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Cell. 2017 Aug 10;170(4):664-677.e11. doi: 10.1016/j.cell.2017.07.042.

Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging.

Author information

1
Center for Epigenetics and Metabolism, U1233 INSERM, University of California, Irvine, Irvine, CA 92607, USA.
2
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain.
3
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
4
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain; ICREA, Catalan Institution for Research and Advanced Studies, Barcelona, Spain. Electronic address: salvador.aznar-benitah@irbbarcelona.org.
5
Center for Epigenetics and Metabolism, U1233 INSERM, University of California, Irvine, Irvine, CA 92607, USA. Electronic address: psc@uci.edu.

Abstract

The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging.

KEYWORDS:

Acetylation; Aging; Circadian Clock; Liver Metabolism; NAD; Reprogramming; SIRT1

PMID:
28802039
DOI:
10.1016/j.cell.2017.07.042
[Indexed for MEDLINE]
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