Older moms get the blame for genetic defects in offspring. Turns out aging dads may be an even bigger problem.
by Anne Kingston on Friday, February 15, 2013 12:40pm
Recent news that artist and filmmaker Julian Schnabel was having a baby with his fiancée, 30-year-old assistant gallery director and Victoria’s Secret model May Anderson, was met with the rolled-eyed indulgence that typically greets April-November procreation among the rich and famous—an orbit in which men siring children in their 50s, 60s and even 70s is a badge of virility, even a bragging point. Schnabel joins a long list that includes Rupert Murdoch, Donald Trump, Woody Allen, Charlie Chaplin, Tony Randall and, of course, Pierre Trudeau, who fathered a daughter when he was 72.
The high-proﬁle parade perpetuates entrenched thinking about the male-female reproduction divide: that women’s shelf life expires with menopause in her mid-40s, give or take a few years, while men’s constantly replenishing sperm allows them to procreate with impunity until the day they die (albeit with a boost from Viagra). It’s a biological double standard that has underlined cultural definitions of sexual—and social—viability for centuries.
But it’s also part fiction, according to a mounting body of scientific research that suggests sperm too has a best-before date. Increasingly we’re learning that the older the father, the higher the rate of infertility. And his children seem to have lower birth weights, some cancers, autism spectrum disorder, schizophrenia, Down syndrome and bipolar disease. Maternal age, a topic of ceaseless debate and directives hurled at women, is, it turns out, only one part of the story.
The topic is timely. Men are, like women, pushing back parenthood. According to Statistics Canada, men born between 1926 and 1930 fathered their first child at 28.4 years of age, on average; women were 25.2. For men born between 1966 and 1970, that age had risen to 32.4; women were 27.8. Those figures, of course, don’t include men starting second—or third—families later in life.
“Paternal age effect,” as it’s benignly known in medical literature, has been flicked at for more than a century. A 1920 Danish population study of almost 15,000 live births, for instance, associated advanced paternal age with cleft lip and palate in their children, independent of maternal age. Studies in the 1950s linked older fathers to achondroplasia, or dwarfism, in offspring, along with other rare syndromes: Marfan (a connective tissue disorder) and Apert (characterized by malformations of the skull, face, hands and feet).
But the notion that aging could affect sperm defied 20th-century medical orthodoxy, says Bernard Robaire, the James McGill Professor in the departments of pharmacology and obstetrics and gynecology at McGill University. “The conventional wisdom was that reproductive aging is a female problem,” Robaire says. “It was well-established that men make about 1,000 sperm every heartbeat from the time they’re teenagers pretty much until death—and that the rate of decline of sperm production is not very big [with age]. So there was no point studying reproductive aging in men.” Robaire, the only scientist in Canada researching the mechanisms behind aging on sperm, faced resistance when he started in the early 1990s: “It was very difficult to get any funding because it was going totally against dogma.”
Slowly, however, studies began revealing that sperm motility, volume and quality, in fact, do diminish with age. “Ability to make sperm doesn’t change between 20 and 80, but quality does,” says biophysicist Andrew Wyrobek of the Lawrence Livermore National Laboratory in Livermore, Calif., who has written more than 150 papers on the topic. “As men age, their sperm begins swimming around purposelessly, not in a straight line.” A 2004 book, The Male Biological Clock, by Harry Fisch, a New York City urologist and fertility specialist, also sounded warnings. Fisch claimed men over 35 are twice as likely to be infertile as men under 25, and are more likely to father a child with genetic abnormalities, even Down syndrome. By then, associations had been made between genetic abnormalities in children and older fathers. A 2001 study at Columbia University published in Archives of General Psychiatry found “a very strong association of schizophrenia risk and father’s age.”
Miscarriage too was tied to paternal age. A 2006 study by Columbia University found women pregnant by older men more likely to miscarry—with odds rising with the father’s age, regardless of the mother’s age.
Yet paternal age-related risks remained under the radar, or were mitigated by social and economic factors, in a way mother’s age wasn’t. One British study published in the Journal of Epidemiology and Community Health in 2006 concluded any adverse effects of advanced paternal age “should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security.” Not everyone bought it. In 2007, Pamela Madsen, then executive director of the American Fertility Association, expressed frustration. “Wake up,’” she said in a New York Times interview. “It’s not just about women anymore, it’s about you, too.”
