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February, 2009 in Biology |

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


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

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

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

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

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

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



It was the first large-scale study to link sporadic cases of schizophrenia to fathers’ age, and few researchers believed it. “We were absolutely convinced it was real, but other people didn’t think it was,” Malaspina says. “Everybody thought men who waited to have children must be different.” That is, maybe these older fathers had some of the makings of schizophrenia themselves—not enough for the disease to be recognized but enough that it took them a little longer to get settled, married and have children.

Other groups tried to repeat the study using different populations. In all these studies, researchers took a close look at whether there was something about the older fathers—unrelated to age—that increased the risk of schizophrenia in their children. When they did, the link with age became even clearer. “That result has been replicated at least seven times,” says Robert K. Heinssen, chief of the schizophrenia research program at the National Institute of Mental Health (which has funded some of Malaspina’s work). “We’re talking about samples from Scandinavia, cohorts in the United States, Japan. This is not just a finding that pertains to Israeli citizens or people of Jewish background.”

Malaspina knew that the draft-induction tests identified young men and women with autism, and she realized that, too, could be looked at to see whether it was linked to paternal age. “There are similarities between autism and schizophrenia—they both have very severe social deficits,” says one of her collaborators, Abraham Reichenberg, a neuropsychologist at the Mount Sinai School of Medicine and the Institute of Psychiatry at King’s College London. “There was some reason to think similar risk factors might be involved.” In 2006 they and their colleagues published a report showing that the children of men who were 40 or older were nearly six times as likely as the kids of men who were younger than 30 to develop autism or a related disorder.

Autism and related disorders—referred to as autism spectrum disorders—occurred at a rate of six in 10,000 among the children of the younger fathers and 32 in 10,000 among the children of the older fathers. (That is closer to five times the risk, but statistical adjustments showed the risk was actually about six times higher in the offspring of the older dads.) In the children of fathers older than 50, the risk was 52 in 10,000.

That was the study I heard about the day after my son Henry was born.

Reichenberg interprets these results as very solid findings: “In epidemiology, you look for an odds ratio of two. Anything above that, you’re happy. When you have an odds ratio more than five, you’re excited.” The study could not absolutely rule out some effect of older mothers, but “we’re pretty confident that the paternal age risk holds no matter what the maternal age,” he says.

As these studies were being done, Mala­spina asked Jay Gingrich, a psychiatrist and neuroscientist at Columbia who works with mice, whether he could look for the same effect in the offspring of older mouse fathers.

Gingrich can’t ask his mice whether they are suffering delusions or hearing voices. But he can give them tests that people with schizophrenia have difficulty passing. In one such test he looked at how mice reacted when startled by a loud sound. Mice are like people—when they hear a loud noise, they jump. And there is more similarity than that: when mice or people hear a soft sound before being startled, they don’t jump as much. It is called prepulse inhibition; the soft pulse inhibits the reaction to the louder one. “It’s abnormal in a number of neuropsychiatric disorders, including schizophrenia, autism, obsessive-compulsive disorders and some of the others,” Gingrich says. And he found that the response was abnormal in mice with older fathers.

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Could becoming a father after age 40 raise the risks that your children will have a mental illness?
By Paul Raeburn

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The results were so striking that Gingrich thought they were too good to be true. He and a postdoctoral researcher, Maria Milekic, collected data on 100 offspring of younger dads and another 100 offspring of older dads before they decided the results were correct.

Missing a Mechanism?
Not everyone agrees on what Malaspina’s results mean. Daniel R. Weinberger, a psychiatrist and schizophrenia expert at the National Institute of Mental Health, for instance, accepts the findings—that the incidence of schizophrenia is higher in the children of older fathers. But he does not agree with Malaspina that this could be one of the most important causes of schizophrenia. The reason, he says, is researchers know too little about which genes conspire to cause schizophrenia: “It’s a seminal observation, but like many seminal observations, it doesn’t identify a mechanism.” Weinberger wants to know exactly how this happens before he can say what it means.

Malaspina has thought a lot about the mechanism. What happens to the sperm of men as they age that could give rise to these increased risks in their offspring? The first thought was a classic kind of genetic mutation—a typo in the DNA, a stutter or some other scramble of the code.

