Peripheral Circadian Landscape Reveals Redox Rhythm Perturbations Drive Rhythmic Reprogramming During Aging

Abstract

Aging leads to the global reduction of physiological fitness with circadian misalignment, yet the comprehensive view of aging-dependent circadian alterations in mammalian peripheral tissues and its underlying driving force remain unrevealed. By portraying the peripheral circadian landscape of 12 tissues from young and aged mice, we discovered the attenuated temporal coherence across tissues and heterogeneous circadian reprogramming in various tissues upon aging. Comprehensive and unbiased analyses recognized redox signaling as a tissue-sharing link between aging and rhythmic pathways. Importantly, perturbations of H₂O₂-CLOCK redox rhythm were observed in aged peripheral tissues, and significantly reduced the fitness of mice as revealed by rhythmic reprogramming similar to aging, impaired glucose metabolism, longer circadian period, and even premature phenotypes. Overall, our study unveiled the previously unappreciated role of redox signaling rhythms to drive aging-associated circadian transcriptome reprogramming across mammalian peripheral tissues, highlighting the therapeutic potential of redox rhythms for aging-related diseases.

Note:
Funding Information: This work was supported by grants from the National Key Research and Development Project of China (2021YFA0804900 and 2020YFC2008003), the National Natural Science Foundation of China (grant numbers: 92149305, 82271615 and 82225007), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant numbers: CIFMS2021-I2M-1-016 and 2021-I2M-1-008), National High Level Hospital Clinical Research Funding (grant numbers: 2022-PUMCH-C-008 and 2022-PUMCH-C-014).

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: All of the animal protocols were approved by the Animal Care and Use Committee at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and Peking Union Medical College.

Keywords: aging, redox rhythms, peripheral transcriptome rhythms, rhythmic reprogramming, H2O2, CLOCK, glucose metabolism, insulin sensitivity