Ginsenoside component extract of <em>Panax ginseng</em> regulates nuclear-encoded subunits of mitochondrial complexes to rescue age-related cognitive decline

Age-related cognitive decline is strongly linked to mitochondrial dysfunction, particularly the impairment of oxidative phosphorylation (OXPHOS) complexes I, IV, and V. While mitochondrial DNA (mtDNA) mutations have been implicated, a critical gap exists in understanding the role and regulation of nuclear DNA (nDNA)-encoded subunits, which constitute the majority of these complexes and are susceptible to age-related dysregulation. This dysregulation contributes to electron leakage, elevated reactive oxygen species (ROS), and compromised ATP production. <em>Panax ginseng C. A. Mey.</em> (ginseng), a functional food with established neuroprotective properties, contains total ginsenosides (GS) as its main bioactive component. Here, we investigated whether GS ameliorates cognitive aging by specifically targeting the expression of nDNA-encoded OXPHOS subunits. Using naturally aged (21-month-old) and D-galactose-induced aging mouse models, <em>Caenorhabditis elegans </em>(<em>C. elegans.</em>), and a D-gal-induced neuronal senescence cell model, we demonstrate that chronic oral GS administration: (1) restored cognitive function (evidenced by improved hippocampal-dependent memory in open field, novel object recognition, and Morris water maze tests); (2) reduced brain aging markers and glial activation (IBA1, GFAP); (3) enhanced overall healthspan, improving systemic functions (hemoglobin oxygen affinity, neuromuscular coordination, cardiac function, glucose/lipid metabolism); and (4) significantly extended lifespan in <em>C. elegans.</em> Mechanistically, brain transcriptomics revealed GS-mediated activation of OXPHOS pathways, characterized by specific upregulation of nDNA-encoded subunits of complexes I, IV, and V, enhancing mitochondrial membrane potential, ATP production, and reducing ROS. Furthermore, we identified six ginsenoside monomers as key bioactive components capable of reaching the brain, and demonstrated in cell models that Rc, in a SIRT1-dependent manner, potently counteracts D-gal-induced senescence. Our findings establish GS as a mitochondria-targeted functional food component that combats cognitive aging and promotes multi-system healthspan by specifically upregulating nDNA-encoded structural subunits of key OXPHOS complexes, with ginsenoside Rc emerging as a pivotal active ingredient.