Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging

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...

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Published in:Cell 2017-08, Vol.170 (4), p.664-677.e11
Main Authors: Sato, Shogo, Solanas, Guiomar, Peixoto, Francisca Oliveira, Bee, Leonardo, Symeonidi, Aikaterini, Schmidt, Mark S., Brenner, Charles, Masri, Selma, Benitah, Salvador Aznar, Sassone-Corsi, Paolo
Format: Article
Language:English
Subjects:
Acetyl Coenzyme A - metabolism
Acetylation
Aging
Aging - metabolism
Aging - pathology
Animals
Caloric Restriction
Circadian Clock
Circadian Rhythm
Histones - metabolism
Liver - metabolism
Liver - pathology
Metabolic Networks and Pathways
Mice
NAD
NAD - metabolism
Proteins - metabolism
Reprogramming
SIRT1
Sirtuin 1 - metabolism
Stem Cells - metabolism
Transcriptome
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Summary: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. [Display omitted] •Aging reprograms clockwork with distinct modalities in the liver versus stem cells•Liver circadian genomic signatures of aging are reverted by caloric restriction (CR)•Cyclic protein acetylation is lost in old mice while CR results in hyperacetylation•CR reorganizes circadian metabolic pathway linked to NAD+-SIRT1-AceCS1 in the liver Aging reprograms the circadian transcriptome in a highly tissue-specific manner
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2017.07.042