Circadian Clock Control by Polyamine Levels through a Mechanism that Declines with Age

Ziv Zwighaft, Rona Aviram, Moran Shalev, Liat Rousso-Noori, Judith Kraut-Cohen, Marina Golik, Alexander Brandis, Hans Reinke, Asaph Aharoni, Chaim Kahana, Gad Asher

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

Polyamines are essential polycations present in all living cells. Polyamine levels are maintained from the diet and de novo synthesis, and their decline with age is associated with various pathologies. Here we show that polyamine levels oscillate in a daily manner. Both clock- and feeding-dependent mechanisms regulate the daily accumulation of key enzymes in polyamine biosynthesis through rhythmic binding of BMAL1:CLOCK to conserved DNA elements. In turn, polyamines control the circadian period in cultured cells and animals by regulating the interaction between the core clock repressors PER2 and CRY1. Importantly, we found that the decline in polyamine levels with age in mice is associated with a longer circadian period that can be reversed upon polyamine supplementation in the diet. Our findings suggest a crosstalk between circadian clocks and polyamine biosynthesis and open new possibilities for nutritional interventions against the decay in clock's function with age.

Original languageEnglish
Pages (from-to)874-885
Number of pages12
JournalCell Metabolism
Volume22
Issue number5
DOIs
StatePublished - 3 Nov 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

Funding

We thank T. Tsimbalist, S. Meir, and I. Rogachev for the polyamines quantification and S. Ovadia for his help in bleeding the mice. We are grateful to U. Schibler for his valuable comments. The work performed in the G.A. laboratory was supported by the Israel Science Foundation (ISF 138/12), the Abish-Frenkel Foundation, the HFSP Career Development Award (HFSP CDA00014/2012), and the European Research Council (ERC-2011 METACYCLES 310320). G.A. and H.R. are funded by GIF collaborative grant (G-1199-230.9/2012).

FundersFunder number
Abish-Frenkel FoundationHFSP CDA00014/2012
European Research CouncilERC-2011 METACYCLES 310320
German-Israeli Foundation for Scientific Research and DevelopmentG-1199-230.9/2012
Israel Science FoundationISF 138/12

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