Editors' ChoiceNeuroscience

Less Pain (Receptors) Means a Longer Life

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Sci. Signal.  03 Jun 2014:
Vol. 7, Issue 328, pp. ec145
DOI: 10.1126/scisignal.2005542

The transient receptor potential cation channel TRPV1, which is located on sensory neurons and conducts calcium ions, is best known for responding to heat and chemicals that trigger pain. Riera et al. found that inhibition of TRPV1 increased longevity in worms and mice. TRPV1-knockout mice lived longer, healthier lives with fewer neoplasms and less cognitive and motor decline than wild-type mice. Although many indicators of metabolism were unchanged in the TRPV1-knockout mice—organ and body size, body temperature, food intake, the ratio of white to brown fat, and the amounts of metabolism-regulating hormones—there were some notable differences in metabolism and insulin responses. Respiratory exchange ratio (RER) can be used to estimate metabolic differences related to burning fat or carbohydrates (lipid or glucose metabolism). The amplitude of the circadian oscillation in RER, which normally decreases with age, did not decrease in aged TRPV1-knockout mice. Both young and old TRPV1-knockout mice showed increased oxygen consumption and aerobic capacity compared with wild-type mice. Although the TRPV1-knockout mice exhibited age-associated differences in glucose metabolism, basal and glucose-induced insulin secretion and the number of pancreatic islet cells were increased in TRPV1-knockout mice. Similar to mice, Caenorhabditis elegans worms with null mutations in genes that encode the functional homologs of TRPV1 also lived longer. In worms, the homolog of calcineurin, a calcium-activated phosphatase, dephosphorylates the transcriptional coactivator CTRC1 to prevent translocation to the nucleus and interaction with the DNA-binding transcription factor CREB. Loss of TRPV1 prevented the nuclear translocation of CTRC1 in worms exposed to factors that increased intracellular calcium, and mutations in CTRC1 that resulted in constitutive nuclear translocation decreased the longevity of worms lacking TRPV1 homologs. In sensory neurons of ex vivo dorsal root ganglia from mice, application of the TRPV1 agonist capsaicin led to the nuclear accumulation of CRTC1, and this effect was prevented in neurons exposed to inhibitors of calcineurin or TRPV1 or in neurons from TRPV1-knockout mice. Dorsal root ganglia neurons innervate pancreatic islet cells and dorsal root ganglia from TRPV1-knockout mice expressed less of the CREB-responsive gene encoding the neuropeptide CGRP. Exposing cultured mouse insulinoma cells to CGRP decreased glucose-stimulated insulin release, and circulating amounts of CGRP increased with age in wild-type, but not TRPV1-knockout, mice. Moreover, injecting aged wild-type mice with a CGRP antagonist restored a youthful RER and increased oxygen consumption. Thus, activation of pain receptors may result in changes in metabolism that promote aging (see Steculorum and Brüning).

C. E. Riera, M. O. Huising, P. Follett, M. Leblanc, J. Halloran, R. Van Andel, C. D. de Magalhaes Filho, C. Merkwirth, A. Dillin, TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 157, 1023–1036 (2014).[PubMed]

S. Steculorum, J. C. Brüning, Die another day: A painless path to longevity. Cell 157, 1004–1006 (2014). [PubMed]