# Investigating Mechanisms of Isoleucine Restriction as an Effective Geroprotective Interventions

> **NIH NIH F32** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $72,082

## Abstract

PROJECT SUMAMRY
 The pursuit of an effective geroprotective strategy has been a critical goal for aging research since it has
became clear that the rapidly graying population will otherwise generate an unbearable socioeconomic strain.
Caloric restriction (CR) is an effective dietary intervention for healthspan and lifespan extension. Recently, other
dietary interventions have been developed as means to improve health and extend lifespan that may be more
sustainable than CR. Amongst these is protein restriction (PR), a dietary regimen that also boasts significant
metabolic, health, and longevity benefits in diverse species. The Lamming Lab has investigated the role of
individual essential amino acids in the effects of PR. Restriction of the branched chain amino acids (BCAAs;
leucine, isoleucine, valine) was found to recapitulate the many metabolic benefits of PR, and extends lifespan in
male mice when the dietary intervention was lifelong. Further study has found the restriction of isoleucine (Ile) to
be both necessary and sufficient for the metabolic benefits of PR. In preliminary experiments, isoleucine
restriction (IleR) in young adult mice improves glycemic control, reduces adiposity, and, in males, delays age-
related increases in frailty and extends lifespan.
 In this proposal, I will first determine if IleR can effectively promote healthy aging when started in late-life.
I will examine how IleR affects metabolic health, physical performance, frailty, and lifespan. We have found that
IleR induces ketogenesis: the production of the ketone body β-hydroxybutyrate (BHB), which has been shown
to have geroprotective properties. In fact, a ketogenic diet has been shown to extend mouse lifespan. In the
second aim of this proposal, I will investigate the role of ketogenesis in the metabolic benefits of IleR using mice
with the conditional deletion of Hmgcs2, the rate-limiting enzyme for ketogenesis, in the liver. In the final aim of
this proposal, I will leverage pharmacological and viral approaches to manipulate the catabolic flux of BCAAs to
test the hypothesis that increasing BCAA catabolism can simulate the effects of IleR by reducing the standing
pool of BCAAs. These experiments will enable us to determine whether the reduction of Ile itself, or of its
catabolites, are responsible for the beneficial effects of IleR, and demonstrate if the manipulation of BCAA
catabolic flux can be a viable geroprotective strategy.
 The overarching goal of this proposal is to further define the effects and identity of the molecular
mechanisms underlying the benefits of IleR. The extensive investigation described here represent the perfect
project for my growth as a trainee and will push forth the development for a feasible, highly effective, and
metabolically focused geroprotective strategy.

## Key facts

- **NIH application ID:** 10466572
- **Project number:** 1F32AG077916-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Chung-Yang Yeh
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $72,082
- **Award type:** 1
- **Project period:** 2022-06-05 → 2023-10-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466572

## Citation

> US National Institutes of Health, RePORTER application 10466572, Investigating Mechanisms of Isoleucine Restriction as an Effective Geroprotective Interventions (1F32AG077916-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10466572. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*