Cold triggers a muscle-to-tissue metabolic network in worms

Moderately cold exposure extended lifespan and improved health in the nematode Caenorhabditis elegans by activating a metabolic network that links muscle to distant tissues, according to a study in Nature. The pathway begins with increased production of dihydrobiopterin, or BH2, in muscle. BH2 then travels to organs including the intestine and nervous system, where it is converted into tetrahydrobiopterin, or BH4. The experiments identify this intertissue BH2–BH4 axis as a mechanism through which low temperature can promote longevity and maintain protein homeostasis across the animal.

The researchers initially used untargeted metabolomics to identify metabolites altered by cold in adult worms maintained at 15 °C, 20 °C or 25 °C. Two independent metabolomic experiments identified a shared set of cold-induced metabolites, among them BH2. Follow-up experiments connected this metabolic response to the enzyme CAT-4, the worm counterpart of human GCH1, which participates in biopterin synthesis. Increasing CAT-4 activity raised BH2 levels, and experimentally elevating CAT-4 in muscle was sufficient to reproduce several effects of cold even when animals remained at normal or elevated temperatures.

The tissue-specific experiments indicate that muscle acts as a metabolic hub in this response. BH2 produced in muscle was detected in distal tissues, including the intestine and neurons, where the salvage enzyme DHFR-1 converts it into BH4. Blocking the relevant steps weakened the cold-associated phenotypes, while restoring activity in selected tissues helped re-establish them. The results therefore support a metabolite-signalling model: a relatively mobile metabolic precursor made in one organ can be transported elsewhere and converted into a functional cofactor in tissues that need it.

BH4 has an important downstream role in the worm pathway. It serves as an essential cofactor for phenylalanine hydroxylase, PAH-1, which supports tyrosine synthesis. The investigators found that the lifespan effect of the BH2–BH4 pathway required this connection, and that supplementing worms with tyrosine reproduced the longevity benefit at normal temperature. These results identify the PAH-1–tyrosine axis as a downstream mediator rather than treating BH2 itself as the endpoint. They also show that the network can influence lifespan without a continuing fall in ambient temperature, provided its metabolic components are engaged.

The pathway had consequences beyond lifespan. Elevated BH2 synthesis in muscle reduced disease-related protein aggregation in distant tissues and preserved neuronal and intestinal function during ageing. Analyses of ageing worms showed less accumulation of aggregation-prone proteins, and tissue-specific perturbations indicated that the proteostatic effect depended on communication between muscle and recipient tissues. Tyrosine again mimicked part of this effect. In the study’s broader interpretation, the BH2–BH4 pathway therefore coordinates longevity and proteostasis rather than operating as an isolated response within individual cells.

Human-cell experiments provided a limited test of whether the pathway’s biochemical logic might be conserved in mammals. Researchers treated human cells with BH2 or tyrosine and measured aggregation of polyglutamine-expanded protein associated with Huntington’s disease, as well as disease-linked variants of TDP-43 and FUS associated with amyotrophic lateral sclerosis. Both BH2 and tyrosine reduced aggregation in the tested cellular models. Additional experiments involving human induced pluripotent stem-cell-derived motor neurons bearing a mutant FUS allele examined effects on cell death and necroptosis-related markers.

These cellular findings do not demonstrate that BH2 or tyrosine prevents neurodegeneration in people. The experiments involved cultured cells rather than patients, and translation may depend on whether and how BH2 is converted into BH4 in a particular mammalian tissue. The authors noted that BH4 is also required by nitric oxide synthase, and that oxidative stress or impaired DHFR activity can disturb the balance between BH2 and BH4 in endothelial cells. Although BH2 did not increase detectable superoxide production in the cellular models used, those experiments did not directly test nitric oxide synthase uncoupling in living animals.

The study also identified a biochemical limitation to the proposed mechanism. Oxidative stress reduced BH2’s protective effect, consistent with interference in the conversion of BH2 to BH4, whereas tyrosine retained its protective effect under those conditions. This difference suggests that the downstream amino-acid pathway can remain effective even when efficient BH2-to-BH4 conversion is compromised. The result is a mechanistic distinction between the cold-induced upstream signal, BH2, and the downstream effector, tyrosine. It also shows why directly supplementing BH2 may not reproduce all of the pathway’s effects in every biological context.

The work was conducted primarily in adult hermaphrodite worms, with synchronized populations, randomized allocation to experimental conditions and lifespan assays generally using 96 animals per condition. Experiments were repeated by at least two researchers, although sample sizes were not determined through statistical power calculations and conditions were not processed in a blinded manner. Metabolomic samples were randomized during processing, while proteomic analysis and molecular assays examined changes across cold temperatures and tyrosine treatment. The worm results therefore establish a causal pathway within the experimental model, but their relevance to mammalian aging, disease prevention and human supplementation remains untested.

Cold also induced numerous metabolites beyond BH2, indicating that the newly identified pathway is likely part of a broader network of temperature-responsive signals. Future work would need to determine how these metabolites interact, whether similar tissue-to-tissue transport occurs in mammals, and whether BH2 delivery can reproduce cold-associated benefits without requiring changes in body temperature. For now, the study offers a detailed molecular account of how moderate cooling in worms can coordinate lifespan and protein quality control: muscle increases production of a transportable BH2 reservoir, distant tissues convert it into BH4, and a PAH-1-dependent tyrosine pathway helps translate that metabolic signal into longer life and reduced protein aggregation.

Subject of Research: Cold-induced BH2 metabolism, intertissue signalling, longevity and proteostasis in nematodes

Article Title: Cold activates a BH2 metabolic network promoting longevity and proteostasis

Article References: Lee, H. J., Doğan, C., Koyuncu, S., Wehrmann, M., Artan, M., Petrovic, D., Loureiro, R., Sahu, A. K., Schnubel, J., Grobushkin, P., Prymidis, D., Georgomanolis, T., Sokol, A., Yang, M., Hoppe, T., Frezza, C., & Vilchez, D. (2026). Cold activates a BH2 metabolic network promoting longevity and proteostasis. Nature. https://doi.org/10.1038/s41586-026-11152-9

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11152-9

Keywords: BH2 metabolism, cold exposure, longevity, proteostasis, Caenorhabditis elegans, BH4, tyrosine, muscle signalling, protein aggregation, human cells, Cold, activates