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

Abstract

Summary Interventions that delay ageing mobilize mechanisms that protect and repair cellular components1–3, but it is unknown how these interventions might slow the functional decline of extracellular matrices4,5, which are also damaged during ageing6,7. 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 adulthood2,8,9, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits1,10,11. 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 longevity12–14, 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.