# Lifespan extension by reverse fasting

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $271,500

## Abstract

Project Summary
In our application entitled" Lifespan extension by reverse fasting," we propose a new model connecting energy
metabolism and aging. In this model, longevity mechanisms are triggered by an energy deficit in which the food
intake does not provide enough energy to match the animal's energy expenditure (classical fasting). This
model further suggests that increasing energy expenditure while keeping food intake constant (reverse fasting)
should also generate an energy deficit that triggers longevity.
In this application, we use C. elegans to test these ideas. We find that the G protein-coupled receptor SER-7
controls energy expenditure. Activation of SER-7 by serotonin dose-dependently increases energy demand,
mitochondrial respiration, and subsequently food intake. In wild-type N2 animals increasing energy demand by
exogenous serotonin is consistently matched by an equivalent increase in food intake, preventing the
generation of an energy deficit. Testing eight different longevity mutants, we find that the ability to upregulate
energy expenditure and food intake is severely restricted in all but one of them, revealing the existence of a
general energy-saving mechanism in longevity mutants. For example, daf-2(e1370) mutants have roughly half
the respiration and food intake rate of wild-type animals, and their food intake in response to serotonin is
severely bunted. However, we identified a daf-2 mutant with an almost wild-type respiration and food intake
profile. Only the response to exogenous serotonin at high concentrations is slightly blunted, suggesting the
proposed energy-saving mechanism observed in daf-2(e1370) is not active. We find that the lack of an energy-
saving mechanism in that daf-2 mutant elevates the metabolic set point at which the dauer pathway is
triggered. The result is an animal that activates the dauer pathway at a point when it already eats twice as
much as wild type. This daf-2 mutant is the first confirmation of the reverse fasting hypothesis. It shows that it
is possible to generate animals that live long and overeat, as long as the energy expenditure is higher than the
energy intake. This application aims to identify the fasting/starvation-induced energy-saving mechanism and to
show that its inactivation will enable many longevity mutants to overeat and live long.

## Key facts

- **NIH application ID:** 10575272
- **Project number:** 1R21AG080376-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Michael Petrascheck
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $271,500
- **Award type:** 1
- **Project period:** 2023-03-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10575272

## Citation

> US National Institutes of Health, RePORTER application 10575272, Lifespan extension by reverse fasting (1R21AG080376-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10575272. Licensed CC0.

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