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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Burkewitz, K; Morantte, I; Weir, HJM; Yeo, R; Zhang, Y; Huynh, FK; Ilkayeva, OR; Hirschey, MD; Grant, AR; Mair, WB

Published Date

  • February 26, 2015

Published In

Volume / Issue

  • 160 / 5

Start / End Page

  • 842 - 855

PubMed ID

  • 25723162

Pubmed Central ID

  • PMC4392909

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2015.02.004


  • eng

Conference Location

  • United States