Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity

Summary

Interventions that delay ageing mobilize mechanisms that protect and repair cellular components ^{1– 3} , but it is unknown how these interventions might slow the functional decline of extracellular matrices ^{4, 5} , which are also damaged during ageing ^{6, 7} . Reduced Insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile C. elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions ( Supplementary Discussion) ^{1, 2} . It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood ^{2, 8, 9} , but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits ^{1, 10, 11} . Here we show that rIIS can promote C. elegans longevity through an program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) ortholog SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity ^{12– 14} , but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix (ECM) genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood ECM remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that ECM remodelling is a generally essential signature of longevity assurance, and that agents promoting ECM youthfulness may have systemic benefit.