Nature Study Reveals the Molecular Mechanism by Which Mild Cold Extends Lifespan
Release time:
2026-11-06
Moderate cold exposure can extend lifespan across many species — a phenomenon observed and recorded for over a century, yet its molecular mechanism has remained unclear. Recently, a team led by David Vilchez and Christian Frezza at the University of Cologne published a study in Nature, reporting a metabolite-mediated, multi-tissue signaling pathway that links cold temperature to both lifespan extension and the maintenance of protein homeostasis.
Muscle tissue is the source of the cold signal. Using the roundworm C. elegans as a model, the researchers found that moving adults from the standard culture temperature of 20°C to mild cold of 15°C significantly extended lifespan. Metabolomic analysis showed that cold induced elevated levels of 45 metabolites, including dihydrobiopterin (BH2). Among them, cold specifically upregulated the expression of the biopterin synthesis enzyme CAT-4 in muscle (the human homolog being GCH1), increasing BH2 production. BH2 is a transportable storage form of the active cofactor tetrahydrobiopterin (BH4).
BH2 is then taken up by distal tissues (neurons, intestine, germline) via ENT transporters, where the DHFR-1 enzyme converts it to BH4 through a salvage pathway; BH4, as a cofactor of phenylalanine hydroxylase PAH-1, promotes tyrosine synthesis. Tissue-specific experiments showed that knocking down CAT-4 in muscle alone shortened the cold-induced lifespan extension, while muscle-specific overexpression of CAT-4 extended lifespan not only at 15°C but also at 20°C and 25°C — an effect independent of the known cold-sensing channel TRPA-1. The paper summarizes this as muscle producing a "cell-nonautonomous" longevity signal.
The cold pathway suppresses pathological protein aggregation. The pathway is also tied to proteostasis. Muscle CAT-4 overexpression reduced aggregation of the Huntington's disease model protein polyQ67 in neurons, along with the corresponding behavioral deficits, and suppressed age-related aggregation of the intestinal protein IFB-2 and the bacterial invasion that follows it.
In human cell experiments (not human trials): HEK293 cells cultured at 37°C supplemented with 10 micromolar BH2 showed reduced SDS-resistant aggregation of the Huntington-related polyQ74 protein as well as the ALS-related mutants TDP-43(A382T) and FUS(P525L); in iPS-derived motor neurons carrying the FUS(P525L) mutation, both BH2 and tyrosine supplementation reduced apoptosis and markers of necroptosis. Tyrosine supplementation also extended worm lifespan at 20°C. The paper's discussion notes that when factors such as oxidative stress hinder the conversion of BH2 to BH4, tyrosine can still retain a protective effect — making it a potential alternative intervention point in this pathway.
The limits of the study. The authors explicitly note translational limitations in their discussion: in mammals, BH4 also participates in nitric oxide synthase function, and an imbalanced BH2/BH4 ratio may be associated with vascular endothelial dysfunction; the cell experiments did not directly examine in vivo effects such as NOS uncoupling. Moreover, the metabolomics identified 45 cold-induced metabolites in total, and the BH2 pathway may be only one component of a larger metabolic signaling network. All of the above results currently come from worm and cell models. The goal the paper proposes is to find interventions that reproduce the health benefits of cold without lowering body temperature.
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