Cell
Volume 170, Issue 4, 10 August 2017, Pages 664-677.e11
Journal home page for Cell

Article
Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging

https://doi.org/10.1016/j.cell.2017.07.042Get rights and content
Under an Elsevier user license
open archive

Highlights

  • 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

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.

Keywords

Circadian Clock
Aging
Acetylation
NAD
SIRT1
Liver Metabolism
Reprogramming

Cited by (0)

5

These authors contributed equally

6

Lead Contact