# Uncovering Conserved Lipid Homeostasis Mechanisms that Mediate Longevity after Germ Cell Loss in C. Elegans

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2021 · $346,450

## Abstract

Project Summary
 Ablation of germ cells (GCs) extends lifespan in various species, providing paradigms for tradeoffs
between reproduction and longevity, modulation of aging by signaling between tissues, and responses to
metabolic perturbation. We recently identified a critical mechanism in this pathway in C. elegans: a response
to fat overload that occurs when lipids that were produced for reproduction are not consumed. In the digestive
system counterpart (intestine), this lipid accumulates and induces nuclear localization of the transcription factor
SKN-1, the Nrf protein ortholog. SKN-1 activates lipid metabolism genes, reduces fat levels, and increases
lifespan. SKN-1 and Nrf proteins are well known to respond to stress from reactive oxygen species (ROS), but
GC ablation activates SKN-1 through a different pathway that is largely uncharacterized. This novel pathway
involves fatty acid (FA)-dependent signals, specific lipid transport and metabolism activities, the
gasotransmitter H2S, and 150 genes we have identified by RNA intereference (RNAi) screening. It is possible
that this pathway may be triggered by particular FAs, or by bioactive lipid mediators (LMs) derived from them.
In C. elegans we have collaboratively detected low-abundance LMs that promote or resolve inflammation in
humans. GC ablation appears to alter their profiles, suggesting an “inflammatory”-like response. Our findings
provide a new genetically tractable platform for (1) uncovering how organisms respond to lipid overload, and
(2) elucidating how specific lipid-based signals regulate gene expression and possibly aging. They also may
represent a paradigm for understanding how mammalian Nrf proteins protect against fatty liver disease.
 This project will address a number of exciting questions. Aim 1 will elucidate lipid-dependent effects of
GC ablation. Analysis of tissue-specific gene expression in the intestine and studies of particular SKN-1
isoforms will reveal FA-dependent effects that are mediated by SKN-1, and other regulators. Studies of FA
profiling and β-oxidation will reveal whether SKN-1 mediates effects that correlate with these gene expression
changes. Our LM detection effort will identify candidate LMs that are modulated by GC ablation, and will
enable study of these important regulators in this genetically tractable organism. Aim 2 will reveal how GC
ablation and lipid signals activate SKN-1 and possibly other regulators. A combination of FA biosynthesis
enzyme knockdown with administration of specific FAs and LMs should identify specific lipids that mediate
these effects. Completion of our RNAi screening will suggest additional mechanisms through which GC
ablation activates SKN-1. Finally, in the centerpiece of this project, epistasis and model-driven experiments
will place H2S and lipid signals within this new pathway, and will elucidate the involvement of candidate
regulatory mechanisms that our results have identified. Completion of these aims will provide ...

## Key facts

- **NIH application ID:** 10107736
- **Project number:** 5R01AG054215-05
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** T Keith Blackwell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,450
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107736

## Citation

> US National Institutes of Health, RePORTER application 10107736, Uncovering Conserved Lipid Homeostasis Mechanisms that Mediate Longevity after Germ Cell Loss in C. Elegans (5R01AG054215-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107736. Licensed CC0.

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