The chemically defined herbal mixture ADAPT-232 delays mitochondrial dysfunction and promotes healthspan through mitophagy-related pathways mediated by the DAF-16/NHR-49 axis

• The adaptogenic combination ADAPT-232 restores mitochondrial function under glucose stress. • The ADAPT-232 activates mitophagy and lipid-catabolic pathways to improve metabolic balance. • The formula enhances healthspan via coordinated DAF-16/NHR-49 signaling. Mitochondrial dysfunction and metabolic imbalance are major contributors to the progression of age-related disorders, including cardiovascular diseases. Current therapeutic strategies increasingly focus on preserving mitochondrial integrity and promoting healthspan to reduce cardiometabolic burden. The standardized, chemically well-defined adaptogenic combination ADAPT-232 has a long history as a stress-protective remedy, enhancing cognitive and physical resilience. However, its effects on healthspan, particularly mitochondrial function, and the underlying molecular mechanisms remain insufficiently understood. The current study investigated whether ADAPT-232 can mitigate glucose-induced metabolic and mitochondrial dysfunction in Caenorhabditis elegans and aimed to elucidate the molecular pathways involved in its biological activity. Healthspan parameters, including lifespan, stress resistance, and body morphology, were evaluated following ADAPT-232 supplementation. To investigate the protective potential of the formula under metabolic stress, a glucose-induced dysfunction model was employed, analysing mitochondrial morphology and lipid accumulation. Expression of markers of mitophagy, autophagy, metabolic regulation, and stress-response was assessed through RT-qPCR and GFP- reporter strains. The herbal combination ADAPT-232 significantly extended lifespan and enhanced thermal and oxidative stress resistance. In glucose-stressed worms, the formula restored mitochondrial integrity and reduced lipid accumulation. At the molecular level, ADAPT-232 upregulated pink-1, dct-1 , and lgg-2 , indicating increased mitophagy and autophagic activity. Upregulation of NHR-49, ATGL-1, and lipl-4 supported improved lipid catabolism and metabolic flexibility. The ADAPT-232 reactivated DAF-16 and skn-1 , consistent with enhanced stress-response signalling. The formula ADAPT-232 alleviates glucose-induced mitochondrial dysfunction by activating mitophagy-related pathways and improving metabolic homeostasis through coordinated regulation involving DAF-16 and NHR-49. These findings position ADAPT-232 as a promising plant-based intervention for promoting healthspan and potentially reducing cardiovascular risk.