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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Catecholamines / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Longevity
  • Mitochondria / metabolism*
  • Neurons / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction*
  • Trans-Activators / metabolism*


  • CRTC-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Catecholamines
  • Cyclic AMP Response Element-Binding Protein
  • NHR-49 protein, C elegans
  • Receptors, Cytoplasmic and Nuclear
  • Trans-Activators
  • AMP-Activated Protein Kinases

Associated data

  • GEO/GSE58931