# Project 2: Spatiotemporal regulation of stress-responsive transcription factors in organismal aging

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $331,482

## Abstract

Abstract
Evolutionarily conserved stress-responsive transcription factors (TFs) are required for longevity in diverse
genetic pathways. Their activities are repressed in early adulthood, preceding physiological decline in animal
models, implicating their central roles in aging. It is poorly understood, however, how they control transcription
to promote longevity, and how their activities are regulated in different tissues at critical life stages to dictate
organismal aging. Our long-term goal is to identify the causes of aging and extend the human healthspan. The
objective of this grant is to understand the function and regulation of stress-responsive TFs in longevity. We use
the nematode C. elegans as a model and focus on two highly conserved stress-responsive TFs, HSF-1 (heat
shock factor 1) and DAF-16 (the C. elegans ortholog of FOXO). Our central hypothesis is that the spatiotemporal
regulation of HSF-1 and DAF-16 dictates a neuron-to-intestine signaling pathway to regulate longevity. Our
hypothesis is based on the following findings: 1) JMJD-3.1, a conserved H3K27 demethylase that facilitates
HSF-1 target binding in stress responses, decreases expression upon reproductive maturity. 2) Inhibition of
germline stem cells preserves JMJD-3.1 expression and extends lifespan in a manner that requires HSF-1. 3)
Expression of JMJD-3.1 is highly enriched in neurons. 4) Over-expression of HSF-1 solely in neurons is sufficient
to promote longevity in a manner that depends on intestinal DAF-16. Our specific aims will test the following
hypotheses: (Aim 1) JMJD-3.1 enhances HSF-1 activity in neurons to promote longevity; (Aim 2) Neural HSF-1
contributes to a neuron-to-intestine signaling pathway involving specific neuropeptides to activate DAF-16 in the
intestine; (Aim 3) Intestinal DAF-16 creates chromatin accessibility for other co-factors to activate diverse
longevity-promoting pathways. Upon completion, our results will reveal the functions and regulation of HSF-1
and DAF-16 in promotion of longevity at the molecular, cellular and organismal levels. This contribution is
significant because it advances our mechanistic understanding of stress-responsive TFs in longevity and their
functional interactions with two hallmarks of aging, namely `epigenetic alterations' and `altered intercellular
communication'. Furthermore, this study will provide a basis for new ideas of modulating stress-responsive TFs
to ameliorate age-related declines. This study is innovative because we investigate HSF-1 and DAF-16 in
longevity beyond their canonical roles in stress responses, and we apply unbiased genomic analyses of
transcription and chromatin in a tissue-specific manner to understand their mechanistic roles in organismal aging.

## Key facts

- **NIH application ID:** 9997968
- **Project number:** 5P20GM103636-08
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Jian Li
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,482
- **Award type:** 5
- **Project period:** 2013-03-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997968

## Citation

> US National Institutes of Health, RePORTER application 9997968, Project 2: Spatiotemporal regulation of stress-responsive transcription factors in organismal aging (5P20GM103636-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997968. Licensed CC0.

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