Cold activates a BH2 metabolic network promoting longevity and proteostasis
Researchers have identified a metabolic pathway involving the BH2-BH4 axis that links cold temperatures to increased longevity and improved protein health in C. elegans. This mechanism, which regulates protein aggregation, shows potential for therapeutic applications in human neurodegenerative diseases.
Why it matters
Understanding how temperature affects cellular health could lead to new treatments for age-related diseases like Huntington's and ALS.
Moderately cold temperatures extend lifespan and promote health across species 1 , 2 , 3 , yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans . Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4). BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2–BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing.
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