Older fathers raise babies' health risks

Biological clock ticks for men, too, studies say
Older fathers raise babies' health risks
By Michael Stroh
From The Baltimore Sun
September 10, 2006
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."