Fasting and Caloric Restriction Activate an ADIOL-NHR-91-Kynurenine Pathway Signaling Axis to Promote Healthspan.

Abstract

The steroid hormone 5-androstene-3β,17β-diol (ADIOL) was discovered nearly a century ago in humans, yet its physiological functions have remained poorly understood. Using C. elegans, we identify ADIOL as essential for several pro-healthspan effects of fasting and caloric restriction (CR). These dietary restriction regimens activate an ADIOL-NHR-91-kynurenic acid signaling axis, partly through transcriptional programs associated with ADIOL biosynthesis. Within this axis, ADIOL acts through NHR-91, a C. elegans homolog of estrogen receptor β, to reduce levels of kynurenic acid, a neuromodulatory metabolite, thereby enhancing healthspan. Critically, ADIOL does not extend lifespan, indicating its healthspan benefits are independent of longevity, and even late-life supplementation is effective. Collectively, this work establishes ADIOL as a physiological link between metabolic cues and neural function, promoting health during aging via the kynurenine pathway. Given that in mammals ADIOL similarly is a ligand for estrogen receptor β and the kynurenine pathway influences neuroprotection mechanisms, ADIOL may represent an evolutionarily conserved signal by which dietary interventions enhance healthy aging.