Cold temperatures prolong life span in both cold-blooded organisms (such as Drosophila, fish, and worms) and warm-blooded animals (such as mice). Rather than a passive effect, in which reduced metabolic rates slow the process of aging, Xiao et al. showed that cold temperatures induced an active transcriptional response that increased longevity in Caenorhabditis elegans. At low temperatures, worms deficient in the cold-sensitive transient receptor potential (TRP) cation channel with an ankyrin domain (TRPA-1) had shorter life spans than wild-type worms. Overexpression of trpa-1, but not a mutant calcium-impermeable receptor, extended life span in cold conditions, suggesting that calcium influx was critical to TRPA-1–mediated longevity. Additionally, overexpression of trpa-1 in neurons or intestinal cells extended life span, indicating a cold-sensing role for nonexcitable intestinal cells. Overexpression of trpa-1 also stimulated the transcriptional activity of DAF-16, the C. elegans ortholog of the forkhead box (FOXO) transcription factor family. Analysis of mutant worms revealed that calcium influx stimulated calcium-sensitive protein kinase C 2 (PKC-2) and that, downstream of PKC2, the serum/glucocorticoid regulated kinase 1 (SGK-1) was required for TRPA1-induced longevity and DAF-16 activation. Deletion of DAF-16 abolished the enhanced longevity of TRPA-1-, PGC-2-, or SGK-1-overexpressed transgenic worms, but its overexpression rescued the shorter life spans of mutants with compromised function of TRPA-1, PGC-2, or SGK-1. Interestingly, expression of human TRPA-1 in C. elegans also prolonged life span at cold temperatures, suggesting that this mechanism may be conserved in humans. Furthermore, treatment with a TRPA-1 agonist increased worm longevity even at warm temperatures, which was not observed by merely overexpressing TRPA-1, emphasizing the role of activated TRPA-1 in promoting longevity.
R. Xiao, B. Zhang, Y. Dong, J. Gong, T. Xu, J. Liu, X. Z. S. Xu, A genetic program promotes C. elegans longevity at cold temperature via a thermosensitive TRP channel. Cell 152, 806–817 (2013). [PubMed]