Cold-triggered Metabolic Pathway Links Longevity to Protein Health

WHO:

Nature - The study investigated *Caenorhabditis elegans* (C. elegans) and human cell models, including HEK293T/17 cells and induced pluripotent stem-cell-derived motor neurons.

Nature - The worm strains included wild-type N2 and mutants affecting genes such as *cat-4*, *trpa-1*, *pcbd-1* and *qdpr-1*; the study also used strains modeling protein aggregation and altered lifespan.

Nature - Human cell experiments included ALS iPS cells carrying the homozygous FUS P525L mutation and control iPS cells verified to lack FUS mutations.

Phys.org - The article describes a newly identified metabolic pathway as helping explain how cold temperatures extend lifespan and delay age-related decline in animals.

WHAT:

Nature - The study examined a cold-activated BH2 metabolic network associated with longevity and proteostasis, the maintenance of protein health.

Nature - Worms were raised at 20 °C until adulthood and then studied at 15 °C, 20 °C or 25 °C.

Nature - The researchers measured lifespan, movement, reproduction, behavior, metabolites, protein abundance, gene expression and protein aggregation.

Nature - BH4 levels were measured by ELISA using 650 µg of total protein from worm lysates.

Nature - Experiments tested BH2 supplementation in worms and human cells, and tyrosine supplementation in worms.

Nature - Human-cell experiments examined aggregation of mRFP-Q74, TDP-43 and FUS proteins, as well as proteasome activity and other cellular measures.

Phys.org - Moderately cold temperatures have been shown to extend lifespan and delay age-related decline in animals; the molecular basis had remained largely unclear.

WHERE:

Nature - Worm experiments used standard nematode growth medium and *E. coli* OP50 or HT115; human-cell experiments used laboratory cell cultures.

Nature - Proteomics analyses were performed at the CECAD Proteomics Facility.

WHEN:

Nature - Worms were maintained at 20 °C until adulthood before transfer to the experimental temperatures.

Nature - Lifespan experiments began with adult worms; animals were scored daily or every other day.

Nature - Human cells were treated with BH2 or tyrosine for 3 days; HEK293T/17 cells were lysed after 72 hours in specified transfection experiments.

WHY:

Phys.org - The research addressed why moderately cold temperatures can extend lifespan and delay age-related decline, while the molecular explanation had been largely unknown.

HOW:

Nature - Lifespan assays used 96 adult worms per condition, with survival comparisons assessed using the log-rank (Mantel–Cox) method.

Nature - Metabolites were profiled using liquid chromatography–mass spectrometry; protein abundance was assessed by mass spectrometry.

Nature - Researchers used gene knockdown, mutant strains, tissue-specific gene expression and auxin-inducible CAT-4 degradation to investigate the pathway.

(UPDATED October 22, 2026 02:18 UTC)

Researchers have identified a metabolic pathway that helps explain how moderate cold can extend lifespan and delay age-related decline in animals. The work focused on a cold-activated network involving BH2, a molecule linked to protein maintenance, or proteostasis. In experiments with roundworms, researchers compared animals kept at different temperatures after they reached adulthood, measuring lifespan, movement, reproduction, behavior and protein aggregation. They also examined metabolites, protein levels and gene activity, using genetic changes and gene knockdown to test how the pathway works. The team tested BH2 supplementation in worms and human cell models, including motor neurons derived from stem cells carrying an ALS-related FUS mutation. In human cells, they assessed aggregation of several proteins, along with proteasome activity. The findings connect cold exposure and BH2 metabolism with the maintenance of protein health, offering a molecular explanation for a long-observed effect of cooler temperatures.