Knockdown of Indy/CeNac2 extends Caenorhabditis elegans life span by inducing AMPK/aak-2

Abstract

Reducing the expression of the Indy (Acronym for ‘I'm Not Dead, Yet’) gene in lower organisms promotes longevity and leads to a phenotype that resembles various aspects of caloric restriction. In C. elegans, the available data on life span extension is controversial. 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 independent experiments, 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.

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice

“…However, our data are restricted to rodents, and it is unclear whether comparable effects can be observed in humans. Despite this uncertainty, notably comparable findings on lipid accumulation were observed in C. elegans and D. melanogaster [21], [22]. Therefore, the relevance of mINDY appears to be a conserved mechanism, and we believe that further experiments including early human studies are warranted to further investigate the potential of this therapeutic approach.…”

“…Decreased activity of mINDY (or its orthologs) in D. melanogaster and C. elegans increased longevity similarly to caloric restriction and was associated with reduced lipid accumulation in those organisms [11], [20], [21], [22], [40], [41]. mINDY deletion in mice decreased HFD-induced adiposity, lipid accumulation into liver and SKM, and improved insulin sensitivity without affecting caloric intake [16].…”

“…In D. melanogaster and Caenorhabditis elegans , down-regulation of INDY facilitated longevity similar to caloric restriction and resulted in reduced fat storage in flies [11], [20], [21]. We have recently shown in C. elegans that longevity induced by INDY knockdown depends on AMPK [22]. Genetic whole-body deletion of mINDY in mice also led to striking similarities to caloric restriction and protected mice from high-fat diet (HFD)-induced obesity, steatosis hepatis, and IR by increasing energy expenditure, improving hepatic mitochondrial biogenesis, enhancing hepatic FA oxidation, and reducing hepatic lipogenesis [16].…”

The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism

“…Reduced Indy gene expression increases the life span in lower organisms in most, (1,3,4,34) but not all, (35) studies. Moreover, deletion or knockdown of Indy or its homologs leads to a lean phenotype by mechanisms akin to caloric restriction, without a reduction in food intake.…”

“…Reduced Indy (“I am Not Dead, Yet”) gene expression in Drosophila melanogaster and Caenorhabditis elegans promotes longevity in a manner akin to caloric restriction in most studies . Long‐lived flies with lower Indy expression have decreased whole‐body fat stores, lower expression of insulin‐like proteins, and increased mitochondrial number .…”