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Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity in C. elegans

ABSTRACT: Although it is postulated that dysfunctional extracellular matrices (ECM) drive aging and disease, how ECM integrity assures longevity is unknown. Here, using proteomics and in-vivo monitoring of fluorescently tagged ECM proteins, we systematically examined the ECM composition during Caenorhabditis elegans aging revealing three distinct collagen dynamics. We show that age-dependent stiffening of inert collagen was slowed by longevity interventions through prolonged replenishing of collagens. In genetic and automated lifespan screens for the regulators that drive this remodeling, we identify hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression across tissues. The hemidesmosome tension-induced adaptation is mediated via transcriptional co-activator YAP. Our data reveal a novel mechanism of mechano-coupling and synchronizing of two functionally distinct and spatially distant ECMs that is indispensable for longevity. Thus, besides signaling molecules, mechanotransduction-coordinated ECM remodeling systemically promotes healthy aging.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Andrea Fossati

LAB HEAD: Ewald Colin

PROVIDER: PXD046470 | Pride | 2023-11-16

REPOSITORIES: Pride

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Source:

			Action	DRS
	20200811_204213_2020_0508_C_elegans_Report.tsv	Tabular
	UP000001940_6239.fasta.gz	Fasta.gz
	anfossat_I20628_009.wiff	Wiff
	anfossat_I20628_009.wiff.scan	Wiff
	anfossat_I20628_010.wiff	Wiff

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Project description:One of the most important issues in the study of aging is to discover compounds with longevity-promoting activity and to unravel their underlying mechanisms. Queen honey bees are continuously fed royal jelly (RJ), and they live more than 10 times longer than hive workers, derived from the same diploid genome, which are fed it only for a short period of time during their larval stages. Therefore, RJ is likely to contain longevity-promoting agents for queens. RJ has been reported to possess diverse pharmacological properties. Furthermore, protease-treated RJ (pRJ) has additional beneficial activities. How RJ and pRJ exert these effects and which components in them play a critical role is largely unknown. The evolutionally conserved mechanisms that control lifespan have been indicated. The nematode Caenorhabditis elegans has been widely used for study of aging and longevity, due to its relatively short lifespan and well-established genetic pathways. The purpose of the present study was to elucidate whether RJ and its related substances contain the life span-extending activity in C. elegans and to obtain some insight into the active agents and their mechanisms. We found that both RJ and pRJ extended the lifespan of C. elegans. The life span-extending activity of pRJ was enriched by ODS column chromatography (pRJ-Fraction 5). pRJ-Fr. 5 extended the life span partly by acting through the FOXO transcription factor DAF-16, the activation of which is known to promote longevity in C. elegans by reducing insulin/IGF-1 signaling (IIS). pRJ-Fr. 5 induced changes in the expression of 3 genes encoding insulin-like peptides. Moreover, pRJ-Fr. 5 and reduced IIS shared some common features in terms of their effect on gene expression, such as up-regulation of dod-3 and down-regulation of dod-19, dao-4 and fkb-4. The dod-19 is a previously identified life span determinant in C. elegans, and the fkb-4 encodes a homologue of the mammalian FK506-binding protein. 10-Hydroxy-2-decenoic acid (10-HDA), which was present in high concentration in pRJ-Fr. 5, increased the lifespan independently of DAF-16 activity.These results demonstrate that RJ and its related substances extended the life span in C. elegans, suggesting that RJ may contain longevity-promoting factors common to diverse species across phyla. pRJ-Fr. 5 had higher life span-extending activity than either RJ or pRJ and extended the life span in part through the IIS-DAF-16 pathway. We provide the first evidence that 10-HDA, a defined natural product in RJ, extended organismal lifespan. It is noteworthy that 10-HDA performed its lifespan-extending function through a mechanism totally different from the IIS-DAF-16 pathway. Further search and characterization of the lifespan-extending agents in RJ and pRJ may broaden our understanding of the gene network of longevity regulation in diverse species and provide the possibility for nutraceutical interventions in the aging process. C. elegans N2 hermaphrodites were untreated or treated with pRJ-Fr. 5 (25mg/ml) for 24 h starting at the larval 4 (L4) stage.

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Mechanotransduction coordinates extracellular matrix protein homeostasis promoting longevity in C. elegans

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