The precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and higher rates of mortality. Anti-aging targeted small molecule screens have been carried outperformed 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 conserved metabolite through eEukaryotes-conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggestsed 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. However, the mechanism study shows itslongevity effects could be fully blocked by a null-allele mutation of the tumor suppressor gene, daf-18 (homologous to mouse Pten), areand was independent of its classical pathway downstream elements, akt or daf-16., but Instead, we found MI effects on aging were dependent on its downstream mitophagy regulator pink-1. MI’s anti-aging effect is was also conserved in mouse model, implicatingindicating a conserved mechanism in mammals that may extend to human. Myo-inositol (MI) was used in both worm and mouse. For worm experiment, 50mM MI was used from adult day 1. Two strains were used in worm experiment, N2 and daf-18-null-allele (ok480). Sample on N2 without any treatment on adult day 4 was also collected. All the other samples were collected on adult day 10. For mouse experiment, female C57BL/6J mice were treated with 580 mg MI per kg bodyweight by gavage, twice per week, from 9 months of age to 12 months. Muscle tissue were used for RNA extraction and sequencing. 3-month-old mice were also used as young control samples. All the other samples were collected in 12-month-old mice.