No Pain, Time Gained
The loss of pain-transducing receptors paves the way to a long life, according to a study published May 22 in Cell. Led by Andrew Dillin of University of California Berkeley, US, the study reports that mice lacking the transient receptor potential cation channel subfamily V member 1 (TRPV1) live longer and have a more youthful metabolism than age-matched wild-type mice. This involves a novel pathway centered on calcitonin gene-related peptide (CGRP). Like ablating TRPV1, blocking CGRP receptors in aged wild-type mice restored their metabolism to a more youthful state.
The new results suggest that TRPV1 blockers in development for pain, or CGRP blockers now being tested to treat migraine headaches, could have some desirable side effects.
“While I am very enthusiastic about the development of therapies targeting CGRP, I have some concerns about the safety of chronically blocking this important vasodilator and neuromodulator,” said Ana Recober, a migraine researcher at the University of Iowa, Iowa City, US, who was not involved in the study. “The exciting thing here is that targeting CGRP therapeutically may actually have additional health benefits.”
CGRP receptor antagonists can stop migraines once they have started, but trials of long-term use of these small molecules to prevent migraine stalled because of liver toxicity in some people, Recober said. This year, researchers reported that long-lasting antibodies to CGRP also successfully prevented migraines, but beneficial effects on metabolism were not mentioned.
The new study highlights emerging overlaps between pain and metabolism. Located on the peripheral endings and cell bodies of dorsal root ganglion (DRG) neurons, TRPV1 channels are activated by scalding heat and the irritant capsaicin. TRPV1 activation leads to CGRP release by DRG neurons of the trigeminal nucleus, which contributes to migraine pain.
Beyond pain, TRPV1-positive DRG neurons innervating the pancreas regulate insulin release through CGRP (Gram et al., 2007). Mice lacking TRPV1 and CGRP are protected from obesity that comes from eating a high-fat diet (Motter and Ahern, 2008; Walker et al., 2010). (Recober studies CGRP as a potential mediator of the association between obesity and chronic migraines.)
The new study bolsters these links with metabolism and connects them for the first time to aging, Recober said.
Model for the neuroendocrine regulation of metabolism by TRPV1 expressing neurons. Stimulation of TRPV1 by external stimuli promotes CGRP secretion from DRG neurons onto the pancreatic b cells and inhibition of insulin release. TRPV1 activation results in calcium influx, activation of calcineurin allowing dephosphorylation of CRTC1 and release from 14-3-3 proteins, resulting in nuclear internalization of CRTC1 and transcription of its targets, such as CGRP. CGRP accumulation has detrimental effects on energy expenditure, glucose tolerance, and aging. In contrast, loss of TRPV1 promotes lifespan extension through increased insulin secretion, metabolic health by inactivating of the CRTC1/CREB signaling cascade. Credit: Riera et al., 2014.
CGRP-less fountain of youth?
The new study was born out of a desire to understand why aging and pain go hand in hand. Old people report more pain than young people do—a difference usually attributed to the accumulation of maladies over time. But Dillin wanted to look at the correlation a different way: “Maybe being in pain drives the aging process,” he told PRF.
First author Celine Riera and colleagues turned to TRPV1 knockout mice, which are unable to sense many painful stimuli. Though the experiment was simple enough—let mice live until they die—it was very expensive, costing over million to house and care for mice over several years.
The TRPV1 knockouts lived up to three years—an 11.9 percent increase in lifespan for males and a 15.9 percent increase for females compared to wild-type controls. This amounted to 100-130 more days of life, on average.
The increased lifespan involved a novel pathway that regulates metabolism through CGRP, rather than other longevity pathways associated with growth rate or dietary restriction. CGRP release in the pancreas decreases insulin secretion, which can compromise the body’s ability to regulate blood glucose. With aging, CGRP levels steadily increase, leaving the body even less able to handle glucose. This leads to all sorts of ills, such as low-grade inflammation, hypertension, diabetes, and obesity.
Aged TRPV1 knockouts, however, skipped these changes. “They are able to keep their metabolism revved up,” Dillin said. “Metabolically, the TRPV1 knockouts look like they’re young when they’re old.”
For example, in young mice, the respiratory exchange ratio (RER), which measures the rate of O2 consumption and CO2 production, peaks at night, when mice are active and burning glucose, and bottoms out during the day, while they sleep and burn fat. In aged mice, this rhythm is lost.
But in aged TRPV1 knockouts, a youthful rhythm was maintained, even though they had the same decrease in movement as old wild-type mice did. Further experiments found that aged TRPV1 knockouts were better at mustering insulin release in response to glucose than aged controls were.
Turning to the worm C. elegans to connect the dots between TRPV1 loss and insulin release, the researchers outlined a pathway that they then showed was conserved in mice: TRPV1 activation increases intracellular calcium, which triggers CGRP transcription through a signaling chain involving cAMP response element-binding protein (CREB) and a cofactor called CREB-regulated transcription coactivator 1 (CRTC1). Loss of TRPV1 inactivates this pathway, leading to less CGRP and more insulin release from the pancreas.
The researchers propose that inflammatory agents that rise with age or pain may activate TRPV1 channels on the DRG neurons innervating the pancreas to promote aging through CGRP release. Though not tested, other TRPV1-expressing neurons of the hypothalamus may contribute, too.
Targeting CGRP with an antagonist restored a youthful metabolism to aging wild-type mice. But whether these mice live longer than usual remains unknown, given the difficulties of infusing CGRP antagonists for a long period of time, Dillin said.
Michele Solis is a science writer and former neuroscientist who lives in Seattle, Washington, US.
Image credit: Riera et al., 2014
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