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Cell. 2015 Feb 26;160(5):842-855. doi: 10.1016/j.cell.2015.02.004.

Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal.

Author information

1
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
2
Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA.
3
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenah Avenue, Ann Arbor, MI 48109, USA.
4
Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Electronic address: wmair@hsph.harvard.edu.

Abstract

Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPARα ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

PMID:
25723162
PMCID:
PMC4392909
DOI:
10.1016/j.cell.2015.02.004
[Indexed for MEDLINE]
Free PMC Article

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