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

Abstract

SummaryInterventions 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.

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…56 Furthermore, Nrf2 signaling has been documented to confer resistance to oxidative stress and promote healthy aging in Caenorhabditis elegans. 57,58 Reduced activation of Nrf2 in aging has been reported to be associated with various chronic diseases, such as progressive respiratory disease, neurodegeneration, and inflammatory disorders. 59 Age-dependent decline in the levels and/or activation of Nrf2 is accompanied by reduced expression of cytoprotective genes and increased susceptibility to oxidative injury.…”

SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat

“…Genes with significant changes in expression (P < 0.05, fold change >1.2) (Yao et al 2015) were further analyzed, and genes whose FPKM (fragments per kilobase of transcript per million fragments) was zero were excluded. Scatter plot (Riedel et al 2013) and heat map analyses (Ewald et al 2015) were performed as previously described. Heat maps were generated by using Cluster 3.0 (Eisen et al 1998) and Java Treeview (Saldanha 2004).…”

SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST-4) by EGF signaling

“…8 Regulatory integration through SKN-1 is now believed to continuously coordinate ER, mitochondrial and cytoplasmic homeostasis. 2,9 As is easily understood from its biochemical functions, SKN-1/Nrf activation plays an important and often essential role in multiple lifespan-extending interventions such as dietary restriction (DR), 10 reduced insulin/IGF-1 signaling (IIS) 4 and others 7,[11][12][13][14][15][16] As such, when a new longevity-promoting compound or longlived mutant is identified, SKN-1 transcriptional activity is often assayed to evaluate whether this transcription factor mediates the effects of said mutation or compound. While the in vivo transcriptional activity of other longevity-associated transcription factors such as the IIS transcription factor DAF-16/FOXO can easily be visualized using direct translational GFP reporters in C. elegans, 17,18 for SKN-1 this can be a more challenging task due to a rather low expression level of its reporter fusion protein.…”