It took an Icelandic study on paternal age, the largest and most definitive to date, published in Nature last year, to capture public attention. A team of researchers lead by respected neurologist Kári Stefánsson found fathers determined the rate of new, or “de novo,” genetic mutations leading to autism, schizophrenia, dyslexia and other conditions involving brain function. De novo mutations are not harmful in themselves; but only one change in a key gene is required to cause some types of disease—the more mutations, the higher the risk. The study found “de novo” gene mutations double every 16.5 years: the baby of a 36-year-old father would, in theory, have twice as many new mutations than one whose father is 20, whose sperm carries about 25 mutations (though it doesn’t mean his child would automatically have twice as many problems; it depends where the mutuations occur). The study concluded the rate of increase in de novo mutations could be ascribed to the father’s age—97.1 per cent or “maybe entirely”—a totally unexpected result, Stefánsson told Maclean’s. “That is amazing, in itself.”
Media greeted the research as a cosmic wake-up call: “The genetic health of the species is now facing a serious threat,” the New Yorker proclaimed. Stefánsson says it’s about time people started paying attention. “Paternal age is a very important contributor to human evolution,” he says. “If you look at demographic changes over the past century or two and look at how the mean age of fathers at conception has changed, there’s a dramatic difference in the load of new mutations. These cultural shifts have had a dramatic impact on the new diversity of gene sequence.”
Advanced DNA testing also helped debunk the myth that a 60-year-old’s swimmers are Ryan Lochte-like. Sperm-producing cells are constantly dividing, so the number of possible mutations grows over time, says New York City urologist Natan Bar-Chama, the director of male reproductive medicine and surgery at the Mount Sinai School of Medicine in New York. He compares the process to a complex printing press: “Over time, the ink supply, the glue, the paper shows the age.” Like the front page of the New York Times after a million copies, the result “is not as clear.”
The cultural fallout is potentially seismic, as men face the questions and pressures women have for decades. Can they afford to wait until their careers are settled before starting a family? Will their sperm be viable for IVF, if need be? Should they eat for “sperm health” or freeze sperm for later in life (something we’re already seeing)?
The answers aren’t yet clear, says Keith Jarvi, the head of urology at Toronto’s Mount Sinai Hospital. “Research in paternal age is a moving target—and evolving rapidly, he says: “I’m sure there will be other conditions we’ll identify in the future.” Fisch agrees: “I think we’re talking about serious risks,” he says. “The more we look, the more we’re finding out.”
It may appear we’ve come a long way since Dutch scientist Antonie van Leeuwenhoek identified sperm under a microscope in the 17th century, believing each contained a fully formed, tiny human—reflecting the view that women are merely incubator-delivery systems. But research in the field remains “primitive,” says Wyrobek. “We’re still sorting out who contributes what genetic material.”
Nor has it translated into prescribed behaviours before having children, he says: “I talk to doctors who still tell patients: ‘Don’t worry about this—just try your best to get pregnant.’ ” Advanced paternal age guidelines are needed, says Jarvi, who notes biology makes them difficult to nail down. For women, age 35 years and up is clearly defined as “advanced maternal age” (AMA) or “elderly gravida” with metrics neatly meted out: according to the Mayo Clinic, by age 35, a woman’s risk of conceiving a child with Down syndrome is 1 in 400; by age 45, it’s 1 in 35.
But no one is yet willing—or able—to time-stamp a best-before date on sperm. “Delayed childbearing,” a 2012 report from the Society of the Obstetricians and Gynecologists of Canada (SOGC) set “advanced paternal age” as 40 years or older at conception. Yet the study focused on women and downplayed paternal age risks, noting they’re “not as well-defined” as those for maternal age–though it noted “a decrease in fertility” and an increase in “genetic disorders” in offspring of older fathers, concluding: “When the male partner is aged ≥ 40, the couple should be treated as any other couple and offered prenatal screening and diagnosis according to SOCG guidelines.”
Sperm health peaks for men in puberty, says Stefánsson, and then declines on a continuum, unlike a woman. “Only healthier eggs survive into older age,” he says. Fertility manifests itself very differently in the sexes, says Jarvi: “Women face a precipitous drop in their early 40s; men peter out—as opposed to going off a cliff. There’s no male menopause; there are small changes per year.”
That could explain, in part, why discussion about paternal age risk is more measured than that surrounding maternal age. Bar-Chama, who sits on the board of the American Fertility Association, welcomes discussion of paternal age risks, particularly infertility. But he’s concerned they’ll be overblown. “Context is important,” he says. In the past year, he has consulted with several couples undergoing IVF who suddenly panicked that they needed to use somebody else’s donor sperm because the male was over 60. “I tell them there’s a real danger but they have to put it in terms of overall risk, which is small, as well as other pressures it puts on the relationship,” he says. In the end, none used donor sperm.
