Researchers at the University of Cologne published a study in Nature identifying how moderately cold temperatures trigger a specific metabolic pathway in muscle tissue that extends lifespan and preserves protein health in the nematode Caenorhabditis elegans.
For more than a century, biologists have documented that cold environments effectively extend the lifespan of animals. While early theories assumed this was simply a passive thermodynamic consequence of chilled, slowed-down body chemistry, a team led by investigators at the University of Cologne has demonstrated that the process involves an actively regulated chemical response driven by muscle tissue.
How Muscle Tissue Coordinates Temperature Responses in Worms
Working with the transparent roundworm Caenorhabditis elegans, researchers kept lab populations at a standard temperature of 20 degrees Celsius before moving adult specimens to 15 degrees Celsius. On average, the chilled worms lived roughly 15 percent longer. By comparing the chemical profiles of worms kept at different temperatures, the scientific team traced the change to an enzyme named CAT-4.
Under cooler conditions, muscle cells ramp up its production substantially. That enzyme jump-starts the creation of an organic compound called dihydrobiopterin, or BH2, which muscle tissue synthesizes, stores, and subsequently releases into the rest of the organism.
We are excited to show that mildly cold temperatures trigger significant production of a specific metabolite, BH2, which is synthesised, stored, and subsequently released by muscle tissue.
David Vilchez, University Hospital Cologne
Once released, BH2 travels to other parts of the body. There, it is converted into tetrahydrobiopterin, or BH4, enabling another enzyme known as PAH-1 to produce the amino acid tyrosine. When investigators genetically disrupted this biochemical pathway, the longevity benefits typically conferred by cold exposure decreased.
Scientists normally maintain laboratory worms at 68 degrees Fahrenheit, or 20 degrees Celsius, and consider 77 degrees Fahrenheit, or 25 degrees Celsius, to be warm for them. When adult worms are transferred to 59 degrees Fahrenheit, or 15 degrees Celsius, their lifespan increases considerably. The research team noted that cold temperatures also cause proteasomes—cellular waste removal structures that break down protein waste—to clear harmful protein clumps.
In the study titled Cold activates a BH2 metabolic network promoting longevity and proteostasis,
the research team utilized C. elegans as its principal animal model. The work was led by Hyun Ju Lee and David Vilchez from Vilchez’s laboratory at CECAD, the aging research center of the University of Cologne. Additional authors listed on the publication include Grobushkin, Dimitrios Prymidis, Theodoros Georgomanolis, Agnieszka Sokol, Ming Yang, Thorsten Hoppe, and Christian Frezza.
BH2 Reduces Protein Buildup in Neurodegenerative Disease Models
Beyond extending overall lifespan, the cold-triggered pathway plays a central role in proteostasis, the biological network that maintains functional proteins and prevents the accumulation of damaged structures. In worm models of Huntington’s disease, the BH2 mechanism successfully suppressed the clumping of harmful proteins.
The research team also tested the pathway using human cell models associated with age-associated neurodegenerative disorders. Adding BH2 reduced the buildup of abnormal proteins linked to both Huntington’s disease and amyotrophic lateral sclerosis. Furthermore, BH2 and tyrosine decreased signs of cell death in human motor neurons carrying a mutation associated with amyotrophic lateral sclerosis.
BH2 then goes to other parts of the body, where it helps to maintain protein homeostasis and contributes to tissue health during ageing.
David Vilchez, University Hospital Cologne
Mimicking Cold Benefits Without Lowering Body Temperature
Because humans are warm-blooded mammals that maintain a stable core temperature around 37 degrees Celsius despite environmental fluctuations, continuously lowering ambient or body temperature is not a practical anti-aging strategy. To explore whether the molecular benefits could be decoupled from actual cold exposure, researchers tested direct metabolite supplementation.
Administering BH2 and tyrosine together produced a protective effect in roundworms and human cell cultures. Notably, supplementing worms with these molecules significantly extended lifespan even when the animals were maintained at standard laboratory temperatures or warmer environments.
Further experiments on human cells encourage us to look for treatments that mimic the beneficial effects of cold without requiring changes in body temperature.
David Vilchez, University Hospital Cologne
While the findings establish a biochemical link between muscle metabolism and longevity in experimental models, scientists emphasized that translating these insights into human therapies remains a distant goal. Researchers cautioned that research is still at a nascent stage in developing a “pill” to mimic these effects, and substantial work is required before establishing whether the pathway operates similarly in people.