A mother's age is often considered a genetic risk factor for offspring, but research is now pointing the finger at fathers, too—particularly when it comes to the mental health of their progeny. Males may have the advantage of lifelong fertility, but as they grow older, the rate of genetic mutations passed on via their sperm cells increases significantly—putting their children at increased risk for psychiatric disorders, especially autism and schizophrenia. Two recent studies support this link at least associatively, but experts remain uncertain if age is the cause of these problems.

The Malaysian Mental Health Survey (MMHS) results, which were published online in March 2011, for instance, revealed that people with older parents as well as those whose fathers were at least 11 years older than their mothers, were at increased risk for certain mental health disorders, including anxiety, depression, obsessive-compulsive disorder and phobias. Offspring whose fathers were 19 or younger when the child was born had just a 9 percent prevalence of mental health disorders. Regardless of paternal age, however, if the father was 11 years or older than the mother, that rate jumped to 24 percent. The greatest risk of mental health disorders—42 percent—was seen in the children of fathers aged 50 and older, with wives at least 11 years younger than their husbands.

The link between paternal age and increased risk of mental illness has long been recognized by practitioners, but researchers are beginning to unravel more details: "We have known that the children of older men have higher susceptibility to sporadic disease since the 1970s, but there has been an explosion of research in this area," says Dolores Malaspina, a professor of psychiatry and environmental medicine at New York University and a leader in the field of paternal age-related schizophrenia (PARS).

Sperm gone bad?
Some researchers disagree about whether the connection between paternal age is purely based on internal genomic mechanisms related to the aging process, aka "sperm gone bad," or whether environmental and epigenetic factors also affect outcomes.

"The links between a father's age and mental outcomes is multifactorial. You have to take into consideration epigenetic, psychosocial and biological factors," says John McGrath, a professor of psychiatry of the Queensland Brain Institute at the University of Queensland in Australia.

The epigenetic approach is based on the theory that accumulated exposure to environmental toxins over time causes genetic expression alterations that are passed on to later generations and lead to disease in the children later in life. For example, children of Vietnam War veterans exposed to the herbicide agent orange have an increased risk for spina bifida due to epigenetic changes. And drinking and smoking can have epigenetic effects in offspring.

"We do know that there are operating mechanisms whereby paternal experience over a man's lifetime can shape the metabolic pathways of his children," Malaspina says. The question is whether these changes affect the long-term mental health of older men's children.

Likewise, a psychosocial approach focuses on external factors that might contribute to the expression of certain genes. "Delayed paternity does increase the risk of mental disorders, but genetic mutations may not be causative," MMSE researcher Kavitha Subramaniam said in a prepared statement. "They may behave more like susceptibility factors, so that children of older fathers may overreact and show phenotypic expression of certain diseases when they face environmental stimuli. Whereas those with no genetic liability may not develop mental health disorders."

Nevertheless, the effect of aging on gene expression is still considered the primary force driving mental health outcomes in the children of older men. Advancing paternal age is associated with spontaneous mutations—changes in the nucleotide sequence of a chromosome. The older men get, the more vulnerable their sperm becomes to such spontaneous genetic mutations.

When it comes to reproductive outcomes, older men are actually disadvantaged compared with older women, due to the high rate of sperm cell division. McGrath points out that during a woman's lifetime, her oocyte cells divide only 23 times. Women are born with all of the eggs they will ever carry. Once boys hit puberty, their sperm cells divide every 16 days. "By the time a man is 40, his sperm cells have undergone 660 cell divisions, and 800 cell divisions by age 50," he says. More divisions translate into a higher risk for genetic alterations.

The magical male age threshold
So at what paternal age does the risk of mental health disorders among offspring increase significantly? The evidence varies.

In a meta-analysis published online in November 2010 Christina Hultman, an epidemiologist at the Karolinska Institute in Stockholm, found that men between the ages of 40 and 49 were 1.4 times more likely to have children with a diagnosis of autism than 15- to 29-year-old men—the reference group for this study. And the risk of autism increased dramatically with the father's age: Between the 50 and 54, men were 2.2 times more likely to have children with a diagnosis of autism compared with the reference group; for men aged 55 and above, comparative risk was 4.4 times greater than the control.

Another study, published online in April 2011, looked at mental health outcomes in the children of fathers aged 40 and above in the Netherlands. With more than 71,000 subjects this research, led by Jacobine Buizer-Voskamp of the Rudolf Magnus Institute of neuroscience at the University Medical Center Utrecht in the Netherlands, was the first large-scale, population-based study to look at the effect of paternal age on four main psychiatric diagnoses—autism spectrum disorder, schizophrenia, major depressive disorder and bipolar disorder.

The researchers found that fathers aged 40 and above are 3.3 times more likely than under-40 fathers to have children with autism spectrum disorder, whereas men aged 35 and older are 0.27 percent more likely to have children who eventually develop schizophrenia, compared with men under 35.* The study did not show any connection between paternal age and bipolar disorder. In the case of depression, the rate was higher not only in the children of men over 40, but also in fathers aged 20 and younger—so it appears that there are different biological and psychosocial mechanisms that influence risk of affective disorders versus risk for autism spectrum disorder and schizophrenia.

The weird gene theory
These findings led Buizer-Voskamp and her colleagues to conclude that the association between paternal age and increased risk of autism spectrum disorder may be a function of self-selection as well as genetics, in which men with autistic tendencies tend to marry later, have children later and pass on those traits to their offspring. Emerging research shows that social function in people with autism spectrum disorder improves as they get older, which leads them to later marriage and older first-time parenthood. When they finally have children, they pass on their genes for autistic tendencies. In contrast, men with bipolar disorder during the pre-morbid phase tend to have improved social and cognitive functioning, so they have no problem getting into relationships and having children at a younger age.

McGrath disagrees with this theory regarding autism spectrum disorder. "That's what I would call a systematic bias," he says. "The idea that dad is weird and the kids are going to get his weird genes has been around for some time, but the evidence suggests there is more going on."

The emergence of this data represents a rare convergence of two fields—genetics and epidemiology, McGrath says. "In epidemiology, we see a higher risk of autism and schizophrenia in the children of older fathers," he says, "while genetically, the focus is on copy number variants and structural variations that could be linked to increased risk of schizophrenia and autism."

Although this convergence is interesting, it is also cautionary for men over 40 who want to start families or have more children. Experts, however, offer some reassurance: "Late fatherhood is a secular trend across many nations," McGrath says. "We all know older fathers whose children turn out just fine."

In fact, Malaspina points out that duration of marriage and being "wanted" (rather than the result of an unplanned pregnancy) are two factors that seem to be protective against the development of schizophrenia in the children of older men. "Based on research I did in 2001, being wanted reduces the risk of schizophrenia threefold in these children," she says.

"People should have children if they want them, but they need to be aware of the individual risks. People have always focused on maternal age, but now we know that paternal age matters, too. This is a true paradigm shift," Malaspina says.

McGrath puts it this way: "For a long time women have been warned about their ticking biological clocks. We now know that it ticks for men, too."

*Correction (8/29/11): This sentence was edited after posting to correct the multiplier.