# Regulation of the transcription factor HLH-30/TFEB in aging

> **NIH NIH R01** · BROWN UNIVERSITY · 2020 · $267,384

## Abstract

PROJECT SUMMARY/ABSTRACT
Autophagy is a cellular recycling process with critical roles in aging and age-related diseases. Autophagy was
originally described as a process mainly regulated at the post-translational level, but a role for transcriptional
regulation has recently started to emerge. The relatively new concept of transcriptional regulation of the
autophagy process provides an important new entry point toward developing therapies against age-related
diseases.
Recent studies in mammals have uncovered that the helix-loop-helix transcription factor EB (TFEB) is a central
regulator of autophagy. We have reported that the C. elegans HLH-30 protein is a functional ortholog of TFEB
and plays a broad role in C. elegans lifespan determination (Lapierre et al., Nature Communications, 2013).
Specifically, we have found that HLH-30 is required for the lifespan extension observed in six independent
longevity models, all of which are also known to be dependent on autophagy. Notably, HLH-30 is localized in
the nucleus of intestinal cells in all of these long-lived mutants. Importantly, we have found TFEB to be similarly
regulated in a mammalian longevity model suggesting that the longevity function of TFEB is also conserved.
Therefore, we hypothesize that TFEB is a central player that modulates aging, at least in part by coordinating
autophagic flux and, as such, represents an attractive longevity factor to molecularly understand in order to
design approaches to promote healthspan and prevent aging.
To address this hypothesis, we propose to use a combination of cutting-edge genetics and biochemical
approaches to understand the spatial- and nuclear requirements for HLH-30 function in C. elegans lifespan
(Aim 1); to address if downstream target genes besides those identified to function in autophagy are critical for
longevity (Aim 2); and, finally, to identify genetic and pharmacological regulators of autophagy and HLH-
30/TFEB function (Aim 3).
These studies are significant as they are the first to identify novel genetic regulators and post-translational
modifications of HLH-30/TFEB in an unbiased fashion, and they will generate important information for future
analysis of mammalian TFEB, a central regulator of autophagy as well as metabolism, in organismal aging.
Furthermore, our studies are innovative because we employ C. elegans and mammalian cells in parallel to
rapidly identify novel, conserved genes with roles in aging and to develop pharmacological solutions to
enhance autophagy in order to prevent age-related diseases.

## Key facts

- **NIH application ID:** 9879560
- **Project number:** 3R01AG051810-04S1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Louis Rene Lapierre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $267,384
- **Award type:** 3
- **Project period:** 2016-08-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879560

## Citation

> US National Institutes of Health, RePORTER application 9879560, Regulation of the transcription factor HLH-30/TFEB in aging (3R01AG051810-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879560. Licensed CC0.

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