Investigating the INDY Longevity Gene in Nematodes

Researchers here fill in some of the gaps regarding the action of the INDY gene on longevity in nematode worms, suggesting that its effects largely arise due to its influence on the nematode version of AMPK, now also well known to be involved in the relationship between metabolism and natural variations in longevity. INDY (I'm Not Dead Yet) was one of the earliest longevity genes to be discovered, uncovered in fly studies. It is a mark of the complexity of cellular biochemistry, in which every system interacts with every other system, that researchers are still tracing mechanisms and signals to establish how exactly manipulations of INDY work to extend longevity.

Reduced expression of the Indy gene in Drosophila melanogaster promotes longevity in most studies. The underlying mechanisms recapitulate multiple characteristics of caloric restriction, i.e. reduced in body fat, insulin like proteins, and increased mitochondrial biogenesis, along with the activation of FOXO and the co-transcriptional regulator PGC-1α. Interestingly, food intake in the long lived, Indy mutant flies is not reduced. Knocking down the Indy homolog CeNAC2 in C. elegans also promotes a moderate increase in lifespan in one study, while another study failed to observe the phenotype. Whether or not the knockdown of CeNAC2 really promotes longevity and by which mechanism remains unclear.

Therefore, the aim of this study was to determine the role of the C. elegans INDY homolog CeNAC2 in life span regulation and to delineate possible molecular mechanisms. siRNA against Indy/CeNAC2 was used to reduce expression of Indy/CeNAC2. Mean life span was assessed in four independents, as well as whole body fat content and AMPK activation. Moreover, the effect of Indy/CeNAC2 knockdown in C. elegans with inactivating variants of AMPK (TG38) was studied.

Knockdown of Indy/CeNAC2 increased life span by 22±3 % compared to control siRNA treated C. elegans, together with a decrease in whole body fat content by ~50%. Indy/CeNAC2 reduction also increased the activation of the intracellular energy sensor AMPK/aak2. In worms without functional AMPK/aak2, life span was not extended when Indy/CeNAC2 was reduced. Inhibition of glycolysis with deoxyglucose, an intervention known to increase AMPK/aak2 activity and life span, did not promote longevity when Indy/CeNAC2 was knocked down. Together, these data indicate that reducing the expression of Indy/CeNAC2 increases life span in C. elegans, an effect mediated at least in part by AMPK/aak2.



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