Blocking pain receptors may extend lifespan, boost metabolism

By blocking a specific pain receptor in mice, researchers from The University of California, Berkeley, were able to both extend the animals’ lifespans and give them a more youthful metabolism – including an improved insulin response.

The findings could spell out a new way to extend longevity, as well as point to a new drug target for developing novel diabetes and obesity treatments.

According to the researchers, they were interested in manipulating pain receptors since chronic pain is often associated with a shorter lifespan.

“If you look at humans as they age, they report that they’re in more pain,” Andrew Dillin, a professor of molecular and cell biology at UC Berkeley, told  “There are two ways to look at that: Either pain is just coming along with the aging process or pain may be driving the aging process.  So we asked if we took an old animal and removed its pain receptors, would it look more youthful.”

Dillin and his team decided to focus on a specific pain receptor called TRPV1 (transient receptor potential cation channel subfamily V member 1).  One of the body’s major pain receptors, TRPV1 is already known to be activated by the “hot” compound in chili peppers called capsaicin.  Constant activation of this receptor can actually lead to its death, and interestingly enough, diets rich in capsaicin have been linked with lower incidences of diabetes and metabolic issues.

With this in mind, the researchers analyzed mice that had been genetically manipulated to lack TRPV1 receptors.  They found that, on average, the mice lived nearly four months – or about 14 percent – longer than normal mice, without any health complications.

“What happens in previous studies that have altered mouse longevity is they either affect the growth of the animal or it has reproductive defects,” Dillin said.  “To our surprise, these animals were completely normal…It was very perplexing.”

Additionally, the genetically altered mice had much faster metabolisms and were much more efficient than other older mice at producing insulin.  When given large amounts of glucose, the mice were able to clear it from the blood extremely fast.

Dillin noted that TRPV1 is actually found in nerve fibers that contact the pancreas, stimulating the release of certain substances.

“Normally when the receptor is functioning, it causes the secretion of a neuropeptide called CGRP, which actually blocks insulin secretion,” Dillin said. “So when you mutate this receptor, you no longer produce this neuropeptide, and now you can freely release insulin.”

Because CGRP is triggered by TRPV1, blocking CGRP produces a similar effect to blocking TRPV1.  When people are younger, they possess very low levels of CGRP, but as they age, levels of this neuropeptide start to increase. Yet in the mutant mice lacking TRPV1, CGRP levels were low in both early life and later life.

Given these findings, Dillin argued that pharmacological manipulation of both TRPV1 and CGRP may help improve overall metabolic health and extend longevity. He noted that wiping out TRPV1 completely may not be a feasible option, since pain is an important mechanism for indicating something is wrong, but many CGRP inhibitors are already on the market as a migraine treatment and are safe to use.

The research also reveals how pain relates to metabolism and how youthful metabolism can lead to a longer life. Dillin said these three areas of health are much more connected the previously thought.

“The next time you’re in pain, see if you’re hungry.  I bet you’re not…When you’re naturally in pain, you want to shut down all of your systems to focus on dealing with that pain.”

The research was published in the May 22 issue of the journal Cell.