Older Men and Fertility

DNA mutation in older men:

These mutations could reflect the differences in male and female reproduction, notes Jabs. By the time females reach their teen years, their eggs have already been formed-just one new egg matures each month. Men, on the other hand, produce millions of sperm cells every time they ejaculate. After each ejaculation, they must literally replicate those cells, and each replication multiplies the chance for a DNA "copy error"-a genetic chink in the sperm DNA. The more ejaculations a man produces, the greater the chance for chinks to arise, leading to increased point mutation and thus increased infertility and birth defects. While a woman's reproductive capacity halts more or less abruptly after all her eggs have been used up somewhere in their forties or fifties, men experience a longer, more gradual winnowing and disintegration. "We believe that something in men's DNA replication machinery keeps becoming less efficient and less accurate with age, and the problems accumulate," says Jabs.

"Researchers found that as a man gets older he loses his natural ability to weed out unhealthy sperm cells through a process known as apoptosis. This means that there is a greater chance that a damaged sperm cell will successfully fertilize the female egg. This could mean that the risk of miscarriage is increased or, at the other end of the scale, that children have a greater chance of developing mild abnormalities such as uneven teeth, or asymmetrical limbs. Lead researcher Dr Narendra Singh told the BBC: "We found there is a significant change by the age of 35."

Sperm quality : Dr Singh's team examined sperm quality in 60 men aged between 22 and 60. All had healthy sperm counts. The researchers found that men aged 35 and older had higher concentrations of sperm with broken strands of DNA, and that the damage was greater."

Early Show medical correspondent Emily Senay explains that the study in the Journal of Urology suggests older fathers have similar risks as older mothers of producing children with greater chances of birth defects, such as Down syndrome, and they also lose their ability to conceive. The report found men over 40 years of age were twice as likely to have a child with down syndrome than those less then 20 years old.It was always thought in the past that a woman's age was the sole determining factor in birth defects, such as Down syndrome, says Dr. Senay. But the new report adds to the growing body of evidence that late fatherhood is a factor when it comes to the health of a baby.

Previous studies have shown a link between paternal age and schizophrenia; and paternal age and a birth defect known as Achondroplasia;the most common cause of dwarfism, or significantly abnormal short stature. Achondroplasia is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head, and characteristic facial features with frontal bossing and mid-face hypoplasia. In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often delayed. Intelligence and life span are usually normal, although compression of the spinal cord and/or upper airway obstruction increases the risk of death in infancy.

Researchers in this latest study were able to look at a large number of births to older women in New York State over a 14-year period. They found a dramatic increase in the number of older parents in general, and saw the greatest increase in the number of Down syndrome cases where the father and mother were both over 40.

Currently, Dr. Senay explains, the emphasis is on counseling parents only if the woman is older. But the idea that sperm quality decreases as a man ages underlines the importance of older couples being aware of that possibility, and the risk of birth defects. Screening can be done at a very early stage to detect genetic abnormalities. The researchers say that prenatal counseling, if either parent is over 40, is probably a good idea.

A study published in 2001 in the Archives of General Psychiatry found the risk of schizophrenia in children was associated with older paternal age. For instance, children of fathers over 50 were almost three times more likely to have schizophrenia than children born to the youngest fathers, the research found. The database included nearly 90,000 people.

In another study, more than 3,400 cases of Down syndrome were studied. The researchers found that the father's age played a significant role when both parents were over 35 at the time of conception. The effect was most pronounced when the woman was over 40. In those cases, the researchers "found the incidence of Down syndrome is related to sperm approximately 50 percent of the time." These findings appeared in the June 2003 issue of The Journal of Urology.

"The message to men is: 'Wake up and smell the java,' " said Pamela Madsen, executive director of the American Fertility Association, a national education and advocacy group. " 'It's not just about women anymore, it's about you too.' "

"I think what we're saying is that men, too, need to be concerned about their aging," Dr. Eskenazi said. "We don't really know what the complete effects are of men's age on their ability to produce viable, healthy offspring."

Geneticists have been aware for decades that the risk of certain rare birth defects increases with the father's age. One of the most studied of these conditions is a form of dwarfism called achondroplasia, but the list also includes neurofibromatosis, the connective-tissues disorder Marfan syndrome, skull and facial abnormalities like Apert syndrome, and many other diseases and abnormalities. Apert syndrome is a form of Craniostenosis characterized by oxycephaly and syndactyly of the hands and feet. Facial manifestations include exophthalmos, high prominent forehead, small nose, and malformation of the mandible and mouth.

