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).

MPNST is a rare and deadly childhood cancer, which mainly affects teenagers and young adults. These tumors grow quickly, spread easily, and don't respond well to current treatments. Metastasis is the leading cause of death in MPNST and there currently are no targeted treatments for metastatic disease.

The study, led by University of Iowa researchers Eric Taylor, PhD, professor of molecular physiology and biophysics, and Rebecca Dodd, PhD, associate professor of internal medicine, identifies a specific metabolic pathway that is critical for MPNST cells' survival and growth, which could potentially be targeted with future therapies.

Targeting cancer metabolism to slow tumor progression

To better understand these tumors, the UI researchers used gene editing to create new research models that closely match the cancer-driving mutations found in patients. Using these models, they then applied state-of-the-art genomic and metabolomic tools to map the metabolic pathways that fuel tumor growth in MPNST.

The study, published in Science Advances, found that these cancers rely on a key metabolic pathway to help them survive oxidative stress and drive tumor growth. This pathway, known as the Pentose Phosphate Pathway (PPP), metabolizes sugar to produce a critical antioxidant molecule that the cancer cells require to combat oxidative stress. When the researchers blocked the PPP, the tumors grew more slowly and were more vulnerable to chemotherapy.

"This is the first time this specific metabolic pathway has been linked to MPNST tumor growth, making it a completely new target for therapy in this cancer type," Dodd says. "It opens the door to treatment strategies that haven't been explored before and could lead to more effective treatments and better outcomes for patients who urgently need new options."

The highly collaborative study combined Dodd's expertise in cancer biology with Taylor's expertise in metabolism. The lead author was UI graduate student Gavin McGivney, PhD, from Bayard in Guthrie County, Iowa, who was co-mentored by Dodd and Taylor. McGivney graduated from the UI Cancer Biology graduate program in 2024, and is now a postdoctoral scholar at University of Chicago. Dodd and Taylor are both members of UI Health Care Holden Comprehensive Cancer Center, and Taylor is a member of the UI Fraternal Order of Eagles Diabetes Research Center.

In addition to Dodd, Taylor, and McGivney, the research team also included UI researchers in the Departments of Internal Medicine, Molecular Physiology and Biophysics, and Radiation Oncology at the UI Roy J. and Lucille A. Carver College of Medicine. Researchers at Washington University School of Medicine, University of Texas MD Anderson Cancer Center, and the University of Toronto, were also part of the team.

The research was funded in part by grants from the Children's Tumor Foundation, the National Institutes of Health, the American Heart Association, the U.S. Department of Defense, and the American Cancer Society through Holden Comprehensive Cancer Center.