# Beneficial effects of Sestrin protein for muscle health during aging and exercise

> **NIH NIH K01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $128,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Preservation of mobility is one of the most significant health concerns of the elderly population associated with
aging. Identification of cost-effective therapies that can preserve independence and mobile capacity in the elderly
would be important and influence many other aspects of mental and physical health. Even though endurance
exercise is the most effective intervention that can reproducibly extend mobile healthspan in humans and animals,
the molecular mechanism underlying exercise benefits has been elusive. I propose to investigate the role of a
potential exercise mediator Sestrins, which may lead to the development of therapeutic or preventive methods
that can harness the benefits of exercise without actual physical movement, which is practically challenging in
this modern society. Sestrins are a family of stress-inducible proteins that can suppress both reactive oxygen
species (ROS) and mTOR complex 1 (mTORC1) signaling pathways. Excessive ROS accumulation and chronic
mTORC1 activation are known as promoters of tissue aging and degeneration. Genetic studies in worms, flies,
and mice demonstrated that loss of Sestrins accelerates various age- and obesity-associated metabolic
pathologies including cardiac dysfunction, insulin resistance and muscle degeneration, associated with ROS
accumulation and hyperactive mTORC1. Interestingly, while Sestrins downregulate ROS and mTORC1, they
induce autophagy and strongly potentiate mTORC2/AKT signaling activation in response to insulin.
The potential anti-aging properties of Sestrins prompted me to investigate whether we are able to attenuate
tissue aging by transgenic supplementation of Sestrins activity. Preliminary experiments in Drosophila indicated
that Sestrin overexpression in muscle tissue can dramatically increase mobility in aged flies: a more than twofold
increase in both climbing speed and endurance was observed in Sestrin-overexpressing flies compared to the
control group. Exercise training in both flies and mice can increase Sestrin expression. Loss of Sestrin in flies
and Sestrin1 in mice nullified the benefits received from exercise training in expanding their endurance and
improving their metabolism. Based on these findings, we propose to (aim 1) characterize skeletal, cardiac and
diaphragm muscle phenotypes of Sestrins-deficient mice across ages, (aim 2) characterize muscle phenotypes
of mice with muscle-specific Sestrins modulation, and (aim 3) examine the mechanism of how Sestrins improve
muscle functionality. Our central hypothesis is that, as in flies, mammalian Sestrins are also important exercise
mediators and can produce mobility-extending activities in later life. Therefore, the proposed research may reveal
the beneficial effects of Sestrin activation in protection against aging and age-associated functional and structural
degeneration of skeletal and cardiac muscle. This may lead to the development of innovative Sestrins-mimicking
methods for preserv...

## Key facts

- **NIH application ID:** 10375365
- **Project number:** 5K01AG061236-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Myungjin Kim
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $128,520
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375365

## Citation

> US National Institutes of Health, RePORTER application 10375365, Beneficial effects of Sestrin protein for muscle health during aging and exercise (5K01AG061236-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10375365. Licensed CC0.

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