Photo by wstryder, via Flickr
Photo by wstryder, via Flickr

No Pain, No Aging

Age brings pain: back pain, eye strain, sore joints, and the like. And pain, too, seems to accelerate aging. Several studies have reported that people with chronic pain have shorter lives than everybody else.

But is the link between pain and aging due to the co-occurance of sickness and decay, or rather to the perception — the feeling — of pain itself?

“If you burn your finger right now, is that going to affect the aging process?” asks Celine Riera, a postdoc in Andrew Dillin’s lab at the University of California, Berkeley. The answer is yes, according a mouse study by Riera appearing today in Cell.

Riera’s study focuses on mice genetically engineered to lack a pain receptor called TRPV1. This receptor binds to capsaicin, the molecule that gives chili peppers their tingly spice.

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After eating a high-fat diet, mice lacking pain receptors (right) are thinner than normal mice (left). From Motter & Ahern, 2008.

In 2008, researchers found that these mutants have a fiery metabolism: When fed a high-fat diet, they gain a lot less weight than normal mice. “We showed that these animals had a greater capacity for energy expenditure,” says Gerard Ahern, a physiologist at Georgetown University who led that study.

Given the robust ties between metabolism and aging, Riera and her colleagues decided to track the lifespan of these mutant mice. They found that the animals live, on average, 100 to 130 days longer than typical lab mice, an increase of 12 to 16 percent. What’s more, the mutant mice showed a “youthful” metabolic profile in old age, including an increased energy expenditure, oxygen consumption, and activity levels.

So how could a pain receptor influence metabolism? Turns out that (in normal animals) these receptors cluster around beta cells of the pancreas, which secrete insulin. When the TRPV1 receptors are stimulated by pain, they release a protein called calcitronin gene-related peptide, or CGRP. And CGRP, in turn, blocks the pancreas from releasing insulin and promotes inflammation. Aging mice “secrete too much of this CGRP,” Riera explains, which leads to a host of metabolic and immunological problems.

Mice that don’t have the pain receptors, the study showed, don’t have this excess CGRP activity, which seems to be why they’re in better metabolic health and live longer than normal.

CGRP is a fascinating protein. Naked mole rats, which outlive their rodent cousins by some 30 years, don’t have the CGRP protein in their sensory nerves. And researchers have reported elevated amounts of CGRP in people with migraine headaches and joint disorders.

Because of the link to migraine, several drugs are in development that target CGRP. The new study suggests that those substances may influence the aging process as well. “It seems like a pathway that’s easily modulated by pharmacological manipulation, and that’s really exciting,” Riera says. (Interestingly, though, targeting the TRPV1 receptor directly isn’t likely to work out. The protein has been the target of several experimental drugs for chronic pain. But in clinical trials patients lose not only their pain but their ability to regulate temperature. “They end up getting hyperthermia or burning themselves in the shower,” Ahern says. “The drugs work too well.”)

There is still much to be figured out about the TRPV1/CGRP pathway and how it influences metabolism. While this new study shows that getting rid of the pain receptor revs up metabolism, other studies have shown that stimulating the receptor — say, by eating capsaicin-rich foods — does the same thing. “So the data is a little bit discordant,” Ahern says, perhaps because these proteins play different roles in different tissues.

The new work is part of a flurry of recent studies to show connections between sensory systems and longevity, notes Joy Alcedo, a neurobiologist at Wayne State University who was not involved in the new study.

For example, in 2004 Alcedo reported that in worms, certain taste neurons promote longevity while others restrict it, probably by influencing insulin signaling. That study showed that odor-sensing neurons, too, influence lifespan by tweaking the worm’s reproductive system. Just this week, another study found that fruit flies that can’t taste water live 43 percent longer than normal flies.

Considering the wide variety of environmental factors that can influence an animal’s lifespan, Alcedo says, “I would not be surprised if many more types of sensory receptors will be found to affect longevity.”

This piece has been changed from the original: People taking TRPV1 drugs sometimes get hyperthermia, not hypothermia.