When it comes to health, not all temperatures are created equal. Existing evidence suggests that low temperatures have a mysterious, beneficial effect on longevity, boosting metabolism and exerting positive influences at the cellular level.
Conversely, excessive heat is not beneficial to the human body. But what exactly makes cold temperatures so advantageous by comparison?
In a new study published in the journal Nature, scientists have identified a mechanism driving this effect, which is mediated by a metabolic substance called dihydrobiopterin (BH2).
“We are excited to show that moderately low temperatures trigger the significant production of a specific metabolite, BH2, which is synthesized, accumulated, and subsequently released by muscle tissue,” says molecular biologist David Vilchez of the University of Cologne in Germany. “BH2 then travels to other parts of the body, where it helps maintain protein homeostasis and promotes tissue health during the aging process.”
Although it has been known for over a century that low temperatures extend the lifespan of various animals—including worms, flies, fish, and rodents—researchers have not fully understood the precise mechanisms by which cold achieves this.
Initially, scientists hypothesized that this might be the result of passive thermodynamic effects; however, recent research indicates that the lifespan extension observed in cold environments is an actively regulated process within the organism, triggering specific biological pathways that enhance survival. Several years ago, Vilchez and his colleagues discovered that low temperatures lead to the removal of harmful protein aggregates in the nematode Caenorhabditis elegans by activating cellular structures called proteasomes, which break down protein waste.
In a new study, the researchers investigated the systemic signals underlying these responses, hypothesizing that metabolites—small molecules produced during metabolic processes—might play a role.
In experiments with Caenorhabditis elegans, the researchers found that exposure to moderately low temperatures (15°C, which extends the worms’ lifespan) increases the production of the enzyme CAT-4, primarily in the worms’ muscles; this, in turn, stimulates the production of a metabolite called BH2.
Once produced, BH2 is transported to other tissues, where it is converted into a bioactive molecule known as tetrahydrobiopterin (BH4). This molecule enables the enzyme PAH-1 to produce the amino acid tyrosine.
The researchers discovered that disrupting this pathway diminishes the lifespan benefits observed in cold-exposed worms. This suggests that the lifespan-extending effects of lower temperatures are not merely a passive consequence of a slowed metabolism, but are, in part, driven by an actively regulated biological process that originates in muscle cells.
In separate experiments, the researchers found that this signaling pathway also helps maintain healthy protein homeostasis (or proteostasis) by suppressing the aggregation of harmful proteins in a C. elegans model of Huntington’s disease. “These results suggest that targeting a single tissue—such as muscle—can provide protection for the entire organism,” says Vilchez. “This opens up new possibilities for therapeutic approaches.”
Perhaps the most exciting finding is that the researchers uncovered evidence suggesting that low temperatures are not a prerequisite for this pathway to function.
By genetically increasing the levels of CAT-4 in the muscles of worms, the team was able to extend their lifespan even at normal or higher temperatures—hinting at the possibility of replicating some of the benefits of cold exposure without actually lowering body temperature.
“We were genuinely surprised to find that the addition of nutrients significantly extended lifespan, even at standard or higher temperatures,” says Vilchez. “Further experiments using human cells encourage us to pursue treatments that mimic the beneficial effects of cold, without the need to alter body temperature.”
In separate experiments using human cells modified to produce proteins associated with Huntington’s disease and amyotrophic lateral sclerosis (ALS), the researchers discovered that adding BH2 to the cells reduced the accumulation of abnormal proteins.
The study showed that the addition of BH2 and tyrosine reduces signs of programmed cell death in human motor neurons carrying a mutation linked to ALS, suggesting that this pathway might also help protect against neurodegeneration.
It is worth emphasizing that, so far, these results have only been demonstrated in experiments involving nematodes and human cells; much more research will be required before we can consider how to safely translate these effects to living patients.
Nevertheless, these findings indicate that we are getting closer to understanding how cold contributes to an extended lifespan—and one day, we may fully grasp the mechanism behind it.
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