# Circadian Rhythms and Lifespan

> **NIH NIH R56** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $333,209

## Abstract

Cellular pathways that have been implicated in aging and longevity are regulated by the
circadian clock. In addition, we have found that overall circadian gene expression in the mouse
declines significantly with aging, both in the number of significantly cycling genes as well as the
amplitude of their oscillations. Since longevity pathways are under circadian regulation, we
hypothesize that age-related changes in circadian function can lead to a decline in multiple
longevity pathways. Thus, interventions that could reduce or rescue the decline in circadian
rhythmicity would be expected to maintain healthy longevity pathways. Since the circadian
clock regulates many longevity pathways, interventions at this level could rescue or reverse the
effects of aging on many independent longevity pathways which could have additive or
synergistic benefits by targeting a single nodal point (the circadian clock).
Thus, the overall theme of this application is that the key pathways that have been implicated in
aging and longevity are under circadian regulation and that the master transcription factors,
CLOCK:BMAL1, regulate these circadian cycles. We propose to use two different types of
“circadian interventions” in order to test whether these interventions can increase lifespan and
healthspan in mice. In order to use a more genetically diverse mouse model, we will use UM-
HET3 (HET3) mice that are being employed in the NIA Intervention Testing Program. First, we
will characterize the circadian phenotypes of HET3 mice as well as the four parental inbred
strains that contribute to HET3 mice. Then we will use two different types of circadian
interventions: 1) Time-restricted feeding (12-hr and 8-hr); and 2) Loss of function of the Clock
gene (Clock knockout mice) vs. over-expression of wild-type Clock gene expression using Clock
BAC transgene mice. Because we have shown a profound decrease in the number cycling
genes and their amplitude with aging, and because CLOCK:BMAL1 regulates these cycling
genes, we will test the hypothesis that enhancement Clock gene expression can lead to a
rescue of the age-related decline in circadian gene expression and that enhancement of Clock
gene expression can extend healthspan and lifespan.

## Key facts

- **NIH application ID:** 10490495
- **Project number:** 1R56AG072736-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carla B. Green
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,209
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490495

## Citation

> US National Institutes of Health, RePORTER application 10490495, Circadian Rhythms and Lifespan (1R56AG072736-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10490495. Licensed CC0.

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