# Circadian-Regulated Aging Physiologies

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $435,023

## Abstract

PROJECT SUMMARY
Circadian regulation, or 24-hour oscillations in behavior and biological function, is a conserved feature of
biology that is present in diverse organisms from plants to vertebrates. While a widely-observed feature of
aging is loss of circadian regulation, whether circadian-regulated processes are major factors that drive aging
remains unknown. Loss of circadian regulation is typically thought to be pathological. In humans, loss of
circadian regulation is associated with higher rates of obesity, diabetes, and infection. In this proposal, we
present evidence from the fly model Drosophila melanogaster that a specific type of circadian dysregulation is
not pathological but delays aging and extends lifespan. Because studies in Drosophila have provided crucial
information about circadian regulation of biological functions such as immunity and metabolism, findings that
have been replicated in vertebrates, Drosophila is well established as a useful model system.
 The core circadian clock consists of transcriptional activators and transcriptional inhibitors that cause
24-hour oscillations in gene expression and biological functions in both single cells and multicellular organisms.
We found that loss of the conserved transcriptional inhibitors Timeless (Tim) or Period (Per) in Drosophila
significantly extends lifespan by a mechanism independent of canonical longevity pathways such as insulin
signaling, but due to upregulation of a conserved metabolic process called mitochondrial uncoupling via
increased expression of the uncoupling protein UCP4C in the intestine. Our studies further implicate an anti-
aging mechanism of lowering ROS levels and suppressing age-related stem cell expansion in the intestine.
These findings suggest novel connections between circadian regulation, mitochondrial metabolism, stem cell
biology, and lifespan.
 In this proposal, we will use the powerful genetic and cell biological methods in Drosophila to
investigate the mechanisms by which circadian regulation modulates animal lifespan on the cellular, tissue-
specific, and organism levels. The highly-conserved nature of both circadian regulation and this fundamental
aspect of cellular metabolism, mitochondrial uncoupling, raise the exciting possibility that these mechanisms
underlying lifespan extension are conserved in vertebrates. We will investigate the mechanisms by which loss
of Per-mediated circadian regulation and upregulated mitochondrial uncoupling lead to lifespan extension in
three ways: 1) we will determine the cellular and molecular mechanisms underlying circadian dysregulation
and mitochondrial uncoupling that suppress age-related intestinal stem cell expansion; 2) we will determine
whether mitochondrial uncoupling in the gut impacts the aging of other tissues; and 3) we will determine the
functional window and other tissue-specific locations in which circadian dysregulation and mitochondrial
uncoupling extend organism lifespan. As both circadian regula...

## Key facts

- **NIH application ID:** 9977876
- **Project number:** 5R01AG045842-07
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Michele M Shirasu-Hiza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,023
- **Award type:** 5
- **Project period:** 2013-08-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977876

## Citation

> US National Institutes of Health, RePORTER application 9977876, Circadian-Regulated Aging Physiologies (5R01AG045842-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977876. Licensed CC0.

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