| Literature DB >> 25723162 |
Kristopher Burkewitz1, Ianessa Morantte1, Heather J M Weir1, Robin Yeo1, Yue Zhang1, Frank K Huynh2, Olga R Ilkayeva2, Matthew D Hirschey2, Ana R Grant3, William B Mair4.
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.Entities:
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Year: 2015 PMID： 25723162 PMCID： PMC4392909 DOI： 10.1016/j.cell.2015.02.004
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582