Bar-Chama says age concerns shouldn’t compel men to procreate before they’re ready: “Having a child is a lifelong commitment. That’s what you should focus on and not feel pressure to jump in before you’re ready.” Jarvi notes the fact men have tens of millions of sperm per millilitre of ejaculate: “There’s a lot of extra play there.” Understanding relative risks is important, says Robaire, who’s now studying aging effect on male stem cells themselves. Almost all research has been done in animal models, he says: “Population-based studies indicate older fathers are associated with a 1.4- to fivefold increase in various conditions passed on to children. It’s a not a huge factor. But it’s a factor for sure.”
A man’s health also influences sperm quality, says Bar-Chama, a point echoed by recent European research that found sperm counts falling in even young men at an alarming rate—up to 38 per cent in a decade—due to high-fat diets, sedentary habits and exposure to toxic, gender-bending chemicals. “Take a 30-year-old who smokes and is obese and takes steroids: his sperm is awful,” Bar-Chama says. “And then you have a 55-year-old who does triathlons and takes care of himself. Which sperm would you rather use?” Wyrobek’s latest study backs him up: men over 44 who consumed a diet rich in vitamins C and E, zinc and folate reversed some genetic damage due to aging: they had 20 per cent less DNA damage in sperm compared to men with deficient diets. He’s hopeful age-related damage can be reversed, though it’s not yet clear whether better diet extends to male fertility only or to the health of offspring as well.
The upshot will be “sperm-friendly” diets and ads encouraging men to freeze sperm due to aging concerns. The latter is already happening, claims Tamer Said, director of the andrology lab and sperm bank at Toronto-based ReproMed. Three years ago, it was unheard of, he says: “Now 10 to 15 per cent of clients are doing so.” The clinic screens all samples to evaluate the feasibility of freezing, which poses its own risks. “There is no age limit; however, we would recommend a more extensive workup for men above 40 that would include sperm DNA assessment,” he says. Men aren’t educated about the risks of aging sperm, Said says: “More work needs to be done.”
Fisch believes far more than that is required; he believes an entire rethink of reproductive roles is in order: “Genetic problems are no longer a mother’s issue; it’s a parental issue.” He points out that focus on a 65-year-old Fortune 500 CEO procreating with a 30-year-old is misdirected: younger mothers mitigate some aging-sperm risks and, more to the point, such pairings are the exception. Of bigger concern, he says, are couples in their late 30s or early 40s who’ve put off having children: “That’s way more of an issue than marrying a Tony Randall”—the Odd Couple actor who fathered two children when he was 77 and 78; his wife was 5o years younger.
Susan Kolod, a New York City psychologist who specializes in gender and sexuality, sees awareness of paternal age risk now on the radar. “I’m hearing men and women talk about it; it’s on their minds,” she says. “There is a recognition that after age 35 both men and women are more likely to produce children with various kinds of developmental difficulties.” She’s also seeing younger men, who planned to put off parenting until their 40s suddenly in a bind: “They’re asking: ‘What should I do?’ ”
She observes that science has long been influenced by social biases. In the ’50s and ’60s, she notes, autism was blamed on “refrigerator,” or cold, unloving mothers: “It was very stigmatizing. And, as we now know, totally wrong.”
Emerging research on aging sperm is potentially “revolutionary,” says Kolod. For one, the science could reframe how women choose mates, particularly younger women who marry much older men to take care of them. “Once, there was never a question she could have a family with this person,” says Kolod. “Now it’s either-or: you can opt for a secure set-up or find someone closer in age and have a family.”
Robaire doesn’t think we’re at the point where male age is a reproductive deal breaker: “But I can see a day five or 10 years down the line when genetic counselling will be advised for a man over 40 or 45 the way it is for women over 35,” he says.
Stefánsson expresses relief that reproductive double standards finally being righted. “The tables have turned on the sexes,” he says. When he was in medical school in the ’70s, he was taught women over 40 shouldn’t have children due to risks of Down syndrome and other conditions. “There was no focus on a father’s age,” he says. “Now it turns out there’s nothing except for Down’s syndrome that seems to be at risk when it comes to maternal age. Women have been unjustly blamed for birth defects for years, when we should have been far more careful when it comes to the older father.” Now that the focus is shifting to men, let’s hope it’ll lead to new insights into the joint contributions both sexes make to reproduction. We’ve already had enough blinkered science on the subject.