(Nick_Thompson/iStockphoto/Getty Images)
When it comes to health, not all temperatures are equal.
Evidence suggests that cold temperatures are mysteriously beneficial for longevity, helping to boost metabolism and delivering positive effects at the cellular level.
On the flip side, excessive heat doesn't seem to do great things for the human body.
But what is it about coldness that's so beneficial in comparison?
In a new study in Nature, researchers identified a mechanism that contributes to the effect, driven by a metabolic substance called dihydrobiopterin (BH2).
"We are excited to show that mildly cold temperatures trigger significant production of a specific metabolite, BH2, which is synthesized, stored, and subsequently released by muscle tissue," says molecular biologist David Vilchez from the University of Cologne in Germany.
"BH2 then goes to other parts of the body, where it helps to maintain protein homeostasis and contributes to tissue health during aging."
Increased production of the enzyme CAT-4 (green) in worms exposed to colder temperatures.
(David Vilchez/University of Cologne/CECAD)
While scientists have known for more than a century that cold temperatures boost longevity in animals, including worms, flies, fish, and rodents, researchers weren't fully sure how coldness achieved this.
Originally, scientists hypothesized it could be a result of passive thermodynamic effects, but in more recent times, research suggests that cold-induced longevity is an actively regulated process inside the body, triggering specific biological pathways that help organisms survive.
A few years ago, Vilchez and fellow researchers discovered that cold temperatures led to the removal of harmful protein clumps in the nematode worm Caenorhabditis elegans, activating cellular structures called proteasomes that break down protein waste.
In the new work, the researchers investigated the systemic signals behind such responses, hypothesizing that metabolites – small molecules produced by metabolic processes – could be involved.
In experiments with C. elegans, the researchers found that exposure to moderately cold temperatures (15 °C, or 59 °F, which extends lifespan in worms) increases the production of an enzyme called CAT–4, largely in the worms' muscles, which in turn stimulates production of the metabolite BH2.
Once produced, BH2 is then transported to other tissues, where it is converted into a bioactive molecule called tetrahydrobiopterin (BH4), which enables an enzyme called PAH–1 to produce the amino acid, tyrosine.
The team found that disrupting this pathway reduced the lifespan benefits seen in worms exposed to the cold, suggesting that the longevity effects of lower temperatures aren't simply a passive consequence of slower metabolism, but are driven in part by an actively regulated biological process that starts with muscle cells.
In separate experiments, the researchers found that the pathway they'd identified also boosted healthy protein homeostasis (aka proteostasis), suppressing the aggregation of harmful proteins in a worm model of Huntington's disease.
"These findings suggest that specifically targeting a single tissue, such as muscle, could provide organism-wide protection," Vilchez says.
"This opens up new avenues for therapeutic approaches."
Perhaps most excitingly of all, the researchers found evidence suggesting that cold temperatures aren't necessary for the pathway to operate.
By genetically boosting CAT–4 levels in the worms' muscles, the team was able to extend their lifespan even at normal or warmer temperatures, suggesting it's possible to reproduce some benefits of the cold without lowering body temperature.
"We were genuinely surprised to find the supplementation significantly extended lifespan, even at standard and warmer temperatures," Vilchez says.
"Further experiments on human cells encourage us to look for treatments that mimic the beneficial effects of cold without requiring changes in body temperature."
In separate experiments involving human cells engineered to develop proteins associated with Huntington's and amyotrophic lateral sclerosis (ALS), the researchers found that supplementing the cells with BH2 reduced the accumulation of the abnormal proteins.
In addition, another experiment showed BH2 and tyrosine supplementation reduced signs of programmed cell death in human motor neurons carrying an ALS-associated mutation, suggesting the pathway could also help protect against neurodegeneration.
It's worth emphasizing that so far these results have only been shown in experiments involving nematodes and human cells, and we'll need a lot more research before we can think about how these effects could safely be transferred to living human patients.
But the findings show we're getting closer to understanding how cold delivers its longevity effects, and one day we might be able to do just that.
The Life of Earth
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