# Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $516,589

## Abstract

Understanding the molecular mechanisms that contribute to the accelerated development of the diseases of
aging is essential for healthy aging. Over the past 10 years, substantial evidence supports the notion that
altered mitochondrial function and metabolic dysregulation play key roles. In this competitive renewal grant
application of my first R01 as an independent PI, our overall goal is to identify how altered metabolism
contributes to the diseases of aging and aging itself. We have made significant progress towards
understanding how acyl-CoA species derived from metabolism induce protein modifications, and how
mitochondrial sirtuin 5 removes them as a layer of metabolic control. Our body of work in the first 5-year
funding period defines a new paradigm of protein acylation and deacylation, and identifies SIRT5 as a
regulator of metabolism and nutrient homeostasis. In the course of these studies, we made the unexpected
discovery that SIRT5 levels are physiologically regulated during normal cell cycle progression, and its absence
leads to altered cell cycle control. This exciting finding identifies a long-sought-after condition under which
sirtuin levels are controlled and is positioned to reveal the underlying biological role of this emerging regulator
of aging. In this proposal, we will build upon these exciting preliminary data and focus on the following Specific
Aims: Aim 1) interrogate the regulation of SIRT5 protein during cell cycle progression; Aim 2) determine how
SIRT5 activity influences nutrient sensing; Aim 3) identify the physiological role of SIRT5 in skeletal muscle
stem cells. Together, these studies combine an innovative conceptual framework and a comprehensive
experimental design to determine the key biological role of SIRT5 in controlling specific nutrient-sensing
responses. Furthermore, this study will build a foundation of knowledge to further understand how the
metabolic state communicates with the cell cycle, and how loss of this communication contributes to the
pathophysiology of aging. Ultimately, these studies will deepen our understanding of emergent, novel
metabolic control mechanisms, and have the potential to inform the development of new therapies to maintain
healthy aging.

## Key facts

- **NIH application ID:** 10000001
- **Project number:** 5R01AG045351-07
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthew D Hirschey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $516,589
- **Award type:** 5
- **Project period:** 2014-02-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000001

## Citation

> US National Institutes of Health, RePORTER application 10000001, Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease (5R01AG045351-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000001. Licensed CC0.

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