Role of circadian CLOCK signaling in cellular senescence

Sep 3, 2025Biogerontology

How the body’s internal clock affects cell aging

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Disruption of the circadian rhythm may be linked to accelerated aging and age-related diseases.

The CLOCK protein plays a crucial role in regulating gene transcription related to tissue maintenance and cellular aging.
In normal cells, CLOCK supports rejuvenation by activating DNA repair factors and modulating metabolism.
In tumor cells, CLOCK signaling can be manipulated by oncogenic drivers, promoting uncontrolled cell growth.
Gut microbiota-derived signals may disrupt the interaction between CLOCK and its partner BMAL1, impacting circadian rhythms.
CLOCK interacts with pathways that regulate cellular waste disposal and inflammation, influencing overall tissue health.

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The circadian rhythm is a key biological mechanism that aligns organisms' physiological processes with Earth's 24-h light-dark cycle, crucial for cellular and tissue homeostasis. Disruption of this system is linked to accelerated aging and age-related diseases. Central to circadian regulation is the CLOCK protein, which controls gene transcription related to tissue homeostasis, cellular senescence, and DNA repair. Research reveals CLOCK's dual role: in normal cells, it supports rejuvenation by activating DNA repair factors like XPA and modulating metabolism; in tumor cells, CLOCK signaling is often hijacked by oncogenic drivers like c-MYC and Pdia3, which inhibit telomere shortening / cellular senescence, thereby fostering uncontrolled proliferation and tumorigenesis. Additionally, gut microbiota-derived aryl hydrocarbon receptor (AhR) signals can disrupt the CLOCK-BMAL1 complex, affecting circadian rhythms. CLOCK also interacts with mTOR and NF-κB pathways to regulate autophagy and mitigate harmful secretions impacting tissue function. This review examines the molecular links between CLOCK and cellular senescence, drawing from animal and human studies, to highlight CLOCK's role in aging and its potential as a target for anti-aging therapies.