# Mechanisms Specific to the Beneficial Effects of Dietary Restriction

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2020 · $326,975

## Abstract

PROJECT SUMMARY
Dietary restriction (DR) is the most potent method for promoting healthy aging and age-onset disease resistance
in animal models. However, DR’s therapeutic potential is limited by associated negative physiological effects,
including impaired growth, immunity and reproductive capacity. Although nutrientsensing mediators of DR have
been identified, such as mTOR, FOXO/As and the sirtuins, these central nodes recapitulate the entirety of the
response, making them sub-optimal therapeutic targets. Our long-term objective is to uncover molecular
mechanisms that specifically mediate only the pro-longevity effects of DR to develop optimal
therapeutics. A key mediator of DR is AMP-activated protein kinase (AMPK), a cellular fuel gauge activated
when energy levels are low. However, like DR, AMPK increases lifespan at the cost of impaired growth and
reproduction.
The objective in this application is to use the genetically tractable model system C. elegans to identify
mechanisms by which AMPK and DR specifically mediates longevity, in order to elucidate the first molecular
targets that recapitulate only the pro-health effects of DR. The central hypothesis is that beneficial and
detrimental effects of DR can be uncoupled. In support of this hypothesis, specific amino acid combinations in
the diet have recently been shown to increase lifespan while maintaining normal reproduction, establishing that
the positive effects of DR on lifespan do not require obligate detrimental side effects. In addition, in the previous
funding period we demonstrated that the transcriptional coactivator and AMPK direct target CRTC-1 could
uncouple the longevity effects of AMPK from other negative side effects such as developmental delay,
reproduction suppression and reduced body size.
We now seek to identify the mechanisms by which CRTC-1 specifically mediates longevity. The rationale for this
project is that, before we can generate viable therapies from DR for clinical application we must first identify
mechanisms that 1) recapitulate only the positive effects of DR and 2) are effective when applied late in life,
post-diagnosis of age-related disease. Based upon strong preliminary data we will test three specific aims. 1)
We will examine the functional role of neuronal CRTC-1 in promoting healthy aging. 2) We will use CRISPR
editing of endogenous AMPK targets to delineate the roles of additional pathways downstream of this key energy
sensor 3) We will define the contribution of mitochondrial and peroxisome remodeling in AMPK and DR longevity.
Collectively, we expect this work to provide the first example of molecular pathways that uncouple the positive
and negative effects of DR, a critical step in transitioning DR research to the promotion of healthy human aging.

## Key facts

- **NIH application ID:** 10118669
- **Project number:** 2R01AG044346-06A1
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** William B Mair
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,975
- **Award type:** 2
- **Project period:** 2013-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118669

## Citation

> US National Institutes of Health, RePORTER application 10118669, Mechanisms Specific to the Beneficial Effects of Dietary Restriction (2R01AG044346-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10118669. Licensed CC0.

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