# Circadian Rhythm and Lifespan

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $653,189

## Abstract

Healthy aging is a critical goal for the human population, and one solution to this problem is to extend healthspan and
lifespan. In model organisms including rodents and non-human primates, caloric restriction (CR) is the most effective
intervention for improving aging-related deterioration of biological functions and for extending lifespan. However,
despite more than 80 years since its discovery, the underlying mechanisms for how caloric restriction extends lifespan
are still largely unknown. A number of pathways have been associated with longevity including those involved with
nutrient signaling, metabolism, growth, genome stability and oxidative stress. Our laboratories have been studying the
behavioral effects of caloric restriction in mice and have found that CR leads to dramatic changes in the pattern of food
intake. In contrast to normally fed mice, which distribute their food intake over the 24-hour day, mice on caloric
restriction adopt a severe feeding and fasting pattern in which they consume all of their food within a few hours each
day. In order to disentangle the contribution of calories, fasting and circadian alignment of eating on longevity, we
recently showed that CR is sufficient to extend lifespan but that the pattern and circadian-alignment of feeding under CR
acts synergistically to extend lifespan in male C57BL/6J mice. Calorie reduction alone increases lifespan only by ~10%,
while time-restricted CR during the active phase extends lifespan more than 3 times longer (35%). Circadian alignment
of feeding enhances CR-mediated benefits on survival independently of fasting duration and body weight. In Aim 1,
because we have found that CR with time-restricted feeding (TRF) extends lifespan from 10% to 35%, we will test
whether TRF without CR can extend lifespan. In Aim 2, we will test whether enhanced Clock gene expression can rescue
the age-related decline in circadian gene expression and can improve health and extend lifespan. Aging promotes
widespread increases in inflammation and decreases in metabolism in the livers from ad lib (AL) fed mice; whereas CR at
night ameliorates these aging-related changes. In our previous work, we found that the gene expression of the cytokine,
Interleukin-1 beta (IL-1b), is directly correlated with lifespan across 6 feeding conditions (AL vs. 5 CR groups). In Aim 3,
we will test the hypothesis that IL-1b is necessary for the effects of CR on lifespan and whether calories, fasting and
circadian alignment of feeding differentially effect lifespan in Il-1b null mice. In summary, we will test: whether circadian
interventions such as TRF or genetic enhancement of CLOCK transcription can extend healthspan and lifespan and
whether IL-1b is critical for these effects.

## Key facts

- **NIH application ID:** 10801903
- **Project number:** 1R01AG072736-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Carla B. Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $653,189
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801903

## Citation

> US National Institutes of Health, RePORTER application 10801903, Circadian Rhythm and Lifespan (1R01AG072736-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801903. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*