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

Ewald CY, Landis JN, Porter Abate J, Murphy CT, Blackwell TK - Nature (2014)

Bottom Line: When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes.These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits.The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.

View Article: PubMed Central - PubMed

Affiliation: 1] Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA [2] Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA [3] Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02215, USA.

ABSTRACT
Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, 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 genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix 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 extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.

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Analyses of SKN-1-regulated daf-2(−) genesa–f, SKN-1-upregulated (a–c) and downregulated (d–f) daf-2(−) gene sets were examined by hierarchical clustering to determine how they were previously found to be affected by SKN-1 under unstressed or oxidative stress conditions18. t-BOOH= tert-butyl hydroperoxide. g, Proportional Venn diagrams show comparisons of SKN-1-upregulated genes identified under daf-2(−), normal, or arsenite treatment conditions18 (Supplementary Tabel 7). In each case, L4 larvae were analysed to avoid embryogenesis effects. Heatmaps are shown in (a-f). h, The SKN-1-upregulated daf-2(−) collagen col-89 is expressed in neurons and the intestine, but not in hypodermis. Transgenic Pcol-89::GFP (BC12533) at day 8 of adulthood is shown. Anterior to the left, ventral side down, scale bar = 100 µm. i-k, SKN-1-mediated collagen gene activation in day 8 daf-2(RNAi) adults. Adulthood daf-2 knockdown (i) activated a Pcol-12::dsRED reporter (j; Scale bar = 100 µm). (k). skn-1-dependence of Pcol-12::dsRED expression. EV: empty RNAi vector. N> 60 for each condition, 3 merged trials, with P value by chi2 (*=P<0.05; ***=P<0.0001; n.s.= not significant).
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Figure 7: Analyses of SKN-1-regulated daf-2(−) genesa–f, SKN-1-upregulated (a–c) and downregulated (d–f) daf-2(−) gene sets were examined by hierarchical clustering to determine how they were previously found to be affected by SKN-1 under unstressed or oxidative stress conditions18. t-BOOH= tert-butyl hydroperoxide. g, Proportional Venn diagrams show comparisons of SKN-1-upregulated genes identified under daf-2(−), normal, or arsenite treatment conditions18 (Supplementary Tabel 7). In each case, L4 larvae were analysed to avoid embryogenesis effects. Heatmaps are shown in (a-f). h, The SKN-1-upregulated daf-2(−) collagen col-89 is expressed in neurons and the intestine, but not in hypodermis. Transgenic Pcol-89::GFP (BC12533) at day 8 of adulthood is shown. Anterior to the left, ventral side down, scale bar = 100 µm. i-k, SKN-1-mediated collagen gene activation in day 8 daf-2(RNAi) adults. Adulthood daf-2 knockdown (i) activated a Pcol-12::dsRED reporter (j; Scale bar = 100 µm). (k). skn-1-dependence of Pcol-12::dsRED expression. EV: empty RNAi vector. N> 60 for each condition, 3 merged trials, with P value by chi2 (*=P<0.05; ***=P<0.0001; n.s.= not significant).

Mentions: SKN-1 has conserved functions in stress defence, protein homeostasis, and metabolism12,18,19 and was required for daf-2 oxidative stress resistance (Supplementary Table 6)13, but only 40/429 SKN-1-upregulated daf-2(−) genes had been identified under normal or stress conditions (Extended Data Fig. 3a–g; Supplementary Table 7)18. Unexpectedly, by far the most overrepresented functional group within the SKN-1-upregulated daf-2(−) gene set consisted of collagen genes, which seemed to be regulated by SKN-1 indirectly (Fig. 2a, Supplementary Table 3, 8, and 9). In humans, collagens constitute about 1/3 of all protein and accumulate damage during ageing, leading to functional decline in tissues throughout the body6,7. C. elegans collagens form basement membranes as well as the cuticle, a complex structure that covers the animal, lines the buccal cavity, pharynx, and rectum, and becomes thickened and wrinkled with age20. The SKN-1-upregulated daf-2(−) collagens are of the type that forms the cuticle, but are expressed in multiple tissues (Extended Data Fig. 3h; Supplementary Table 9). Collagen production decreases in human skin during ageing21, and 27 SKN-1-upregulated daf-2(−) collagens are among a set of genes that decline in expression as C. elegans ages22 (Supplementary Table 10). These and other collagens were prominently upregulated in each of 20 C. elegans longevity-associated gene sets we examined (Extended Data Table 2; Supplementary Table 10). Moreover, in mice extracellular matrix genes were overrepresented in some longevity or Nrf2-dependent sets (Supplementary tables 11, 12), and in silico analysis of longevity-associated genes identified a predicted ECM network23. The possible significance of these expression signatures has not been explored.


