# Circadian Rhythms and Innate Immune Response in Aging

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $493,559

## Abstract

Circadian rhythms play crucial roles in a wide range of physiologic and behavioral processes. In mammals,
variations in light intensity and other environmental cues are integrated by a master pacemaker in the
suprachiasmatic nuclei of the hypothalamus, which entrains multiple peripheral circadian clocks via
neuroendocrine mechanisms. The clock at the molecular level consists of a network of transcription factors
organized in a series of highly conserved transcription-translation feedback loops. While circadian rhythms in
mammals are typically associated with sleep-wake, body temperature, cardiovascular, and metabolic
regulation, circadian periodicity has also been reported for immunologic processes as well, including daily
oscillation in levels of cell populations such as CD4 and CD8 T cells and cytokine expression. We were the
first to report that Toll-like Receptor (TLR)-9, one of the pattern recognition receptors of the innate immune
system, shows daily variation in expression and function that is modulated by circadian clock components in
mice. We found that both response to a TLR9 adjuvanted vaccine and disease severity in a TLR9-dependent
sepsis model were dependent on the timing of vaccination or sepsis induction, implicating circadian control as
a novel mechanism of innate immune regulation. Our preliminary data also suggests circadian variation of
TLR responses in humans as well. Several lines of evidence suggest that circadian rhythms are disrupted by
aging in humans and mice, and knockout mice deficient in “clock” genes develop phenotypes associated with
premature aging. However, there remains a knowledge gap as to whether aging influences circadian variation
in TLR responses in mice and humans. We hypothesize that such variation will be attenuated by aging in both
humans and mice, and have assembled in interdisciplinary group of investigators with expertise in human and
mouse immunology, sleep research, chronobiology and aging research to test this hypothesis. We will focus
on evaluating TLRs associated with response to viral infection (TLR3, 7, 9 in mice and TLR3, 7-9 in humans)
for which our published and unpublished data in mice suggest circadian variation. We will assess circadian
TLR gene expression in purified populations of B cells, monocytes, and dendritic cells, as well as in vivo and in
vitro circadian variation in TLR-dependent cytokine production, costimulatory protein expression, and response
to viral infection in young and aged (20-22 months of age) mice and young (21-30 years) and older (≥ 65
years) humans. The proposed human studies will integrate immunologic data with physiologic parameters of
circadian cycling standard in chronobiology, such as polysomnography, and measurements of cortisol and core
body temperature. The study of circadian innate immune function is likely to break new ground in considering
temporal variation in susceptibility or outcomes of infection, or in response to treatment. These insights would
...

## Key facts

- **NIH application ID:** 9868260
- **Project number:** 5R01AI142624-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Erol Fikrig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $493,559
- **Award type:** 5
- **Project period:** 2019-02-08 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868260

## Citation

> US National Institutes of Health, RePORTER application 9868260, Circadian Rhythms and Innate Immune Response in Aging (5R01AI142624-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868260. Licensed CC0.

---

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