# SIRT1 as a regulator of health and lifespan of mammals

> **NIH NIH R37** · HARVARD MEDICAL SCHOOL · 2021 · $373,815

## Abstract

Abstract of the Research Plan
Despite significant research effort to understand the aging process, we are still not able to confidently answer
fundamental questions: Why do we age and can we delay it in humans? Recent studies suggest that various
age-related pathophysiological conditions may have common underpinnings, the so-called hallmarks of aging
that include mitochondrial defects, cellular senescence and inflammation. Our research group has worked for
more than a decade on NAD+-dependent lysine deacetylases known as the Sirtuins (SIRT1-7).
Thanks to this grant, we discovered a new cause of aging that explains why mitochondrial function declines
with age, a process we call “Genome Asynchrony”. Genome asynchrony manifests in heart and muscle tissue
(and possibly other tissues) as a breakdown in nuclear-mitochondrial communication due to a decline the
NAD+ levels and loss of SIRT1 activity. The result is the stabilization of the hypoxia factor HIF-1α in the
absence of hypoxia (a phenomenon we call “pseudohypoxia”) and a potent inhibitory effect on nuclear-
mitochondrial communication. Importantly, by feeding old mice the NAD+ precursor, nicotinamide
mononucleotide (NMN), for one week, thus restoring NAD+ to youthful levels, the mitochondrial defects of old
muscle can be rapidly reversed, demonstrating that NAD+ is a key regulator of aspects of aging in mice and
that aspects of aging are reversible. During the study we discovered that the NMN treatment was able to
rapidly reverse key markers of aging in the muscle, suggesting declining NAD+ levels may underlie
inflammation during aging. We find that NAD+ levels and HIF-1α specifically control the secretion of IL-18 and
IL-1β by regulating the activity of the inflammasome, a key regulator of healthspan in mammals.
In the next phase of the grant, we will determine the NAD+-dependent mechanisms that regulate inflammation
along with its role in the secretory phenotype of senescent cells (SASP) and test interventions to counteract
these pathways. Aim 1 is to use primary macrophages from genetically modified mice (GEMMs), along with
novel epigenetic manipulation technologies and clinic-ready small molecules to test our hypotheses. In Aim 2,
we will perform a comprehensive study of this pathway in vivo using young and old mice from colonies of both
wildtype and GEMMs with altered levels of NAD+ and HIF-1 throughout the body or in specific tissues such as
muscle and brain. In Aim 3, we will evaluate the efficacy of the best NAD+ modulating compounds (from Aim 1)
to prolong healthspan and lifespan in mice. We will also test the best compounds for their efficacy in a gold-
standard model of acute gout (a common age-associated inflammatory disease for which there are no effective
treatments) thereby paving the way for rapid human clinical trials. The work will have far-reaching implications
by changing our understanding of why aging occurs and creating novel therapeutics to prolong human
healthspan and lo...

## Key facts

- **NIH application ID:** 10116232
- **Project number:** 5R37AG028730-15
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DAVID A. SINCLAIR
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,815
- **Award type:** 5
- **Project period:** 2007-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116232

## Citation

> US National Institutes of Health, RePORTER application 10116232, SIRT1 as a regulator of health and lifespan of mammals (5R37AG028730-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116232. Licensed CC0.

---

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