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

Ewald CY, Landis JN, Porter Abate J, Murphy CT, Blackwell TK - Nature (2014)

Analyses of SKN-1-regulated daf-2(−) genesa–f, SKN-1-upregulated (a–c) and downregulated (d–f) daf-2(−) gene sets were examined by hierarchical clustering to determine how they were previously found to be affected by SKN-1 under unstressed or oxidative stress conditions18. t-BOOH= tert-butyl hydroperoxide. g, Proportional Venn diagrams show comparisons of SKN-1-upregulated genes identified under daf-2(−), normal, or arsenite treatment conditions18 (Supplementary Tabel 7). In each case, L4 larvae were analysed to avoid embryogenesis effects. Heatmaps are shown in (a-f). h, The SKN-1-upregulated daf-2(−) collagen col-89 is expressed in neurons and the intestine, but not in hypodermis. Transgenic Pcol-89::GFP (BC12533) at day 8 of adulthood is shown. Anterior to the left, ventral side down, scale bar = 100 µm. i-k, SKN-1-mediated collagen gene activation in day 8 daf-2(RNAi) adults. Adulthood daf-2 knockdown (i) activated a Pcol-12::dsRED reporter (j; Scale bar = 100 µm). (k). skn-1-dependence of Pcol-12::dsRED expression. EV: empty RNAi vector. N> 60 for each condition, 3 merged trials, with P value by chi2 (*=P<0.05; ***=P<0.0001; n.s.= not significant).
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Figure 7: Analyses of SKN-1-regulated daf-2(−) genesa–f, SKN-1-upregulated (a–c) and downregulated (d–f) daf-2(−) gene sets were examined by hierarchical clustering to determine how they were previously found to be affected by SKN-1 under unstressed or oxidative stress conditions18. t-BOOH= tert-butyl hydroperoxide. g, Proportional Venn diagrams show comparisons of SKN-1-upregulated genes identified under daf-2(−), normal, or arsenite treatment conditions18 (Supplementary Tabel 7). In each case, L4 larvae were analysed to avoid embryogenesis effects. Heatmaps are shown in (a-f). h, The SKN-1-upregulated daf-2(−) collagen col-89 is expressed in neurons and the intestine, but not in hypodermis. Transgenic Pcol-89::GFP (BC12533) at day 8 of adulthood is shown. Anterior to the left, ventral side down, scale bar = 100 µm. i-k, SKN-1-mediated collagen gene activation in day 8 daf-2(RNAi) adults. Adulthood daf-2 knockdown (i) activated a Pcol-12::dsRED reporter (j; Scale bar = 100 µm). (k). skn-1-dependence of Pcol-12::dsRED expression. EV: empty RNAi vector. N> 60 for each condition, 3 merged trials, with P value by chi2 (*=P<0.05; ***=P<0.0001; n.s.= not significant).
Mentions: SKN-1 has conserved functions in stress defence, protein homeostasis, and metabolism12,18,19 and was required for daf-2 oxidative stress resistance (Supplementary Table 6)13, but only 40/429 SKN-1-upregulated daf-2(−) genes had been identified under normal or stress conditions (Extended Data Fig. 3a–g; Supplementary Table 7)18. Unexpectedly, by far the most overrepresented functional group within the SKN-1-upregulated daf-2(−) gene set consisted of collagen genes, which seemed to be regulated by SKN-1 indirectly (Fig. 2a, Supplementary Table 3, 8, and 9). In humans, collagens constitute about 1/3 of all protein and accumulate damage during ageing, leading to functional decline in tissues throughout the body6,7. C. elegans collagens form basement membranes as well as the cuticle, a complex structure that covers the animal, lines the buccal cavity, pharynx, and rectum, and becomes thickened and wrinkled with age20. The SKN-1-upregulated daf-2(−) collagens are of the type that forms the cuticle, but are expressed in multiple tissues (Extended Data Fig. 3h; Supplementary Table 9). Collagen production decreases in human skin during ageing21, and 27 SKN-1-upregulated daf-2(−) collagens are among a set of genes that decline in expression as C. elegans ages22 (Supplementary Table 10). These and other collagens were prominently upregulated in each of 20 C. elegans longevity-associated gene sets we examined (Extended Data Table 2; Supplementary Table 10). Moreover, in mice extracellular matrix genes were overrepresented in some longevity or Nrf2-dependent sets (Supplementary tables 11, 12), and in silico analysis of longevity-associated genes identified a predicted ECM network23. The possible significance of these expression signatures has not been explored.

Bottom Line: When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes.These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits.The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.

View Article: PubMed Central - PubMed

Affiliation: 1] Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA [2] Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA [3] Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02215, USA.

ABSTRACT
Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, 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 genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix 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 extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.

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