Investigating the Mechanisms of Cold Hormesis
Many forms of cell stress provoke much the same response of increased maintenance and damage repair activities, such as increased autophagy. A mild level or intermittent stress can result in overall benefit to cell and tissue function, and when applied over time to an organism this can modestly slow aging. How the cell regulates this response to stress and the fine details of the response to stress vary between different forms of stress, however. Thus developing a therapy to mimic, for example, the response to the low nutrient stress of calorie restriction, may be quite a different exercise to mimicking the response to cold, or heat, or toxin exposure. For illustration, researchers here dig into some of the regulatory mechanisms involved in the beneficial response to cold stress in nematode worms, and one can see the differences from what is known of calorie restriction in the same species.
Moderately cold temperatures extend lifespan and promote health across species, 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. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal 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, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.