Ginsenoside Rg3 Promotes Healthy Aging Through Phosphoinositide-Associated Lysosomal Regulation in Caenorhabditis...

Lysosomal decline and proteostasis collapse are defining features of aging and major contributors to neurodegenerative vulnerability, yet interventions that preserve neuronal lysosomal function across aging remain poorly defined. Here, we identify 20(S)-ginsenoside Rg3, a ginseng-derived natural product, as a geroprotective small molecule in Caenorhabditis elegans. Rg3 extended lifespan and preserved key physiological outputs, including locomotion and pharyngeal pumping, indicating that Rg3 delays functional aging. Rg3 also maintained mechanosensory neuron integrity and touch sensitivity, suppressed neuronal polyglutamine aggregation, and protected dopaminergic neurons against α-synuclein-induced degeneration. At the cellular level, Rg3 restored age-impaired lysosomal function and autophagic flux in neurons. Mechanistically, Rg3 shifted neuronal phosphoinositide reporter signatures toward a PI(4)P-enriched and PI(3)P-reduced state, consistent with signaling lipid remodeling at lysosomal membranes. This phosphoinositide shift coincided with reduced RSKS-1/S6K phosphorylation, indicating suppression of TOR complex 1 (TORC1), and promoted nuclear localization of HLH-30, the C. elegans ortholog of transcription factor EB (TFEB), thereby engaging a conserved lysosomal program. Collectively, these results define Rg3 as a natural-product geroprotector that couples lysosomal lipid remodeling to TORC1-HLH-30 signaling to preserve lysosomal competence, neuronal proteostasis, and organismal fitness during aging. Our study nominates phosphoinositide control of lysosomal identity as a therapeutic entry point for healthy aging and neuroprotection.