Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits.

Research for this project in the lab of S.A.B. was supported by the European Research Council (ERC), the Spanish Ministry of Economy and Development, and the Institute for Research in Biomedicine (IRB-Barcelona). F.O.P. is supported by a La Caixa International Ph.D. fellowship, and P-S.W. is supported by a Juan de la Cierva postdoctoral fellowship. Research in the lab of P.M.C. is supported by the Spanish Ministry of Economy and Development (SAF2015-67369-R), AFM, E-Rare/ERANET, Fundació La Marató TV3, MDA, and Convenio CNIC-UPF. We are grateful for the excellent technical support from the IRB Functional Genomics Core Facility, the PCB (Scientific Park of Barcelona) Animal Unit and FACS Unit, the IRB Advanced Digital Microscopy Unit, and IRB Biostatistics/Bioinformatics Core Facility, the IRB FACS unit, the PCB (Scientific Park of Barcelona) Animal Unit, the IRB Imaging Unit, the IRB Histology Unit for technical assistance and support, the UPF/CRG FACS Unit, and the UPF Advanced Light Microscopy Unit (especially to Jaume Boix for microscopy advice and assistance). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). The DCESX/UPF is recipient of a “María de Maeztu” Programme for Units of Excellence in R&D MDM-2014-0370 (Government of Spain). We thank Veronica Raker for manuscript editing. We apologize to the authors whose work was not cited due to space limitations.