Reviewer #3 (Public review): Fourfold lifespan extension in C. elegans daf-2 mutant males

Aging is a universal biological process driven by conserved genetic networks that balance somatic maintenance with growth and reproduction. The insulin/insulin-like growth factor I signaling pathway is a central architect of this balance, and inhibiting its activity has long been established as a primary mechanism to extend lifespan across diverse species. However, our understanding of this pathway’s limits has been constrained by a historical focus on hermaphroditic models, which inherently link longevity extensions to a rigid trade-off involving immense reproductive costs and restricted somatic growth. Here we show that the latent potential of this canonical aging pathway is profoundly amplified by male-specific biology. We demonstrate that a classic insulin receptor mutation extends male survival to an unprecedented extreme, vastly surpassing the established benchmarks of the field. We reveal that this extraordinary lifespan expansion remains strictly dependent on the canonical FOXO transcription factor, yet it fuels a male-specific metabolic reprogramming that uncouples aging from stunted growth—massively accumulating neutral lipids to support sustained somatic preservation. These findings establish biological sex as a primary determinant of longevity potential and provide a new framework for identifying hidden, sex-specific mechanisms capable of promoting extreme healthy longevity.