Aging exerts a major influence on the brain and acts as the leading contributor to neurodegenerative conditions, primarily via pathways involving mitochondrial impairment. Although this connection holds substantial clinical importance, the underlying molecular processes are not fully understood, and there is an immediate demand for safe and potent treatments. In this work, we explored the neuroprotective capabilities of ginseng by screening blood-brain barrier-crossing saponins for superior protective effects and pinpointed ginsenoside Re (Re) as the main mitochondrially directed neuroprotective component. Administering Re during midlife, coinciding with the natural phase of mitochondrial hyperfusion, effectively countered age-associated degenerative changes in Drosophila. Re treatment reduced the loss of dopaminergic neurons, lessened muscle deterioration, enhanced cognitive and motor performance, and prolonged healthspan. Mechanistic investigations showed that Re binds directly to Drp1 from various species at the highly conserved L94 site, promoting strong phosphorylation at S616. This modification facilitates Drp1 movement to mitochondria, rebalancing fission and fusion dynamics. Additionally, Re coordinated fission with mitophagy via the Drp1-Atg1/ULK1 pathway, supporting autophagosome formation and the efficient removal of impaired organelles. This combined action boosted cellular energy production and slowed functional deterioration. Removing the L94 residue in Drp1 through genetic means eliminated Re’s protective outcomes, while studies in mice verified that healthspan benefits depended on functional Drp1-L94. Importantly, Re retained its neuroprotective effects in human iPSC-derived dopaminergic neurons and a Drosophila Parkinson’s disease model, highlighting the evolutionary conservation of the Drp1-mitophagy mechanism. These results position Re as a geroprotective agent that acts on the conserved Drp1-L94 residue to reinstate mitochondrial balance. By linking fission to Atg1-driven mitophagy specifically during the critical midlife hyperfusion period, Re postpones neurodegeneration and offers a molecular foundation for therapies aimed at age-related deterioration.
