Partial inhibition of class III PI3K VPS-34 ameliorates motor aging and prolongs health span.

Global increase of life expectancy is rarely accompanied by increased health span, calling for a greater understanding of age-associated behavioral decline. Motor independence is strongly associated with the quality of life of elderly people, yet the regulators for motor aging have not been systematically explored. Here, we designed a fast and efficient genome-wide screening assay in Caenorhabditis elegans and identified 34 consistent genes as potential regulators of motor aging. Among the top hits, we found VPS-34, the class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI(3)P), regulates motor function in aged but not young worms. It primarily functions in aged motor neurons by inhibiting PI(3)P-PI-PI(4)P conversion to reduce neurotransmission at the neuromuscular junction (NMJ). Genetic and pharmacological inhibition of VPS-34 improve neurotransmission and muscle integrity, ameliorating motor aging in both worms and mice. Thus, our genome-wide screening revealed an evolutionarily conserved, actionable target to delay motor aging and prolong health span.

Ketogenic diet reshapes cancer metabolism through lysine ß-hydroxybutyrylation.

Lysine ß-hydroxybutyrylation (Kbhb) is a post-translational modification induced by the ketogenic diet (KD), a diet showing therapeutic effects on multiple human diseases. Little is known how cellular processes are regulated by Kbhb. Here we show that protein Kbhb is strongly affected by the KD through a multi-omics analysis of mouse livers. Using a small training dataset with known functions, we developed a bioinformatics method for the prediction of functionally important lysine modification sites (pFunK), which revealed functionally relevant Kbhb sites on various proteins, including aldolase B (ALDOB) Lys108. KD consumption or ß-hydroxybutyrate supplementation in hepatocellular carcinoma cells increases ALDOB Lys108bhb and inhibits the enzymatic activity of ALDOB. A Kbhb-mimicking mutation (p.Lys108Gln) attenuates ALDOB activity and its binding to substrate fructose-1,6-bisphosphate, inhibits mammalian target of rapamycin signalling and glycolysis, and markedly suppresses cancer cell proliferation. Our study reveals a critical role of Kbhb in regulating cancer cell metabolism and provides a generally applicable algorithm for predicting functionally important lysine modification sites.