There is, however, another possibility. The genetic code we are familiar with is expressed in the DNA itself. But there is a second genetic code, separate from what is embedded in the DNA. To distinguish it from the genetic code, it is referred to as “epigenetic” information. It is like a bar code imprinted on the outside of a gene. The information in that bar code can turn the gene on or off—sometimes inappropriately. If it turns the wrong genes on or off, it can affect health and disease just as surely as can changes in the DNA itself.

Malaspina has not yet proved it, but she suspects that as men grow older they develop defects in the machinery that stamps this code on the genes. These imprinting defects may give rise to the increased risk of schizophrenia, autism and perhaps some of the other ailments related to paternal age.

It is not possible to poke around in people’s brains to see whether those who have schizophrenia show errors in this imprinting. But that can be done in Gingrich’s mice. He is just now beginning to examine the imprinting in the brain tissue of his mice, and he is betting he will find errors there. That is precisely the kind of research that could address Weinberger’s concerns about the mechanism responsible for increasing the incidence of schizophrenia in the children of older dads.

This research could represent an important advance in understanding schizophrenia and autism. “This is work that we will pursue and fund, because we’re so eager to get the genetics worked out,” says Thomas R. Insel, a psychiatrist and director of the National Institute of Mental Health. “It’s a very interesting observation.” With persistence—and some luck—the research could lead to better treatments or even, one day, a cure for schizophrenia and autism.

Some researchers worry that these new findings are just among the first of the problems that might ultimately be associated with older dads. “If there is one common disease that we know is associated with older biological fathers, we can safely assume there are more remaining to be discovered,” says University of Chicago psychiatrist Elliot S. Gershon.

Gershon’s prediction has already come true. In September 2008 researchers in Sweden, in collaboration with Reichenberg, reported that the children of older fathers had an increased risk of acquiring bipolar disorder. And the risk increased as the fathers’ age rose, encouraging confidence in the results.

For now, prospective parents might want to rethink their plans about when to have children, says Herbert Meltzer, a psychiatrist and widely recognized schizophrenia expert at Vanderbilt University. He believes the risks for children of older fathers will eventually be seen to be as noteworthy as the risks facing older mothers. “It’s going to be more and more of an issue to society,” he notes. “Schizophrenia is a terrible disease, and anything that can be done to reduce it is terribly important.”

Meltzer thinks women should take a man’s age into consideration when choosing a partner to have children with. And men might want to think about having sperm stored when they are young. Because despite the advances in understanding autism and schizophrenia, treatment is limited and difficult, and a cure remains elusive.

His advice? "If my son or daughter was to ask, I'd tell them to have kids early -- and that's before 30."

Yo, dude, check your bio clock -- now
New studies warn that it isn't just women who become less fertile as they age
Sarah Treleaven , The Ottawa Citizen
Recently, I've had a lot of conversations about baby-making with my male friends.
"I worry that I might be too selfish to ever have children," said my friend Joe, 29, somewhat pensively over gin and cucumber cocktails. Ditto for Colin, who just broke up with a woman he loves because she wants to have kids in the next few years and, at 35, he just doesn't feel ready yet. Kids or no, they both feel like they have all the time in the world to decide.

I, on the other hand, just turned 30 and have been making a lot of jokes about needing an apartment with a second bedroom for my soon-to-be-frozen eggs.



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Font:****Lots of women wring their hands about having a baby. Not only do we have to worry about our plummeting fertility (which begins to tank in our mid-20s), but we also have to worry about job retention and advancement once those kids (come biology, adoption or surrogacy) eventually appear. And it's the physical limitations of the female ability to procreate that have placed such a heavy emphasis on the reproductive biological clock, shaping the way many women live, work and even date.

But evidence is increasingly emerging that men, too, have a reproductive biological clock -- and that it ticks much more loudly than most of us have thought. Even as stories occasionally emerge about septuagenarian and octogenarian men becoming proud papas -- author Saul Bellow, for example, fathered a child at 84 -- several recent studies are challenging the conventional wisdom that men have an invincible ability to procreate.

A French study released in July found that women's pregnancy rates drop and miscarriages increase when the mother is over 35 and the father is over 40. Another study suggests that a man's fertility begins to decrease as early as his 20s. Researchers from the University of California at Berkeley and the Lawrence Livermore National Laboratory tested men between the ages of 22 and 80, and found that semen volume and sperm motility were both significantly compromised by aging.

