses. Since 1980, U.S. birth rates have shot up as much as 40 percent for men ages 35 to 49. Meanwhile, they have decreased up to 20 percent for men under 30, according to the National Center for Health Statistics.

As a result, some scientists say, it's important that men understand there are more potential consequences to becoming a latter-day dad than fertility troubles.

"I would not discourage an older man from having children any more than I would discourage an older woman from having children," says Malaspina, whose research was the first to show a link between paternal age and schizophrenia. "But we must understand that the optimum ages for having children are in younger adulthood for both sexes."

Clues that parental age might play a role in disease were first noted nearly a century ago.

In 1912, a German obstetrician named Wilhelm Weinberg realized that achondroplasia, an inherited form of dwarfism, was more common in the youngest children of large families than their older siblings.

Even in the early days of genetics, Weinberg was able to deduce why: A child's chances of having the disease grew as parents aged.

In 1955, British geneticist Lionel Penrose pinned the condition to aging fathers and, specifically, to gene mutations within their sperm. The find ignited a hunt for other paternally influenced conditions. In time, researchers identified Apert syndrome, Marfan syndrome and more than a dozen other rare genetic diseases. One lingering mystery is how aging alters sperm DNA. It has been only in the past few years that scientists have developed the sophisticated genetic tools required to probe male sex cells.

What they're finding isn't always pretty.

When researchers at the Lawrence Livermore National Laboratory in California examined sperm collected from healthy men ages 22 to 80, they found a steady increase in the number of broken DNA strands and other genetic rubble within cells as they age. The report, published this summer in the Proceedings of the National Academy of Sciences, showed that men in their 40s generally had twice as much DNA damage as men in their 20s.

Surprisingly, none of this DNA damage was obvious from the sperm's appearance or behavior, says biophysicist Andrew Wyrobek, who led the study.

Among the potential consequences of DNA damage are fertility problems and miscarriage. Last month, researchers at Columbia University reported that women whose partners are 35 and older tend to suffer more pregnancy losses than women with younger partners.

Concerned over genetic damage and its potential health effects, the American Society for Reproductive Medicine recommends that sperm banks around the country set the cutoff age for donors at 40.

Scientists still don't know precisely why the DNA gets fouled up in the sperm of older men - and how this damage leads to disease.

One popular explanation is the "copy error" hypothesis: The cellular machinery that packages DNA inside the sperm slips up over time, allowing errors to creep in. Sperm, after all, are churned out from puberty through old age.

Starting at puberty, cells in the testes that give rise to sperm divide every 16 days. By age 30, they have split 380 times. By 50, the number has climbed to 840. Each division, scientists say, boosts the chance of error. A woman's ovaries, on the other hand, are stocked just once before birth. This supply, roughly 400,000 eggs at puberty, gradually dwindles until she reaches menopause, typically around her 50th birthday.

Epidemiologists, meanwhile, are trying to tease out the link between paternal age and disease by studying birth certificates and medical records.

In the latest effort, Abraham Reichenberg of Mount Sinai School of Medicine in New York and his colleagues studied government medical records of more than 378,000 Israelis born in the 1980s and found that paternal age was an important risk factor for autism, a condition marked by poor language and social skills.

Reichenberg and his team are commencing a hunt for specific genes in older men and their autistic offspring that might account for the disease. The study was reported this month in the Archives of General Psychiatry .

Scientists caution that autism, schizophrenia and other behavioral conditions linked to paternal age in recent years are complex and most likely influenced by other factors as well.

As a result, physicians remain divided on just how much weight to give the notion of a male biological clock.

Dr. Eugene Katz, director of the Greater Baltimore Medical Center Fertility Center, said that the new studies on paternal age and health haven't changed the way he counsels patients - nor do any men seem worried enough to ask.

"If age does play a role," he says, "it's a much subtler role that occurs over a much longer period of time than in women."

Dr. Karen Boyle, a male infertility specialist at the Johns Hopkins' Brady Urological Institute, adds, "I don't think clinically we've been really sensitive to age as an issue for men. We're just starting to think about men as a contributor to genetic disease."

Ultimately, researchers say, they hope to develop easier tests to probe sperm for disease, much the way physicians use pre-implantation genetic diagnosis to test embryos.

"There are couples who don't want anything but the perfect child," says Dr. Ethylin W. Jabs of the Johns Hopkins' Institute of Genetic Medicine. "Even if the risk is one in a billion, they would take the test."

michael.stroh@baltsun.com

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