Buck professor Pankaj Kapahi, PhD, senior author of the study says the public health implications of the research are significant. "Even though women are routinely asked about their menstrual and childbirth history when they receive medical care, this information has rarely factored into the care they receive outside of OB/GYN," he says. "These risk factors, whether positive or negative, clearly have significant influence on a variety of age-related diseases and should be considered in the larger context of overall health."

The research was based on one of the most comprehensive analyses to date, using regression analysis on nearly 200,000 women in the UK Biobank to confirm genetic associations. "We identified 126 genetic markers that mediate the effects of early puberty and childbirth on aging," said postdoctoral fellow Yifan Xiang, MD, who led the research. "Many of these markers are involved in well-known longevity pathways, such as IGF-1, growth hormone, AMPK and mTOR signaling, key regulators of metabolism and aging."

Genetic associations for antagonistic pleiotropy in humans

Evolution is based on natural selection acting on traits early in life to encourage reproduction and survival of the species. The antagonistic pleiotropy theory of aging suggests that traits beneficial in the young can have negative effects later in life. "Our study provides some of the strongest human evidence for this theory," Kapahi says. "We show that genetic factors favoring early reproduction come with the significant cost later in life including accelerated aging and disease. It makes sense that the very factors that help enhance survival of the offspring may lead to detrimental consequences for the mother."

The role of BMI in aging and disease risk

Kapahi says the study highlights the role of Body Mass Index (BMI) as a critical mediator of this process, finding that early reproductive events contribute to a higher BMI, which in turn increases the risk of metabolic disease. "One can envisage that enhancing the ability to absorb nutrients would benefit the offspring but if nutrients are plentiful then it can enhance the risk of obesity and diabetes."

Implications for public health and basic science

Kapahi says understanding the long-term impact of reproductive timing allows for the development of personalized healthcare strategies that could help mitigate the risks associated with early puberty and early childbirth, adding that lifestyle modifications, metabolic screenings and tailored dietary recommendations could improve long-term health in women. He says taking reproductive timing into account is currently relevant based on research that shows the age at which girls in the US begin menstruating has dropped by about three months per decade since the 1970s. No specific causes for the phenomena have been identified, but research suggests obesity may play a role.

While updated research guidelines call for the use of both sexes in preclinical research in mice, Kapahi says this current study still challenges traditional experimental design, noting that most disease models use virgin female mice, which may not accurately represent real-world aging patterns.

"If evolution has shaped us to prioritize early reproduction at the cost of aging, how can we leverage this knowledge to extend healthspan in modern society? Kapahi asks. "While we cannot change our genetic inheritance, understanding these genetic tradeoffs empowers us to make informed choices about health, lifestyle and medical care." The study also identifies several genetic pathways that can be manipulated to optimize health for mothers as well as her offspring Kapahi says.

Other Buck researchers involved in the study include: Vineeta Tanwar, Parminder Singh, and Lizellen La Follette.

Acknowledgments: This research was supported by Hevolution Foundation (PK), National Institute of Health grant R01AG068288 and R01AG045835 (PK), Larry L. Hillblom Foundation (PK), and Larry L. Hillblom Foundation (PS).