title: TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling.
abstract: The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.
authors.affiliation: Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; The Glenn Center for Aging Research, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Céline E
authors.initials: CE
authors.lastname: Riera
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Huising
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; The Glenn Center for Aging Research, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Follett
authors.affiliation: The Glenn Center for Aging Research, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Leblanc
authors.affiliation: Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Halloran
authors.affiliation: Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Van Andel
authors.affiliation: The Glenn Center for Aging Research, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Carlos Daniel
authors.initials: CD
authors.lastname: de Magalhaes Filho
authors.affiliation: The Glenn Center for Aging Research, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Carsten
authors.initials: C
authors.lastname: Merkwirth
authors.affiliation: Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; The Glenn Center for Aging Research, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: dillin@berkeley.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D004032:Diet; D005260:Female; D007328:Insulin / Q000378:metabolism; D008136:Longevity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C519509:Crtc1 protein, mouse; D007328:Insulin; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014157:Transcription Factors; D050882:CREB-Binding Protein