# Link between epigenetic modifiers and fat metabolism for healthy aging

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $414,536

## Abstract

PROJECT SUMMARY
Chromatin modifiers integrate environmental stimuli to physiological outputs via epigenetic changes, which can
be long lasting and even transcend generations. Chromatin remodeling has been found to extend lifespan in
several organisms, but how chromatin modifiers promote longevity is unknown. We have made the tantalizing
observation that deficiency in the COMPASS methyltransferase complex, which trimethylates histone H3 at
lysine 4 (H3K4me3), leads to lifespan extension in C. elegans that is causally coupled to changes in fat
metabolism. Intriguingly, H3K4me3 modifiers act in the germline of C. elegans to trigger fat metabolism
changes in somatic tissues, suggesting a non-cell autonomous signaling between germline and soma for fat
metabolism. Using high throughput mass spectrometry, we find H3K4me3-methyltransferase deficient worms
are enriched for several specific mono-unsaturated fatty acids (MUFAs): oleic acid, palmitoleic acid, and cis-
vaccenic acid. This fat metabolic switch to MUFAs requires a conserved network involving the transcription
factors SPB-1/SREBP1, NHR-49/PPARα, and delta-9 fatty acid desaturases, and remarkably endogenous
MUFA accumulation is necessary for lifespan extension. Interestingly, dietary supplementation of individual
MUFAs is sufficient to extend lifespan in worms.
Excessive fat storage has been associated with diseases such as atherosclerosis and diabetes, but our data
suggest fat composition is critical, and that epigenetic remodeling can result in specific fatty acids that
increase longevity. Because the genes that generate unsaturated fatty acids are highly conserved throughout
evolution, endogenous or dietary MUFAs could promote longevity in humans. Exciting new questions raised by
these observations are: how is MUFA metabolism influenced by epigenetic changes and environmental
stimuli? How is the communication between germline and somatic tissues orchestrated to influence fat
composition? Are the changes in fat composition inherited in the progeny in a transgenerational manner? And
how do MUFAs act to extend lifespan? C. elegans is an excellent model for fat metabolism because of its
genetic power and because the machinery for conversion of saturated to unsaturated fatty acids is entirely
conserved. This proposal will test the hypothesis that epigenetic changes in H3K4me3 in the germline
initiates a signal that induces a switch to MUFA accumulation in specific somatic tissues, resulting in
lifespan extension.
Three specific aims will be developed to test this new idea:
1. To determine how germline H3K4me3 modifiers lead to change in somatic fat composition in parents and
progeny.
2. To identify the molecular mechanisms that induce a switch to mono-unsaturated fatty acids and longevity in
response to altered germline H3K4me3 and environmental stimuli.
3. To characterize the regulation and mode of action of specific fatty acids that promote longevity.
These studies will give mechanistic insights ...

## Key facts

- **NIH application ID:** 9923525
- **Project number:** 5R01AG054201-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** ANNE BRUNET
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $414,536
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923525

## Citation

> US National Institutes of Health, RePORTER application 9923525, Link between epigenetic modifiers and fat metabolism for healthy aging (5R01AG054201-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9923525. Licensed CC0.

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