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

Area of Science:

• Endocrinology
• Neuroscience
• Aging Research

Background:

• The physiological functions of the steroid hormone 5-androstene-3β,17β-diol (ADIOL) remain largely unknown despite its discovery nearly a century ago.
• Dietary interventions like fasting and caloric restriction (CR) are known to promote healthspan, but the underlying molecular mechanisms are not fully elucidated.

Purpose of the Study:

• To investigate the role of ADIOL in the pro-healthspan effects of fasting and CR.
• To identify the signaling pathways through which ADIOL influences healthspan and aging.

Main Methods:

• Utilized the model organism C. elegans to study ADIOL's function.
• Investigated the ADIOL-NHR-91-kynurenic acid signaling axis.
• Examined transcriptional programs associated with ADIOL biosynthesis.

Main Results:

• ADIOL is essential for the healthspan benefits of fasting and CR in C. elegans.
• ADIOL acts via NHR-91 (a homolog of estrogen receptor β) to reduce kynurenic acid levels, enhancing healthspan.
• ADIOL enhances healthspan independently of lifespan extension, with late-life supplementation proving effective.

Conclusions:

• ADIOL serves as a physiological link between metabolic cues and neural function, promoting healthy aging.
• The ADIOL-mediated pathway involves the kynurenine pathway and may be evolutionarily conserved.
• ADIOL represents a potential target for interventions aimed at enhancing healthy aging through dietary strategies.