It has been known for some time now that a simple – but not an easy – way to live longer is to eat less. Caloric restriction extends the life span of organisms from worms to primates, suggesting that the method works, as well, for the rare human who is willing and able to stick to it. Now, researchers from the University of California at Berkeley finally have a better deal on offer – live longer through suffering less pain.

Senior author Andrew Dillin and his colleagues found that they were able to expand the life span of mice by about four months, or 15 percent, by knocking out their TRPV-1 receptors, which sense pain, inflammation and heat.

They published their findings in the May 22, 2014, issue of Cell.

The pathway the team has identified is independent of the longevity mechanisms that are activated by caloric restrictions, which activate sirtuins and the insulin-like growth factor-1 (IGF-1), though they also affect metabolism.

Mice lacking TRPV1 receptors, senior author Andrew Dillin told BioWorld Today, "can switch from glucose to fat metabolism very easily," even as they age. Normally, the ability to switch easily between different fuels is a signature of a young organism. But the TRPV1 knockout animals "had this really robust [switching ability] late in life."

Dillin and his team first looked at the effects of targeting TRPV1 to understand the relationship between pain and aging.

Humans, as they get older, report that they are in pain much more than in their younger years. But it is an unanswered question whether they are in pain because they are getting older – or also getting older because they are in pain.

When Dillin and his team created knockout animals that lacked TRPV1, both male and female animals lived longer than their wild-type counterparts.

Dillin and his team originally thought that the life span increase was likely mediated through the known longevity pathways that center on IGF-1.

But IGF-1 knockouts are noticeably smaller than normal mice, and have a number of other abnormalities. The TRPV1 knockouts did not show any of those symptoms, prompting the team to look for which mechanisms were allowing the animals to live longer instead.

TRPV-1 is a receptor on sensory neurons. But it is also broadly expressed in the body, including both in the pancreas and in the brain. The researchers found that in the pancreas, one consequence of TRPV-1 activation was the production of calcitonin gene-related peptide (CGRP).

CGRP, in turn, blocks insulin secretion. Because they had lower levels of CGRP as a result of lacking TRPV-1, knockouts were able to respond to dietary sugar more efficiently.

"When we challenged these animals, with glucose, they handled it exceptionally well," Dillin said. "They don't have more insulin just sitting around. But when they are challenged, they release it much better."

Dillin and his team want to see whether TRPV-1 receptors elsewhere in the body – particularly in the brain – also play a role in aging, and whether blocking either TRPV-1 or CGRP will replicate the effects of knocking out the gene for TRPV-1.

In their paper, the team treated mice with a CGRP antagonist and found that the elderly animals receiving the treatment had a more youthful metabolic profile.

Like TRPV-1, CGRP appears to play a role in pain. In particular, this peptide is linked to migraine pain, and several biopharma companies are working to develop inhibitors. At the American Academy of Neurology's annual meeting in late April/early May, two CGRP-targeting antibodies – ALD403 (Alder Biopharmaceuticals Inc.) and LY2951742 (Eli Lilly and Co.) presented phase II data showing that such antibodies could reduce the incidence of migraines.

TRPV-1 antagonists, too, are in clinical trials as analgesics. And an ironic piece of anecdotal evidence comes from the fact that eating chilies – whose heat comes from the TRPV-1 ligand capsaicin – appears to have beneficial metabolic effects.

At first glance, this may seem puzzling, since capsaicin activates TRPV-1 receptors rather than blocking them. But the solution lies, as so often, in the dose: ultimately, capsaicin can hyperactivate TRPV-1-sensing neurons to the point of killing them off.