The interplay between diet and mating status in influencing ovarian aging and healthspan in flies and humans

The National Institute on Aging awarded the Buck Institute for Research on Aging $821,486 on August 15, 2026, under the Aging Research program (CFDA 93.866) to investigate how diet and reproductive status interact to influence ovarian aging and systemic healthspan in fruit flies and humans.

The research integrates large-scale human population datasets with mechanistic studies in Drosophila melanogaster. In the first aim, the recipient will leverage human datasets and plasma proteomics to define molecular signatures of ovarian and systemic aging, construct a proteomic "ovarian aging clock," and assess causal relationships between reproductive timing and age-related outcomes using Mendelian randomization approaches. In the second aim, the recipient will employ Drosophila models to dissect how reproductive effort and dietary restriction modulate aging pathways. The work tests the hypothesis that early childbirth in humans or mating in flies accelerates both reproductive and systemic aging in an evolutionarily conserved manner, and that dietary restriction can modulate these aging effects by reprogramming metabolic and transcriptional pathways.

Performance occurs in Novato, California, with work extending through July 31, 2031. The award is assistance type Project Grant and represents one year of funding within the five-year project period.

Abstract

Reproductive effort imposes significant physiological stress, yet its long-term consequences on systemic and reproductive aging trajectories remain poorly characterized. Evolutionary theories such as antagonistic pleiotropy and the disposable soma hypothesis suggest reproductive tradeoffs such that reproductive effort diverts resources away from somatic maintenance, thereby accelerating aging and increasing vulnerability to age-related diseases. Our prior research shows that early reproductive events-such as first childbirth before age 25, are associated with earlier menopause and increased risk of age-related diseases, including type 2 diabetes, cardiovascular disease, and dementia. These findings underscore reproduction as a biological driver of systemic aging rather than merely a demographic event. The overall goal of this proposal is to elucidate how reproduction and diet interact to influence the aging of the reproductive system and drive other age-related changes over the lifespan. Our central hypothesis is that, consistent with the disposable soma theory, early childbirth in humans or mating in flies, accelerates both reproductive and systemic aging in an evolutionarily conserved manner. We further posit that dietary restriction can modulate these aging effects by reprogramming conserved metabolic and transcriptional pathways. To test this hypothesis, we will integrate large-scale human population datasets with mechanistic studies in drosophila melanogaster. In aim 1, we will leverage large-scale human datasets and plasma proteomics to define molecular signatures of ovarian and systemic aging and construct a proteomic "ovarian aging clock". We will also assess causal relationships between reproductive timing and age-related outcomes using mendelian randomization (MR) approaches. In aim 2, we will employ drosophila models to dissect how mating and diet modulate transcriptional networks that drive reproductive aging. We have identified transcriptional regulators that mediate mating-induced changes in the ovary; notably, inhibition of these regulators in the ovary extends lifespan in flies. We have uncovered a novel mating-induced transcriptional program that accelerates reproductive aging in flies, suggesting that reproductive activity itself may contribute to ovarian decline and systemic aging. This research is significant because IT will uncover evolutionarily conserved, diet-modifiable pathways that connect reproductive investment to systemic aging, a fundamental GAP in aging biology and women's health. IT also highlights the importance of incorporating reproductive and mating status into aging models to more accurately capture SEX-specific aging trajectories. The innovation lies in bridging human multi-omic data with experimentally tractable model systems to establish causality and mechanistic insight. By defining how reproductive and nutrient states shape aging trajectories, this work will identify novel molecular targets and lifestyle strategies to promote healthy longevity and reduce the burden of age-related disease.