Chicago Forget those famous old dads of yore, including Saul Bellow (who became a father at 84), Charlie Chaplin (71), Pablo Picasso (68) and Abraham (100), immortalized in the Bible.
Age does make a difference for men who want to have babies, just as it does for women.
A growing body of research suggests that late-in-life dads are more likely to have fertility problems and are at higher risk of fathering children with conditions such as schizophrenia, autism and dwarfism.
And for the first time, sophisticated new scientific tests are suggesting a reason for the phenomenon: As men get older, the DNA in their sperm and its supporting protein scaffolding are more likely to break and suffer damage.
"For a long time, we labored under the assumption that sperm quality was universal throughout the life span of the male, but what we've found recently is that isn't so," said Dr. Richard Rawlins, director of the assisted reproduction laboratory at Rush University Medical Center.
"Instead, we now know sperm quality deteriorates over time."
In other words, men apparently also possess a "biological clock" for reproduction - albeit one that works differently than in women.
"We can't say there's a definite point before which (men) should try to have children or face the potential of an adverse outcome," said Brenda Eskenazi, a professor of epidemiology at the University of California at Berkeley.
"But we can say delaying fatherhood increases risk."
Not all convinced
That assertion is controversial, as some doctors aren't convinced that the scientific evidence is conclusive or the potential harm is significant enough to cause substantial concern.
The risks are small, "the data is very limited and the pool of men potentially affected relatively restricted," said Dr. David Cohen, chief of reproductive endocrinology and infertility at the University of Chicago. "Very few 50-, 60- or 70-year-old men are trying to have a baby."
"Keep in mind, men produce hundreds of millions of sperm each day, and even if large numbers of these sperm are damaged with age, large numbers remain unaffected," said Dr. Craig Neiderberger, chief of male fertility at the University of Illinois Medical Center in Chicago. "The jury is out about the real impact."
But new evidence underscoring the impact of paternal age on reproduction continues to accumulate.
In one report, published in June in the Proceedings of the National Academy of Science, Eskenazi and a team of researchers analyzed semen samples for 97 well-educated, healthy, non-smoking male employees of Lawrence Livermore National Laboratory in Berkeley, Calif.
The key finding: DNA breaks in men's sperm and its accompanying protein scaffolding increased gradually but steadily over time, rising fivefold between 22 and 80 years of age.
While age appears to contribute to DNA fragmentation, other cumulative factors - including what men eat and drink and what chemicals they're exposed to - also probably play a part, according to Andrew Wyrobek, a co-author and chairman of the department of radiation biosciences at Lawrence Berkeley National Laboratory.
When DNA strands break, chromosomes in the sperm can be deleted, rearranged or damaged. In turn, those genetic abnormalities may give rise to birth defects or health problems in a child, or make it impossible for an embryo to develop normally.
In this study, researchers found a connection between a mutation in sperm DNA and a form of dwarfism known as achondroplasia. As more becomes known about the genetic underpinnings of human development and disease, more such links may become evident.
How it works
Scientists don't understand yet how the mechanism behind aging's effect on sperm, though they have several ideas.
One is that the stem cells that spawn sperm throughout a man's life may begin generating more errors. Unlike women, who are born with a lifetime supply of eggs, men generate sperm constantly, raising the opportunity for more mistakes.
Biological mechanisms designed to destroy defective sperm may begin to fail. The process that allows a man's DNA to fold up in sperm and then unfold again after fertilization may become compromised.
Several large population studies that have suggested late-in-life fathers are more likely to have children with various health problems, findings that make it clear fertility is not the only thing at stake.
A connection between paternal age and schizophrenia was first documented by Dr. Dolores Malaspina, chairwoman of psychiatry at New York University, in a 2001 study in the Archives of General Psychiatry. She found the age of fathers accounted for one-quarter of all cases of schizophrenia, and risks for the dads over 50 were almost three times that of dads in their 20s.
The results have since been replicated in other countries.
Still, some experts caution that the association of paternal age with these problems is just that: a possible link with no proof of causality. It's possible that factors not considered in the analyses could account for the results.
By now, many men hoping to have children will be asking: When does my biological clock start ticking? The answer is that the evidence is still coming in.
In 2000, researchers reported that nearly twice as many men over the age of 35 failed to get partners pregnant within the first 12 months of trying, compared with men under age 25 (15 percent vs. 8 percent).
In 2003, California scientists demonstrated that vigorous sperm movement and semen volume declined in older men; 50-year-old men were shown to have an 80 percent probability of clinically abnormal sperm motility.
And last May, French researchers reported that men 40 or older are 70 percent less likely to make their partners pregnant than men younger than 30, according to their study of nearly 2,000 couples trying to conceive.
"It is generally considered that the female clock starts ticking at the age of 35," Dr. Elise de La Rochebrochard told a London newspaper. "This study suggests that the male clock starts at 40."