Endogenous chondroitin extends the lifespan and healthspan in C. elegans

Abstract

Chondroitin, a class of glycosaminoglycan polysaccharides, is found as proteoglycans in the extracellular matrix, plays a crucial role in tissue morphogenesis during development and axonal regeneration. Ingestion of chondroitin prolongs the lifespan of C. elegans. However, the roles of endogenous chondroitin in regulating lifespan and healthspan mostly remain to be investigated. Here, we demonstrate that a gain-of-function mutation in MIG-22, the chondroitin polymerizing factor (ChPF), results in elevated chondroitin levels and a significant extension of both the lifespan and healthspan in C. elegans. Importantly, the remarkable longevity observed in mig-22(gf) mutants is dependent on SQV-5/chondroitin synthase (ChSy), highlighting the pivotal role of chondroitin in controlling both lifespan and healthspan. Additionally, the mig-22(gf) mutation effectively suppresses the reduced healthspan associated with the loss of MIG-17/ADAMTS metalloprotease, a crucial for factor in basement membrane (BM) remodeling. Our findings suggest that chondroitin functions in the control of healthspan downstream of MIG-17, while regulating lifespan through a pathway independent of MIG-17.

Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans

“…Aged decline in the defecation cycle and pumping rate are often used as indicators of senescence rate in C . elegans [ 11 , 16 , 17 ]. We examined the defecation cycle of wild type and mig-17 mutant animals.…”

“…The cycle was around 50 seconds at the young adult stage (day 1) and extended to 90 seconds until day 5 in the wild type ( Fig 3A–3F ). Although mig-17 mutants showed a cycle comparable to the wild type at day 1, it became significantly longer after day 3 compared to the wild type, suggesting that the senescence rate of mig-17 mutants is faster than that of the wild type ( Fig 3A–3F ) [ 11 ]. We then investigated whether the let-2 and fbl-1 mutants could suppress the mig-17 defect.…”

“…Body length was analyzed as previously described [ 11 ]. Briefly, young adult animals were collected as day 1 adults for synchronization.…”

“…Defecation cycle and pumping rate were analyzed as previously described [ 11 ]. Briefly, average of five defecation cycles were scored for individual animal.…”

“…mig-17 mutants exhibit an earlier decline in periodic behaviors, including the defecation cycle and pumping rate, as well as a decrease in motility rate, and show earlier shortening of body length compared to the wild type. [ 11 ].…”