# RNA splicing regulation of lipid metabolism and longevity in C. elegans

> **NIH NIH F31** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2024 · $35,118

## Abstract

PROJECT SUMMARY
Concurrent increase in life expectancy and the prevalence of age-related metabolic diseases
highlights how the biology of aging and metabolic dysfunction are intertwined. Dietary restriction
(DR) promotes healthy aging and disease resistance through the manipulation of canonical
nutrient sensing pathways, like TORC1 (target of rapamycin complex I) signaling. However,
manipulation of such critical metabolic pathways results in pleiotropic effects, making it critical to
understand their distinct downstream mechanisms. Previous studies in C. elegans suggest a
critical role for the spliceosome component REPO-1 (reverse polarity 1) in modulating lipid
accumulation and longevity downstream of DR and TORC1 specifically. Knockdown of REPO-1
causes an increase in lipid accumulation in genetic models of DR and reduced TORC1 signaling.
We have identified specific lipid species such as the C18:1 fatty acid as targets of REPO-1
modulation. Additionally, REPO-1 binds pod-2 (polarity and osmotic sensitivity defect 1) Pre-
mRNA and pod-2 is similarly and specifically required for DR and TORC1 lifespan extension.
Further, knockdown of pod-2 phenotypically mimics knockdown of repo-1 causing increased lipid
accumulation. However, it remains to be determined whether this constitutes a causal pathway.
Therefore, the overarching aim of this proposal is to uncover the contribution of pre-mRNA
splicing and lipid metabolism in TORC1 lifespan extension. My central hypothesis is that
REPO-1 regulates TORC1 lifespan extension by modulating alternative splicing and specific lipid
species through POD-2. In aim 1, we will use Crispr/Cas9 mediated tagging of endogenous
REPO-1 to assess tissue-specific effects of REPO-1 on alternative splicing, modulation of lipid
accumulation and longevity downstream of TORC1 signaling. In aim 2, we will achieve tissue-
specific degradation of POD-2 to determine the tissue where it modulates longevity and fat
reserves in TORC1 signaling. We will also define the changes to the lipidome of TORC1 regulated
by POD-2, compare them to REPO-1 dependent changes, and test their contribution to longevity.
Altogether this work will broaden our mechanistic understanding of RNA homeostasis as a
novel paradigm of aging and physiology and expand our knowledge of target pathways to
promote healthy aging.

## Key facts

- **NIH application ID:** 10821907
- **Project number:** 1F31AG077729-01A1
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Maria Camila Perez Matos
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,118
- **Award type:** 1
- **Project period:** 2024-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821907

## Citation

> US National Institutes of Health, RePORTER application 10821907, RNA splicing regulation of lipid metabolism and longevity in C. elegans (1F31AG077729-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10821907. Licensed CC0.

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