Urolithin A Modulates PER2 Degradation via SIRT1 and Enhances the Amplitude of Circadian Clocks in Human Senescent Cells

Abstract

Background/Objectives: Circadian clocks are endogenous systems that regulate numerous biological, physiological, and behavioral events in living organisms. Aging attenuates the precision and robustness of circadian clocks, leading to prolonged and dampened circadian gene oscillation rhythms and amplitudes. This study investigated the effects of food-derived polyphenols such as ellagic acid and its metabolites (urolithin A, B, and C) on the aging clock at the cellular level using senescent human fibroblast cells, TIG-3 cells. Methods: Lentivirus-infected TIG-3 cells expressing Bmal1-luciferase were used for real-time luciferase monitoring assays. Results: We revealed that urolithins boosted the amplitude of circadian gene oscillations at different potentials; urolithin A (UA) amplified the best. Furthermore, we discovered that UA unstabilizes PER2 protein while stabilizing SIRT1 protein, which provably enhances BMAL1 oscillation. Conclusions: The findings suggest that urolithins, particularly UA, have the potential to modulate the aging clock and may serve as therapeutic nutraceuticals for age-related disorders associated with circadian dysfunction.