Ziyu glycoside I suppresses senescence and ameliorates age-related functional decline by stabilizing LDHA and restoring lactate output

INTRODUCTION: Cellular senescence contributes to age-related tissue dysfunction and is closely linked to metabolic remodeling and mitochondrial redox imbalance. However, senotherapeutic strategies with defined molecular targets and functionally validated downstream mechanisms remain limited. OBJECTIVES: This study aimed to identify natural-product modulators of cellular senescence and determine whether their anti-senescence activity is mediated through a targetable metabolic pathway. METHODS: An image-based high-content screen of 175 medicinal extracts identified candidate anti-senescence agents. The lead compound was validated across mammalian cell models, Caenorhabditis elegans, and mouse models of D-galactose (D-gal)-induced and physiological aging. Mechanistic studies combined target-engagement and protein-stability assays, genetic and pharmacological perturbations, proteomics, and metabolic and mitochondrial analyses. RESULTS: Ziyu glycoside I (Zg I), a triterpenoid saponin from Sanguisorba officinalis, suppressed senescence-associated phenotypes across multiple cellular models. In C. elegans, Zg I extended lifespan, improved locomotor and physiological fitness, reduced age-associated biomarkers, and enhanced oxidative stress resistance. In D-gal-induced and naturally aging mice, Zg I attenuated functional decline and multiorgan abnormalities. Mechanistically, Zg I directly engaged lactate dehydrogenase A (LDHA), reduced LDHA-associated ubiquitination, and slowed proteasomal turnover, thereby preserving LDHA abundance and restoring lactate production. LDHA depletion or LDH inhibition weakened the anti-senescence effects of Zg I, whereas lactate supplementation rescued senescence-associated phenotypes in LDHA-depleted cells. Pharmacological and genetic perturbations further implicated lactylation-associated regulation downstream of the LDHA-lactate axis. Proteomic and functional analyses revealed coordinated remodeling of glucose metabolism and improved mitochondrial redox and bioenergetic homeostasis. In naturally aged mice, inhibition of lactate production attenuated Zg I-mediated suppression of tissue senescence and injury despite preserved LDHA restoration. CONCLUSION: Zg I suppresses senescence and age-related dysfunction by directly engaging and stabilizing LDHA, thereby restoring lactate-dependent metabolic output. These findings identify the LDHA-lactate axis as a mechanistically defined and potentially actionable pathway for geroprotective intervention.