Fasting Hormone ADIOL Boosts Healthspan Gains

A Specific Hormone Drives Healthspan Gains During Fasting

Researchers from the University of California, San Francisco have identified a previously obscure steroid hormone as a key player in the health benefits of fasting. In a study published in Aging Cell, the team found that fasting and caloric restriction trigger a cascade involving 5-androstene-3β,17β-diol (ADIOL). This hormone activates a pathway that reduces levels of a neuroactive metabolite called kynurenic acid, leading to improved healthspan—the period of life spent in good health—in the model organism C. elegans. Crucially, this mechanism operates independently of lifespan extension.

ADIOL: A Century-Old Hormone with New Healthspan Functions

The hormone ADIOL was first detected in humans nearly 100 years ago, but its biological roles were poorly defined. The UCSF team, led by Ana Guijarro-Hernández and supervised by Kaveh Ashrafi, discovered that ADIOL is essential for the pro-healthspan effects of dietary restriction in worms. Fasting and caloric restriction boost ADIOL biosynthesis. This hormone then binds to a nuclear hormone receptor called NHR-91—a homolog of the human estrogen receptor β.

The activated NHR-91 receptor initiates a change in metabolite levels, specifically reducing kynurenic acid. Kynurenic acid is a byproduct of amino acid metabolism with neuromodulatory properties, and its accumulation has been associated with various age-related neurological conditions. By lowering this metabolite, the ADIOL-NHR-91 axis improves markers of healthspan, such as mobility and stress resistance. Importantly, supplementing ADIOL alone did not extend the worm’s maximum lifespan, separating the concept of healthspan from longevity.

Human Evidence for Fasting Remains Preliminary and Focused on Metabolism

While the worm study reveals a precise mechanism, translating these findings to human longevity requires caution. Matthew Steinhauser and Pouneh Fazeli from the University of Pittsburgh Aging Institute reviewed the human evidence base. They note that humans possess “adaptive mechanisms that enable survival even with zero calories for periods of months or longer.” Intermittent exposure to fasting stress may activate health-promoting pathways.

The authors conclude, however, that benefits for longevity “have not been proven in humans.” The current, more solid evidence supports fasting for improving metabolic health and promoting weight loss in overweight or obese individuals. For a motivated patient without specific risk factors, a trial of intermittent fasting or time-restricted eating is “reasonable.” The widespread adoption of fasting for longevity, they argue, is not yet justified by evidence. This perspective aligns with other research on the evolutionary basis of fasting benefits.

From Dietary Practice to Potential Drug Target

The ultimate goal of this research is not to mandate difficult fasting regimens for everyone. Steinhauser and Fazeli propose that understanding these mechanisms is critical “to ultimately be targeted with a fasting mimetic drug to obviate the need for long-term adherence to onerous dietary restriction.” The ADIOL pathway identified by the UCSF team represents one such potential target.

This approach mirrors other strategies in longevity science, such as the development of senolytics like fisetin or the use of compounds like rapamycin to mimic the benefits of caloric restriction without the diet. Future studies will need to incorporate detailed mechanistic and multi-omics analyses in humans to validate if pathways like the ADIOL axis are conserved and actionable.

Applying the Science: A Measured Approach to Fasting

For those considering fasting, the research suggests a focused, healthspan-oriented approach. The proven application is for improving metabolic parameters—such as insulin sensitivity, blood lipids, and body weight—particularly through protocols like time-restricted eating, which may also align with circadian rhythms for added benefit.

It is vital to heed the warnings from the Pittsburgh review. Fasting is not advisable for individuals with frailty, osteoporosis or osteopenia, or a history of eating disorders. For others, it can be a tool for metabolic health, with the hope that its deeper mechanisms—like triggering cellular autophagy or modulating specific hormone pathways—contribute to a healthier aging process. The discovery of the ADIOL pathway provides a concrete biological story for how fasting might work, moving the field from observation toward potential intervention.

Sources:
https://pubmed.ncbi.nlm.nih.gov/42043665/
https://pubmed.ncbi.nlm.nih.gov/42021510/
https://pubmed.ncbi.nlm.nih.gov/41889977/