Additionally, the increased odds for older fathers producing genetic abnormalities have been well documented, and studies have demonstrated that fathers over 40 are six times more likely to produce an autistic child than fathers under 30.

The numbers related to schizophrenia are similarly compelling. A study utilizing health databases in Jerusalem found that fathers over 40 were twice as likely to produce schizophrenic children as fathers who were under 25; for fathers over 50, the odds tripled when compared to fathers who were under 25.

Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center and the author of The Male Biological Clock, says that he's been ringing the alarm bell for years.

"There's a female biological clock; we all agree on the decline in fertility, more genetic problems and a decline in estrogen.

"The same thing happens in men -- a little bit differently, but essentially the same," Fisch says. "Why is it important? Well, demographically more men and women are waiting until they're over 30 to have a baby."

Yo, dude, check your bio clock -- now
New studies warn that it isn't just women who become less fertile as they age
Sarah Treleaven , The Ottawa Citizen
"Over 35, the women are at risk for genetic problems, the men's sperm is at risk for genetic problems; put it together and I consider it a public health concern."

Women in their mid-30s routinely panic about their odds of conception and the health of their baby. The key question associated with the emerging science is this: Is it time for men to start panicking too?

Many fertility experts remain unconvinced that these recent findings are significant. Dr. Paul Claman of the Ottawa Fertility Centre says that men do indeed have a reproductive clock, but that it pales in comparison to the biological reality women face.



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Font:****"Recent data have shown that there are some genetic issues with men as they get older, but much less profound than with women," Claman says.

Dr. Armand Zini, associate professor of urology at McGill University, agrees. "(With) women, there's a real time point where it ceases. Once you cease to ovulate, there's no fertility. In men, it's a very gradual decline from 30s or early 40s."

Women only produce a set number of eggs, and by the time they've reached their early 30s, that supply is significantly compromised. Men, on the other hand, produce sperm throughout their lives, which explains how a 90-year-old farmer in India became a father last year to his 21st child.

Both men and women who choose younger partners (under the age of 35) increase their odds for both conception and newborn health. "An older woman married to a younger man has a much higher chance of getting pregnant than an older woman married to a man her age or older," says Claman.

Interpretations of these new studies may be varied, but will any of this new evidence be enough to get men thinking about the sand running through their reproductive hourglass?

Jason McBride, a 39-year-old writer without children, says the recent studies about male fertility don't concern him in the least. He does acknowledge that he gets pressure from his family to have kids -- "mostly from my hilarious aunt who's always talking about how old my sperm is." But he believes that his option to become a biological parent will remain available for a long time yet. "My biological clock is still on snooze," he says.

Dustin Parkes, on the other hand, is a 28-year old public relations consultant who feels compelled to have kids while he's still relatively young. "I definitely don't want to be a broken-down old man chasing around a toddler." He holds out little hope that he'll meet his goal of being a dad before he's 30, but he, too, acknowledges that the recent studies are of little concern.

There are still a lot of unanswered questions about male fertility, and recent studies are far from eclipsing the well-established reproductive limitations of women. But these recent studies might serve as the start of a reproductive wakeup call for men.

For those who do delay fatherhood, Zini says living a healthy lifestyle can help to prevent the decline of sperm production and testicular function, which invariably diminish with age. He recommends avoiding environmental toxins (including smoking) and excessive exposure to heat (such as saunas and whirlpools) and certain occupational hazards (such as taxi driving, which requires sitting for prolonged periods of time).

Fisch says that having a baby over the age of 35 -- male or female -- still increases the odds of infertility and genetic disorders. His advice? "If my son or daughter was to ask, I'd tell them to have kids early -- and that's before 30."

McBride admits that the ticking of his clock occasionally becomes audible. "As I get more and more infirm," he jokes, pointing to his new orthotic, "I worry about not being able to run around with my kids."

Parkes feels it too, and anticipates that the ticking will get louder in the next few years. "It helps that my circle of friends doesn't seem to be as into having kids, but who knows how much longer that will last? If I get to 35 without a kid, I think I'll throw all my mating standards away and just try to impregnate anything."



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