Understanding the role of insulin signaling in female reproductive ageing
Date
2025
Authors
Athar, Faria
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Abstract
Preserving female reproductive health is crucial for maintaining the survival and sustenance of a species as well as for overall health and well-being. Reproductive health is mutable and has a strong life-history basis; two of its important regulators are chronological age and nutrition. Insulin signaling is an evolutionarily conserved mechanism for interpreting nutrition levels. To better understand the role of this pathway, I leverage its conservation to study impacts on reproductive function in a cross-species approach using human, mouse and Caenorhabditis elegans data. Analysis of longitudinal data from the Study of Women's Health Across the Nation (SWAN) revealed that women with higher fasting insulin levels at mid-life experienced an earlier onset and longer duration of vasomotor symptoms, independent of body mass index. To test the causal role of insulin in female reproductive ageing, I conducted longitudinal analysis of a mouse model and found that reducing endogenous levels of insulin production protects against high-fat, high-sucrose-induced reproductive dysfunction. Insulin-reduced dams maintained higher pregnancy rates and ovarian reserve compared to hyperinsulinemic littermates, despite similar levels of glycemia. In C. elegans we showed that glucose enrichment accelerates reproductive ageing by compromising oocyte quality and altering mitochondrial dynamics. However, reducing insulin signaling through mutation of the daf-2 insulin-like receptor protected against reproductive decline, even though it did not mitigate somatic ageing. I also found that insulin signaling in the intestine and body wall mediates reproductive ageing through non-autonomous mechanisms. Together, these studies provide evidence of insulin signaling being an evolutionarily conserved regulator of reproductive ageing.