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Biological Clock Tolls for Men Too


LIVERMORE, Calif. - As healthy men age, they become less likely to father a successful pregnancy. They have an increased risk for having children with musculoskeletal and craniofacial mutations.

LIVERMORE, Calif., June 7 ? As healthy men age, they become less likely to father a successful pregnancy, according to investigators here. Aging men have an increased risk for having children with musculoskeletal and craniofacial mutations.

Evidence shows that the genetic quality of sperm deteriorates significantly with age, wrote Andrew J. Wyrobek, Ph.D., of the Lawrence Livermore National Laboratories here, and colleagues, in the online edition of the Proceedings of the National Academy of Sciences.

"This study shows that men who wait until they're older to have children are not only risking difficulties conceiving, they could also be increasing the risk of having children with genetic problems," they said.

"We know that women have a biological time clock, with an increase in risk of miscarriage and producing children with trisomy-an extra chromosome, such as in Down's syndrome-as women age, and with a seemingly abrupt end of fertility around perimenopause," added Brenda Eskenazi, Ph.D., of the University of California at Berkeley School of Public Health, a co-author.

"Our research suggests that men, too, have a biological time clock-only it is different," she added. "Men seem to have a gradual rather than an abrupt change in fertility and in the potential ability to produce viable healthy offspring."

The investigators looked at the quality of sperm from 97 healthy male volunteers between the ages of 22 and 80 years. They found that as men age, their ability to successfully father a pregnancy declines gradually beginning in their early reproductive years, and that in a small fraction of men as they age their risk for fathering children with achondroplastic mutations and Apert syndrome (a craniofacial and limb development disorder) rises significantly.

In contrast, aging men, unlike women, do not appear to be at increased risk for having children with aneuploid mutations (such as Down, Klinefelter, Turner, triple X or XYY syndromes) or triploid mutations.

The key appears to lie in increasing DNA fragmentation and mutations in the gene encoding for the fibroblast growth factor receptor 3 as sperm get on in years the investigators found.

Using as their cohort 97 current or retired Lawrence Livermore Lab employees, the investigators evaluated the relative effects of advancing age on various measures of genomic damage in their sperm, including chromatin integrity, gene mutations, sex ratio, and numerical chromosomal abnormalities.

The authors also assessed correlations among the genomic defects with measures of semen quality such as sperm motility and numbers, and they estimated the proportion of men who have abnormally high frequencies of sperm with multiple genomic defects.

After adjusting for confounders such as medical and lifestyle factors, the authors found significant major associations between age and the frequencies of sperm with DNA fragmentation index and fibroblast growth factor receptor 3 gene mutations associated with achondroplasia (P

They did not, however, find any significant associations between age and the frequencies of sperm with immature chromatin, aneuploidies, diploidies, FGFR2 mutations (Apert syndrome), or sex ratios.

The findings regarding Apert syndrome contrast with those of a different study out of Johns Hopkins, which found a significant association between aging and risk for having children with the FGFR2 mutation. The cohort in that study included more men of African and Asian descent (compared with the largely white cohort in this study), suggesting that genetic differences among the men may play a role in susceptibility, the investigators noted.

They also found that semen-quality endpoints, as a rule, could not accurately predict genomic damage, although there was a consistent correlation between DNA fragmentation index and sperm motility.

"Our findings predict that as healthy males age, they have decreased pregnancy success with trends beginning in their early reproductive years, increased risk for producing offspring with achondroplasia mutations, and risk of fathering offspring with Apert syndrome that may vary across cohorts, but with no increased risk for fathering aneuploid offspring?or triploid embryos," the investigators wrote.

"Our findings also suggest that the burden of genomic damage in sperm cannot be inferred from semen quality, and that a small fraction of men are at increased risk for transmitting multiple genetic and chromosomal defects," they added.

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