Tuesday, June 17, 2014

TRPv1 receptors and aging

TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling
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.
Other than having to substitute (as usual) the word "nociception" for the word "pain" throughout, this is an absolutely fascinating paper, which presents all sorts of evidence in favour of the idea that TRPv1 receptors are one of the big causes of the evils of aging.
It makes some sense.. when nociceptors go off they start chain reactions in other nociceptors (peripheral sensitization) that encourages them to make more TRPv1 receptors.. all that. And the function of C fibres in the first place is to sit there and make CGR, Substance P, etc., and leak it strategically out into tissue as "growth factors" to help tissue heal, or keep on "growing".. But this paper takes it a step more - Too many TRPv1 receptors leads to more aging, and more inflammation.. inactivating CGRP receptors slows decline. Knocking out the TRPv1 receptor slows decline. Reverses it even. 
All over the inside of the body, organs, brain itself..

I know it's behind a paywall. Alas.

So, read No Pain, Big Gain on the paper, and this one, No Pain, Time Gained from Pain Research Forum.

If you can get it, it's good to read this one first: The Hallmarks of Aging, open access.

TRPv1 receptors, I gotta admit, they are pretty weird and powerful.. This open access paper, Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier, from 2010, explains how they are able to open the spinal-cord-blood barrier for up to a week, but not just the spinal cord - brain too! Frontal lobes and cerebellum are spared, though, for some strange reason, which I'm sure will be made more clear as time goes on.. maybe to do with how the brain develops in the first place, before it grows those big blobs of cerebellum and frontal lobes.

This more recent paper, Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain, explains how they are kept "fanned" by serotonin from nuclei in the medulla. Read Stephani Sutherland's post about it in order to fathom better what is implicated by this particular descending facilitation. Remember that thin C sensory neurons have one foot on the platform and the other on the train. I.e., one end out in the periphery and the other in the dorsal horn. A cell body in between, living in a dorsal root ganglion, responding to input at either end, presumably being stimulated to crank out even more TRPv1 receptors..

The Riera paper. It's amazing. Maybe some day it will be possible to go get a TRPv1-ectomy or something. Take a pill to block unwanted ravages of CGRP. 

I had not come across the concept "health-span" before. Clearly it's a more attractive proposition than mere "life-span."


1. Céline E. Riera, Mark O. Huising, Patricia Follett, Mathias Leblanc,  Jonathan Halloran, Roger Van Andel,  Carlos Daniel de Magalhaes Filho, Carsten Merkwirth, Andrew Dillin;  TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling. Cell, Volume 157, Issue 5, 22 May 2014, Pages 1023–1036

2. Kate Yandell; No Pain, Big Gain. The Scientist May 22, 2014

3. Michele Solis; No Pain, Time Gained; PainResearchForum Jun 4, 2014

4. Carlos López-Otín, Maria A. Blasco, Linda Partridge, Manuel Serrano, and Guido Kroemer; The Hallmarks of Aging. Cell. Jun 6, 2013; 153(6): 1194–1217.

5. Simon Beggs, Xue Jun Liu, Chun Kwan and Michael W Salter; Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier. Molecular Pain 2010, 6:74

6. Kim YS, Chu Y, Han L1, Li M, Li Z, Lavinka PC, Sun S, Tang Z, Park K, Caterina MJ, Ren K, Dubner R, Wei F, Dong X; Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain. Neuron. 2014 Feb 19;81(4):873-87

7. Stephani Sutherland;  Central TRPV1 Contributes to Neuropathic Hyperalgesia:

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