# mTORC1 signaling in aging and metabolism

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $438,514

## Abstract

Project Summary/Abstract
Many signaling pathways linked to aging are linked to the regulation of metabolic signaling and stress
response pathways. For instance, the target of rapamycin (TOR) pathway is an evolutionarily-conserved
nutrient-sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Two complexes,
mTORC1 and 2, have overlapping upstream regulators and downstream effectors. Reduced mTOR signaling,
either by genetic intervention or with the clinically approved drug rapamycin, extends longevity in mice (as well
as yeast, worms and flies) and delays many pathologies of aging. Given its central role in aging and
metabolism, it is critical to understand how different perturbations of the mTOR pathway impact aging and
metabolism. Here, we use mouse models and cell culture studies to test one of the major downstream targets
of mTORC1, 4E-BP1. Justifying the emphasis on 4E-BP1, enhanced 4E-BP activity is associated with lifespan
extension in worms and flies, and we find that transgenic mice overexpressing 4E-BP1 are resistant to high fat
diet-induced metabolic dysfunction. We will employ multiple mouse models of 4E-BP1 overexpression in both
overnutrition and aging studies. Preliminary data indicates that an inflammation-induced loss of 4E-BP1
expression in the context of a high fat diet underlies the specific propensity of males to become glucose
intolerant and insulin resistant. We will determine the mechanisms underlying this gender dimorphism and its
impact on the mTOR pathway. Gender-specific responses to diet and aging are rampant in mouse models and
in humans, but the underlying causes of gender-specificity is largely unknown. In addition, we will determine
why muscle specific activation of 4E-BP1 preserves both skeletal muscle function and brown fat content during
overnutrition and aging, focusing on recent findings linking the benefits to skeletal muscle production and
secretion of the myokine, FGF21. Together, these studies will yield several new insights regarding the
specifics of mTOR signaling in the context of aging and metabolism, providing a better understanding about
how this pathway modulates aging and linking modulation of the mTOR pathway to other pharmacologic
interventions in aging.

## Key facts

- **NIH application ID:** 9939413
- **Project number:** 5R01AG050441-05
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** BRIAN K KENNEDY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,514
- **Award type:** 5
- **Project period:** 2016-09-30 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939413

## Citation

> US National Institutes of Health, RePORTER application 9939413, mTORC1 signaling in aging and metabolism (5R01AG050441-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939413. Licensed CC0.

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