What it is
Moderately cold temperatures extend lifespan and promote health across species, yet the molecular mechanisms behind these benefits have remained unclear. The authors define a metabolite-driven signalling system spanning several tissues that links cold temperature to longer life and better proteostasis, the upkeep of properly folded proteins, in the nematode worm Caenorhabditis elegans. Cold 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 distant tissues, including the intestine and neurons, where the salvage enzyme DHFR-1 converts it into BH4. BH4 is an essential cofactor for the enzyme phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and the neuronal dysfunction that follows it during ageing. Increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distant tissues, even at normal or elevated temperatures. In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, and of mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. The authors identify BH2 as a cold-induced metabolite whose synthesis, transport between tissues and conversion into BH4 preserve proteostasis across the organism and extend lifespan.
Why it matters
In worms, cold raised muscle production of a metabolite, BH2, that other tissues turn into BH4, extending lifespan and curbing disease-related protein aggregation. Moderately cold temperatures extend lifespan across species, but how has been unclear. Here, making more BH2 in muscle alone was enough to extend the worms' lifespan and suppress pathological protein aggregation in distant tissues, even at normal or elevated temperatures. BH4 works as a cofactor for an enzyme that promotes tyrosine synthesis, and adding BH2 or tyrosine to human cells reduced aggregation of proteins associated with Huntington's disease and of mutant proteins that cause amyotrophic lateral sclerosis.
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Filed underGenetics, Aging, and Longevity in Model Organisms, Metabolism and Genetic Disorders, Amino Acid Enzymes and Metabolism
