# Cell Non-autonomous Regulation of Aging via Neuronal TORC1

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2020 · $398,750

## Abstract

PROJECT SUMMARY
Progress in the genetics of aging field has demonstrated that, while chronological aging is unavoidable,
biological aging is malleable, and targeting cellular processes to promote homeostasis is an alternative
strategy to disease based approaches to alleviate the health burdens of old age. Both environmental
conditions and conserved genetic pathways strongly influence the rate of physiological aging and organisms
alter the rate at which they age and succumb to disease in response to external cues. The most potent
example of this is dietary restriction (DR), reduced food intake without malnutrition, which slows aging in every
organism tested thus far and protects against multiple chronic diseases, including cancer, cardiovascular
disease and neurodegeneration. Our long-term objective is to elucidate how DR promotes healthy aging
to allow the development of novel therapeutics to treat age-related disease.
Multiple molecular mechanisms have been implicated as critical mediators of DR, including the Target of
rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK), conserved nutrient sensors that
antagonistically modulate metabolism and ageing. Surprisingly however, how and where AMPK and TORC1
interact to modulate systemic aging is unclear. We find that neuronal AMPK is essential for lifespan extension
from TORC1 inhibition in C. elegans. Further, lifespan extension by null mutations in raga-1 (an upstream
TORC1 activator) or rsks-1 (homologue of mammalian S6K) is fully suppressed by neuronal specific recues.
Neuronal RAGA-1 abrogates raga-1 mutant longevity via neuropeptide signalling. Previously we have identified
key roles for regulation of mitochondrial dynamics and RNA splicing in AMPK and TORC1 longevity
respectively. We now show that these downstream effectors receive neuronal signals mediated by TORC1 to
modulate aging. Our results highlight a new role for neuronal TORC1 in cell non-autonomous regulation of
metabolism, RNA homeostasis and ageing, and suggest TORC1 in the central nervous system might be
targeted to promote healthy ageing. Our central hypothesis is therefore that the beneficial effects of DR
may be recapitulated via identification of cell nonautonomous signals regulated by neuronal TORC1.
The objective of this application is to define the specific neuronal signals mediated by TORC1 that pertain to
healthy aging, and how these signals are received in peripheral tissues to modulate mitochondrial networks
and RNA splicing to promote longevity.

## Key facts

- **NIH application ID:** 9902279
- **Project number:** 5R01AG059595-03
- **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:** $398,750
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902279

## Citation

> US National Institutes of Health, RePORTER application 9902279, Cell Non-autonomous Regulation of Aging via Neuronal TORC1 (5R01AG059595-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9902279. Licensed CC0.

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