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A key metabolic pathway has been identified that provides a deeper insight into the link between moderately cold temperatures and enhanced longevity.
We’ve heard it before: there’s a link between cold temperatures and longevity, but we know very little about the actual mechanism underlying this link. Now, researchers at the University of Cologne (Germany) have uncovered a key signaling system in a model organism that could shed light on the link, potentially helping to prevent age-related diseases in the future.
Previous studies have shown that – across species, from fruit flies to rodents – exposure to moderately cold temperatures extends lifespan and promotes health. The effects have also been documented in humans; interestingly, average body temperature has steadily declined in the decades since the Industrial Revolution, potentially contributing to the lifespan extension we’ve seen in those decades. These findings have led researchers to further explore the possibility that cold temperatures drive evolutionarily conserved programs that promote longevity.
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In this recent study, the researchers were primarily interested in exploring the signals that actively coordinate cold-induced tissue responses: longevity mechanisms and proteostasis. To do this, the team raised wild-type Caenorhabditis elegans at a standard temperature of 20°C until adulthood before transferring them to environments that were either 15°C, 20°C or 25°C. On day 5 of adulthood, an untargeted metabolomics analysis revealed 64 metabolites that were significantly increased at 15°C compared to 20°C and 25°C. The most strongly induced metabolite in the 15°C condition was dihydrobiopterin (BH2), so the team focused its efforts on this metabolite.
Quantitative proteomics demonstrated that the production of an important enzyme in BH2 synthesis, GTP cyclohydrolase I (cat-4), was upregulated at 15°C. To see where this enzyme was expressed, they used a GFP-based fluorescent reporter. In the cold condition, cat-4 expression was increased in the intestine (an effect observed at regular temperature) as well as in muscles, which was not found in the other conditions. Tissue-specific cat-4 knockdown experiments revealed that when cat-4 expression was silenced in muscle tissue alone, it reduced cold-induced longevity, an effect that wasn’t seen when knockdown occurred in the intestine or other tissue types, such as the epidermis.
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Muscle was established as a metabolic hub, from which BH2 is transported to other tissues. BH2 can then be converted into BH4, its bioactive form, which activates cofactor PAH-1 and tyrosine synthesis. Furthermore, they found that the increase in BH2 synthesis in muscle suppressed pathological protein aggregation and preserved the functions of other tissues in the body, indicating that this metabolic pathway could be harnessed to help prevent age-related diseases. These results were mirrored in human cell cultures, although more research is needed to determine their translational potential – as additional cell processes and signals will likely interfere with the process modeled in C. elegans and controlled cell culture.
“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. BH2 then goes to other parts of the body, where it helps to maintain protein homeostasis and contributes to tissue health during aging,” explained principal investigator David Vilchez. “These findings suggest that specifically targeting a single tissue, such as muscle, could provide organism-wide protection. This opens up new avenues for therapeutic approaches.”
The post Giving short lifespans the cold shoulder: the metabolic pathway linking cold temperatures to longevity appeared first on BioTechniques.
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