4.6 Article

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

Journal

PLOS BIOLOGY
Volume 21, Issue 7, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3002165

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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.
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.

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