Flavonoid compounds from Shenrong Guben Huanshao Pill alleviates senescence-associated mitochondrial dysfunction through NDUFV2 and LDHB mediated metabolic reprogramming.

Senescence is widely recognized as a key driving factor in the onset and progression of many chronic diseases. Although numerous animal studies have demonstrated that various drugs can delay senescence, their clinical application is severely limited due to significant toxic side effects. As a result, developing safer, natural anti-senescence agents has become an urgent priority. In this study, we identified mitochondrial dysfunction as a critical contributor to cellular senescence. In addition, we identified Shenrong Guben Huanshao Pill (SRW) as an effective agent that alleviates mitochondrial dysfunction and consequently delays cellular senescence by regulating mitochondrial metabolism. Mechanistically, SRW enhances mitochondrial function by upregulating the expression of reduced nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase subunit V2 (NDUFV2), a core component of mitochondrial respiratory chain complex I. Simultaneously, SRW reduces lactate-induced mitochondrial dysfunction by regulating the glycolytic enzyme lactate dehydrogenase B (LDHB), thereby decreasing lactate accumulation. Collectively, our findings indicate that SRW alleviates cellular senescence by coordinately regulating NDUFV2 expression and LDHB-mediated lactate metabolism to improve mitochondrial function. In addition, several flavonoids in SRW were identified to possess potential anti-senescence activity. Molecular docking and cellular experiments confirmed that myricetin, luteolin, and gamma-mangostin effectively alleviate cellular senescence.