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Reproduction, Lifespan Show Antagonistic Pleiotropy in Genetic Analysis

Biological clock generic

NEW YORK – Research by investigators in the US and China suggests genetic variants associated with a rise in reproductive potential tend to coincide with abbreviated lifespans, pointing to selection for genetic trade-offs between individuals' longevity and reproductive capabilities. The findings appeared in Science Advances on Friday.

"Although observations of reproduction-lifespan trade-offs were previously made in some species, it has been difficult to prove that the trade-offs were caused by genetic instead of environmental factors," senior and corresponding author Jianzhi Zhang, an ecology and evolutionary biology researcher at the University of Michigan, Ann Arbor, said in an email.

To explore potential genetic ties between early reproduction or the production of more offspring and aging, the researchers brought together array-based genotyping profiles, reproductive data, and death records for 276,406 UK Biobank participants. Consistent with an antagonistic pleiotropy hypothesis proposed nearly seven decades ago by Michigan State University researcher George Williams in the journal Evolution, they found that reproductive trait-boosting variants tended to curb lifespan.

In the past, Zhang noted, "it was found that a particular mutation antagonistically impacts reproduction and lifespan, but it is unclear whether such cases reflect general rules or are exceptions."

"Hence, it is necessary to conduct a whole-genome analysis of the genetic relationship between reproduction and longevity to test Williams' hypothesis," Zhang explained. "This is exactly what we did in this study, and our results strongly support the antagonistic pleiotropy hypothesis."

When the researchers put together polygenic scores comprised of 583 genetic variants implicated in reproductive traits ranging from age at menarche, age at menopause, or polycystic ovary syndrome diagnoses to individuals' ages at first sex, age at first birth, or number of children, for example, they found that participants with higher-than-usual reproduction scores were less likely to survive to 76 years old than their low reproduction PGS counterparts.

Based on genetic data for half a dozen cohorts involving individuals born between 1940 and 1969, meanwhile, the authors saw an uptick in scores on the reproduction PGS over time — a pattern that they attributed to "natural selection for higher reproduction."

"Together," the authors reported, "the analyses of PGS for reproduction provide evidence for i) antagonistic pleiotropy between reproduction and life span and ii) natural selection for higher reproduction (presumably to the detriment of life span), supporting the antagonistic pleiotropy hypothesis of the origin of aging."

The findings contrast with rising life expectancies reported in most populations in the years leading up to 2019, Zhang explained in a statement, noting that actual lifespan increases are thought to reflect "substantial environmental shifts, including changes in lifestyles and technologies, and are opposite to the changes caused by natural selection of the genetic variants identified in this study."

Across the 583 variants included in the reproduction PRS, 98 variants appeared to have antagonistic effects on reproduction and aging, while just 25 variants were predicted to have concordant effects.

Likewise, the team reported similar relationships for specific genetic risk variants, where variants implicated in reproductive traits tended to turn up in regulatory regions influencing the expression of a genes involved in hormone signaling, immune response, age-related pathology, and other processes in multiple human tissues.

Together, the authors explained, results from the current analyses "support the antagonistic pleiotropy hypothesis of aging in humans and point to potential molecular mechanisms of the reproduction-lifespan antagonistic pleiotropy."

They noted that "one needs to be cautious when generalizing our findings to other populations because of their different social and environmental factors and genetic backgrounds," and argued that "validation of our finding in other populations, especially those currently underrepresented in biobanks, is highly desired."

Still, the investigators suggested that further research into the genetic relationships between reproduction and aging may foster future research and an improved understanding of the biological pathway behind aging and related conditions.

"We hope that our general finding and the specific genetic variants discovered that show opposite effects on reproduction and longevity will help aging research," Zhang said.