# Epoxide metabolism as a modulator of aging

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $290,250

## Abstract

PROJECT SUMMARY
Low chronic inflammation is a hallmark of aging. The arachidonic signaling cascade is arguably
one of the most important lipid signaling pathways in inflammation. It consists of three branches
that are defined by their key lipid-modifying enzymes called cyclooxygenases (COX),
lipoxygenases (LOX) or epoxygenases, a group of cytochrome P450 type enzymes (CYP). The
COX and LOX branches are fairly well understood while the CYP branch remains largely
unexplored. It signals through epoxyeicosatrienoic acids, epoxides generated through the
oxidation of fatty acids by CYP epoxygenases. The lifetime of these epoxides is controlled by a
soluble epoxide hydrolase (sEH) through hydrolysis. In mammals, pharmacological inhibition of
sEH leads to wide-ranging benefits, particularly in the context of diabetes, improving metabolic
function and preventing complications like neuropathy. These beneficial effects imply the
existence of an endogenous epoxide that accumulates upon inhibition of sEH. However, neither
the CYP epoxygenase nor the endogenous epoxide mediating the beneficial effects of sEH
inhibition have been identified. In chemical screens for compounds that extend C. elegans
lifespan, we identified inhibitors that target the sEH homolog of C. elegans to extend lifespan.
Our data suggest that the accumulation of an unknown endogenous epoxide, produced in the
CYP branch of the arachidonic signaling cascade, promotes tissue health and survival by an
ancient evolutionarily conserved lipid signaling mechanism. In this current application, we
propose to elucidate the major components of the CYP branch in C. elegans to gain insight on
how it modulates aging and how it links aging to inflammation at the molecular level.

## Key facts

- **NIH application ID:** 9874893
- **Project number:** 1R21AG065710-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Michael Petrascheck
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $290,250
- **Award type:** 1
- **Project period:** 2020-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9874893

## Citation

> US National Institutes of Health, RePORTER application 9874893, Epoxide metabolism as a modulator of aging (1R21AG065710-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9874893. Licensed CC0.

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