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.

Automated summary

The increase in global life expectancy is not accompanied by an increase in health span, requiring a better understanding of age-related decline in behavior. A genome-wide screening in Caenorhabditis elegans identified 34 genes as potential regulators of motor aging, with VPS-34 being crucial in aged but not young worms. This phosphatidylinositol 3-kinase primarily functions in aged motor neurons by regulating neurotransmission, and inhibition of VPS-34 improves motor aging in worms and mice.