Abstract
Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates—metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI’s anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.
Highlights
Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality
We define MI metabolic pathway as the reactions forming an unbroken chain with MI upstream or downstream as annotated by the three KEGG pathways: Inositol phosphate metabolism, Phosphatidylinositol signaling system and Glycosylphosphatidylinositol (GPI)-anchor biosynthesis
To avoid the strong osmotic stress associated with these concentrations, we performed further analysis to delineate its molecular pathways at 50 mM MI in downstream experiments, which extended worm mean lifespan by 14% (p < 0.01, Fig. 1b)
Summary
Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Abnormally high levels of PI(3,4,5)P3, a key lipid component in the insulin and insulin-like growth factor signaling pathway (IIS), is known to promote cancer and shorten lifespan through activation of AKT in mouse/mammals[27] Another derivative, IP7 is reported to inhibit AKT in mouse[28], but has not been reported to influence aging. Both PI(3,4,5)P3 and IP7 in aging were indirectly studied by perturbations of their synthases, i.e., loss of function (LOF) of worm Phosphatidylinositol 3-kinase (age-1)[29], mouse liver phosphatidylinositol-4,5-bisphosphate 3kinase (Pi3k)[30] and LOF of inositol hexaphosphate kinase (Ip6k1) in mouse[28], respectively. It remains unknown whether or how the other derivatives influence aging
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