Molecular genetic studies on factors that regulate aging affected by dietary glucose and by mitochondrial respiration in C. elegans

Abstract

Aging is a biological process that gradually decrease physical functions. Various environmental and genetic factors regulate aging. In this study, my colleagues and I characterize factors that mediates excessive dietary glucose-mediated accelerated aging and longevity conferred by mitochondrial respiration mutation. Glucose is a major nutrient for making energy but feeding excessive glucose or abnormal glucose metabolism associate with several diseases, such as diabetes, obesity, and cardiovascular disease. Therefore, glucose metabolism should be tightly regulated. Here, I show that Lipin1/lpin-1, a phosphatidic phosphatase, is required for preventing lifespan-shortening effect of dietary glucose through an RNAi-based lifespan screen. My colleague and I then show that levels of ω-6 polyunsaturated fatty acids (PUFAs), including linoleic acid and arachidonic acid, are increased by lpin-1 RNAi but glucose feeding decrease the high levels of the PUFAs. I next show that supplementation of linoleic acid and arachidonic acid restores the short lifespan of lpin-1 RNAi-treated worms on glucose-rich diets. Overall, this study shed lights on how LPIN-1 prevents glucose toxicity by regulating proper ω-6 metabolism during aging. The Golgi apparatus plays a crucial role in trafficking of macromolecules such as proteins and lipids. Defects in the Golgi apparatus associates with diseases, but how the Golgi affects organismal longevity remains unclear. By performing a quantitative proteomics, our group previously found that a Golgi protein, MON-2, was required for the long lifespan of diverse interventions. I show that knockdown of snx-3 (sorting nexin 3) and tbc-3 (an ortholog of human TBC1D22A implicated in transport between endosomes and the Golgi) also shorten the long lifespan of mitochondrial mutants, suggesting that the role of MON-2 in trafficking between the Golgi and endosome contributes to the longevity. My colleague and I show that MON-2 is required for upregulating autophagy in respiration mutants. Thus, inter-organellar communication between the Golgi, endosome, and autophagosome contributes to regulation of longevity.