Dietary restriction promotes neuronal resilience via ADIOL.

The steroid hormone 5-androstene-3β,17β-diol (ADIOL) was discovered in humans nearly a century ago, yet its physiological roles remain poorly defined. Here, we show that fasting and caloric restriction, two forms of dietary restriction, induce transcriptional upregulation of genes encoding CYP11A1, CYP17A1, and 17β-hydroxysteroid dehydrogenase family enzymes, promoting ADIOL biosynthesis. ADIOL, in turn, acts on the nervous system to reduce levels of kynurenic acid, a neuroactive metabolite linked to cognitive decline and neurodegeneration. This effect requires NHR-91, the homolog of estrogen receptor β, specifically in the RIM neuron, a key site of kynurenic acid production. Consistent with the known benefits of fasting and caloric restriction on healthspan, enhancing ADIOL signaling improves multiple healthspan indicators during aging. Conversely, animals deficient in ADIOL signaling exhibit reduced healthspan under normal conditions and in genetic models of caloric restriction, underscoring the functional significance of this pathway. Furthermore, ADIOL suppresses cellular stresses induced by the Alzheimer's-associated APOE4 variant, highlighting its potential as a neuroprotective agent. Notably, ADIOL does not significantly impact lifespan, indicating that its healthspan benefits are not simply a byproduct of lifespan extension. Together, these findings establish a physiological role for ADIOL in mediating the neuroprotective and pro-healthspan effects of fasting and caloric restriction and suggest that boosting ADIOL signaling may help narrow the gap between lifespan and healthspan. This positions ADIOL as a promising mimetic of dietary restriction effects on healthspan that could be used as a therapeutic strategy for age-related neurodegenerative conditions.