Like humans, the nematode Caenorhabditis elegans suffers locomotory decline as it ages. Slowing of movement on plates or in liquid parallels a physical decline of bodywall muscle that involves loss of sarcomeres. Since C. elegans muscle decline has cellular features strikingly similar to human muscle decline, we have been interested in defining genetic influences on this process. We have shown that down-regulation of insulin signaling prolongs muscle healthspan at the behavioral and cellular levels. It is interesting that the C. elegans genome encodes nearly a score of insulin-like proteins, but has only one readily identifiable insulin-like receptor(INSR), DAF-2. Dlakic previously published sequence profile searches that identified 54 putative INSR-like proteins in C. elegans . These likely secreted extracellular proteins are related to INSR in ligand binding domains, but lack transmembrane domains and the cytoplasmic kinase domain. Whether these proteins impact insulin signaling, lifespan or healthspan is unknown. Here we report on the analysis of INSR-related proteins on locomotory aging in C. elegans. To test whether insulin receptor-related genes had any role in locomotory decline, we used feeding RNAi to disrupt the 32 INSR-related genes in the Ahringer library and 22 self-constructed INSR-related genes. We scored the frequency of body bends during swimming for young adults and for aged (11 day old) animals. We identified at least two receptor-related protein genes for which RNAi conferred a significantly higher index of movement than control animals at old age. RNAi for these INSR-like genes did not cause hyperactive swimming in young adults. Thus, these two INSR-related proteins normally promote age-associated muscle decline. Inactivation of either of these INSR-related genes extends lifespan modestly. Decreased
daf-2 signaling promotes DAF-16 transcriptional functions and causes lifespan extension that depends on
daf-16 gene activity. We found that the
daf-16 mutation accelerates the decline in swimming during aging. Interestingly, however, RNAi inactivation of the two receptor-related proteins still delayed the decline swimming in
daf-16 mutants. Moreover, inactivation either of the two receptor-related genes further improved the swimming healthspan of
age-1 mutants. These results suggest that the effects of insulin receptor-related gene inactivations are independent of the canonical insulin signaling pathway and
daf-16 gene activity. We now are investigating the DAF16-independent pathway by which the two INSR-related proteins modulate the muscle healthspan.