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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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Adulthood knockdown of collagens important for longevity does not affect morphology of cuticle-associated structuresa, Schematic cross-section of C. elegans illustrating the proximity of the cuticle (black), hypodermis (red), basal lamina (blue), and bodywall muscles (purple). Annuli, Furrow, and Alae are characteristic cuticle structures. b-j, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect cuticle morphology. b-f, One-day old wild-type animals were exposed to either empty vector (control) or the indicated RNAi clone by feeding. 10 days later animals were incubated in DiI for 16 hours, the cuticle was imaged as described in92. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm. g-j, Cuticle morphology revealed by the collagen COL-19, detected by a translational fusion protein (kaIs12 [COL-19::GFP]). We did not identify col-19 as being regulated by daf-2 and skn-1, and daf-2(RNAi) did not detectably alter COL-19::GFP levels (not shown). k-n, Adulthood knockdown of SKN-1-upregulated daf-2(−) collagens does not affect the pattern of chEx1682 QUA-1::GFP, a marker of cuticle adhesion. QUA-1 encodes a hedgehog related protein required for molting, cuticle adhesion, and alae formation42. o-r, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect the pattern of muscle-hypodermis-cuticle adhesion, as indicated by upIs1 MUP-4::GFP. MUP-4 is a transmembrane protein that is part of a complex that attaches hypodermis and muscles to the cuticle35. s-v, Adulthood collagen knockdown does not affect mitochondrial morphology in muscle. For g-v, animals where placed on RNAi at the first day of adulthood and scored and imaged at day 8 of adulthood. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm.
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Figure 9: Adulthood knockdown of collagens important for longevity does not affect morphology of cuticle-associated structuresa, Schematic cross-section of C. elegans illustrating the proximity of the cuticle (black), hypodermis (red), basal lamina (blue), and bodywall muscles (purple). Annuli, Furrow, and Alae are characteristic cuticle structures. b-j, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect cuticle morphology. b-f, One-day old wild-type animals were exposed to either empty vector (control) or the indicated RNAi clone by feeding. 10 days later animals were incubated in DiI for 16 hours, the cuticle was imaged as described in92. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm. g-j, Cuticle morphology revealed by the collagen COL-19, detected by a translational fusion protein (kaIs12 [COL-19::GFP]). We did not identify col-19 as being regulated by daf-2 and skn-1, and daf-2(RNAi) did not detectably alter COL-19::GFP levels (not shown). k-n, Adulthood knockdown of SKN-1-upregulated daf-2(−) collagens does not affect the pattern of chEx1682 QUA-1::GFP, a marker of cuticle adhesion. QUA-1 encodes a hedgehog related protein required for molting, cuticle adhesion, and alae formation42. o-r, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect the pattern of muscle-hypodermis-cuticle adhesion, as indicated by upIs1 MUP-4::GFP. MUP-4 is a transmembrane protein that is part of a complex that attaches hypodermis and muscles to the cuticle35. s-v, Adulthood collagen knockdown does not affect mitochondrial morphology in muscle. For g-v, animals where placed on RNAi at the first day of adulthood and scored and imaged at day 8 of adulthood. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm.

Mentions: Adulthood collagen RNAi did not affect body size, detectably impair cuticle function, or increase markers of various stresses (Extended Data Fig. 5a–v, 6a–i). Collagen RNAi sensitized to exogenous oxidative stress, however, and increased the prominence of ageing markers in daf-2 mutants at 15°C, and in rapamycin-treated animals (Fig. 4a, 4b, Extended Data Fig. 6j–m; Supplementary Table 16). Apparently, knockdown of these collagens interfered with the capacity of these interventions to delay ageing.


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

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

Adulthood knockdown of collagens important for longevity does not affect morphology of cuticle-associated structuresa, Schematic cross-section of C. elegans illustrating the proximity of the cuticle (black), hypodermis (red), basal lamina (blue), and bodywall muscles (purple). Annuli, Furrow, and Alae are characteristic cuticle structures. b-j, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect cuticle morphology. b-f, One-day old wild-type animals were exposed to either empty vector (control) or the indicated RNAi clone by feeding. 10 days later animals were incubated in DiI for 16 hours, the cuticle was imaged as described in92. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm. g-j, Cuticle morphology revealed by the collagen COL-19, detected by a translational fusion protein (kaIs12 [COL-19::GFP]). We did not identify col-19 as being regulated by daf-2 and skn-1, and daf-2(RNAi) did not detectably alter COL-19::GFP levels (not shown). k-n, Adulthood knockdown of SKN-1-upregulated daf-2(−) collagens does not affect the pattern of chEx1682 QUA-1::GFP, a marker of cuticle adhesion. QUA-1 encodes a hedgehog related protein required for molting, cuticle adhesion, and alae formation42. o-r, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect the pattern of muscle-hypodermis-cuticle adhesion, as indicated by upIs1 MUP-4::GFP. MUP-4 is a transmembrane protein that is part of a complex that attaches hypodermis and muscles to the cuticle35. s-v, Adulthood collagen knockdown does not affect mitochondrial morphology in muscle. For g-v, animals where placed on RNAi at the first day of adulthood and scored and imaged at day 8 of adulthood. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm.
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Figure 9: Adulthood knockdown of collagens important for longevity does not affect morphology of cuticle-associated structuresa, Schematic cross-section of C. elegans illustrating the proximity of the cuticle (black), hypodermis (red), basal lamina (blue), and bodywall muscles (purple). Annuli, Furrow, and Alae are characteristic cuticle structures. b-j, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect cuticle morphology. b-f, One-day old wild-type animals were exposed to either empty vector (control) or the indicated RNAi clone by feeding. 10 days later animals were incubated in DiI for 16 hours, the cuticle was imaged as described in92. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm. g-j, Cuticle morphology revealed by the collagen COL-19, detected by a translational fusion protein (kaIs12 [COL-19::GFP]). We did not identify col-19 as being regulated by daf-2 and skn-1, and daf-2(RNAi) did not detectably alter COL-19::GFP levels (not shown). k-n, Adulthood knockdown of SKN-1-upregulated daf-2(−) collagens does not affect the pattern of chEx1682 QUA-1::GFP, a marker of cuticle adhesion. QUA-1 encodes a hedgehog related protein required for molting, cuticle adhesion, and alae formation42. o-r, Adulthood RNAi against SKN-1-upregulated daf-2(−) collagens does not affect the pattern of muscle-hypodermis-cuticle adhesion, as indicated by upIs1 MUP-4::GFP. MUP-4 is a transmembrane protein that is part of a complex that attaches hypodermis and muscles to the cuticle35. s-v, Adulthood collagen knockdown does not affect mitochondrial morphology in muscle. For g-v, animals where placed on RNAi at the first day of adulthood and scored and imaged at day 8 of adulthood. N>30 animals per condition scored, with typical images shown. Scale bar = 10 µm.
Mentions: Adulthood collagen RNAi did not affect body size, detectably impair cuticle function, or increase markers of various stresses (Extended Data Fig. 5a–v, 6a–i). Collagen RNAi sensitized to exogenous oxidative stress, however, and increased the prominence of ageing markers in daf-2 mutants at 15°C, and in rapamycin-treated animals (Fig. 4a, 4b, Extended Data Fig. 6j–m; Supplementary Table 16). Apparently, knockdown of these collagens interfered with the capacity of these interventions to delay ageing.

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.

Show MeSH
Related in: MedlinePlus