mTOR signalling, not clock gene rhythms, organises daily physiology
Year: 2026
Type: preprint
Abstract: Summary Daily rhythms in mammalian physiology are widely attributed to rhythmic transcription of “clock-controlled genes” driven by the circadian transcriptional/translational feedback loop (TTFL). Here we show that daily physiology can be uncoupled from the TTFL: inhibiting the mechanistic target of rapamycin (mTOR) abolishes most daily variation in cellular and organismal physiology, whilst clock protein rhythms persist. In cultured cells and mouse liver, functional rhythms are lost, including the proteome, RNA abundance, substrate utilisation and drug metabolism. In forebrain, most daily variation in protein abundance and phosphorylation is lost, yet locomotor activity and sleep-wake architecture are largely preserved in mice and zebrafish. PERIOD2 binds mTORC1 and limits its activity, providing a route by which clock proteins shape daily mTOR signalling. mTOR inhibition preferentially suppresses output over clock gene rhythms in Arabidopsis and Neurospora . We conclude that mTOR is a conserved conduit through which circadian and environmental timing impose daily organisation on physiology.
Authors: Aiwei Zeng, Andrei Mihut, Madhanagopal Anandapadamanaban, Alejandra Goity, Luíza Lane de Barros Dantas, Sew-Yeu Peak-Chew, Edward A. Hayter, Linda C. Andersson, Tom Smith, Giacomo Pasquini, Estere Seinkmane, Alessandra Stangherlin, Tomos E. Morgan, Nathan R. James, Charley Beresford, Jasmine Farnsworth, Joseph Menzies, Aymen al-Rawi, Liam J. Holt, Emmanuel Derivery, Rachel S. Edgar, Ralitsa R. Madsen, David A. Bechtold, Luis F. Larrondo, Antony N. Dodd, Jason Rihel, Gian Michele Ratto, Julie Williams, Peter Newham, Constanze Hilgendorf, Andrew D. Beale, Claudia Lodovichi, John S. O’Neill
Institutions: MRC Laboratory of Molecular Biology, The Francis Crick Institute, Imperial College London, European Molecular Biology Laboratory, Pontificia Universidad Católica de Chile, Millennium Institute for Integrative Biology, John Innes Centre, Norwich Research Park, University of Manchester, AstraZeneca (Sweden), Scuola Normale Superiore, National Enterprise for NanoScience and NanoTechnology, National Research Council, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne, NYU Langone Health, New York University, University of Dundee, MRC Protein Phosphorylation and Ubiquitylation Unit, Cancer Research UK Scotland Institute, University of Glasgow, University College London, AstraZeneca (United Kingdom), Veneto Institute of Molecular Medicine
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204824899