"We have counseled for quite a long time that as paternal age increases, there is an increased frequency in new mutations," said Dr. Joe Leigh Simpson, president-elect of the American College of Medical Genetics.

Some studies suggest that the risk of sporadic single-gene mutations may be four to five times higher for fathers who are 45 and older, compared with fathers in their 20s, Dr. Simpson said. Even grandchildren may be at greater risk for some conditions that are not expressed in the daughter of an older father, according to the American College of Medical Genetics. These include Duchenne muscular dystrophy, hemophilia and fragile-X syndrome. Duchenne is the most common form of muscular dystrophy, in which fat and fibrous tissue infiltrate muscle tissue, causing eventual weakening of the respiratory muscles and the myocardium. The disease, which almost exclusively affects males, begins in early childhood and usually causes death before adulthood.

A recent study on autism attracted attention because of its striking findings about a perplexing disorder. Researchers analyzed a large Israeli military database to determine whether there was a correlation between paternal age and the incidence of autism and related disorders. It found that children of men who became a father at 40 or older were 5.75 times as likely to have an autism disorder as those whose fathers were younger than 30. Studies elsewhere had similar findings, she said: a threefold increase in schizophrenia among offspring of older fathers. Another study on schizophrenia found that the risk of illness was doubled among children of fathers in their late 40s when compared with children of fathers under 25, and increased almost threefold in children born to fathers 50 and older.

Another study by Fisch has found that when both parents are over 35, paternal aging may be responsible for as many as half of all cases of Down syndrome, formerly thought to be inherited from the mother. And recent studies show that half a dozen or more rare but serious birth defects appear to be inherited exclusively from the father, including Apert syndrome, Crouzon syndrome, and Pfeiffer syndrome (all characterized by facial abnormalities and the premature fusion of skull bones) as well as achondroplasia (the most common form of dwarfism).

"But what we're finding now is that in humans as well as in other mammals, when there's a new genetic change-called 'de novo or sporadic point mutation'-it almost always happens in the male parent," says Dolores Malaspina, chair of psychiatry at New York University Medical Center. And these de new mutations increase in frequency with the age of the male parent.

The biggest news - the father's role in brain disorders - has come to light largely because of research from Israel, where birth records routinely include the age of the male parent. The first unsettling finding linked paternal age and schizophrenia.

"In our first study, looking at every pregnancy in Jerusalem from 1964 to 1976, we found that increased age in the father predicted increased cases of schizophrenia in the children," explains Malaspina, who was on the team doing the work. "In our second study we found that when the cases arose from new mutations-not familial inheritance-it almost always could be traced to the genetics of the father. Somewhere between a quarter and a third of the cases could be explained only by the age of the father-a threefold risk linked to fathers older than 50 compared with those in their 20s." Studies in Sweden and California produced almost identical results.

The autism findings are even more disturbing: Men 40 and older in the Israeli study were almost six times as likely to have offspring with autism than men under 30. Some researchers believe that older fathers may hold a clue to the vast upsurge in autism cases in the past decade. "With older and older couples having children-in the past two years, for the first time, more babies are being born to women over age 30 than under age 30, and on average, male partners tend to be older than female partners-it's very feasible that paternal age is a major predictor of autism," asserts Fisch.

Perhaps the worst aspect of the new findings is that a little genetic damage in men's sperm may actually be worse than a lot of damage. "When we started doing the research, our first concern was fertility, and these new studies do show that fertility maybe compromised by DNA damage. But that's not the most important thing," declares Charles Muller, lab director of the Male Fertility Clinic at the University of Washington in Seattle.

The greater threat to offspring is the less flagrant DNA damage that gets passed on. Experts like Muller believe that a substantial amount of the damage is caused by free radicals-the destructive, highly reactive particles produced by our body's energy factories, the mitochondria, as we metabolize oxygen. "One of the scariest things we're finding is that sperm DNA is damaged by even low levels of free radicals. Whereas high levels of damage lead to infertility, miscarriages, or spontaneous abortions, low levels chew up the DNA but the sperm can still fertilize," Muller states. Damage may then be passed from one generation to the next.

"In short, the biggest genetic threat to society may not be infertility but fertile old men," says University of Wisconsin in Madison geneticist James F. Crow.

The new findings have profound implications for any potential parent. Women may increasingly feel they share the onus of potential infertility and birth defects with men. Older women, focused though they are on their own reproductive timetable, may increasingly view their partner's age with a wary eye. When both parents are aging, the risks to offspring multiply. "If women are under age 35, the father's age may not matter that much, but if the mother is over 35, advanced male age can be a real problem." says Jabs.

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