The gut microbiota-metabolome axis mediates the adaptive protective effects of a high-altitude probiotic against distinct aging etiologies.

Aging is a major driver of chronic diseases and mortality, yet effective interventions against distinct aging etiologies remain limited. Hypobaric hypoxia at high altitudes accelerates aging, while D-galactose (D-gal) injection mimics metabolic aging. The gut microbiota is a key regulator of aging, but whether indigenous probiotics from the high plateaus of Tibet exert comparable or differential efficacy against distinct aging etiologies remains unclear. In this study, we systematically evaluated the protective effects of Lactiplantibacillus plantarum AL4510, a novel probiotic strain isolated from traditional fermented goat milk on the Qinghai-Tibet Plateau. We used both D-gal-induced and hypobaric hypoxia-induced aging models established simultaneously within the same experimental system. AL4510 significantly alleviated oxidative stress in both models, as evidenced by restored serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and reduced malondialdehyde (MDA) levels. Systemic inflammation was attenuated, with lower interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) concentrations. Cellular senescence, assessed using senescence-associated β-galactosidase (SA-β-gal) and p16 immunofluorescence, was markedly reduced in both liver and colon tissues by approximately 50-60%. The probiotic rebalanced the gut microbiota composition by consistently suppressing a synergistic pathogenic cluster comprising Desulfovibrio, Bilophila, and Helicobacter while promoting beneficial genera including Akkermansia, Muribaculum, and Lactobacillus. Metabolomic profiling revealed that AL4510 replenished short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate in both models, indicating restoration of gut fermentative capacity. Importantly, AL4510 engaged in stress-specific metabolic reprogramming: in the D-gal model, it elevated the levels of autophagy-inducing polyamine spermidine and the anti-inflammatory lipoxin B4; in the hypoxia model, it upregulated neuroprotective catalpol, lupeol, and energy-related calcium pantothenate. Integrative correlation and co-occurrence network analyses suggested that AL4510 was associated with a beneficial microbial consortium that correlated with host metabolism potentially involving the microbiota-SCFA axis. Collectively, these findings suggest that AL4510 exerts broad spectrum anti-aging effects potentially involving a "dual-track" mechanism: convergent restoration of gut ecological balance and divergent, stress-adapted reprogramming of host metabolism. This study provides a scientific basis for developing AL4510 as a functional probiotic ingredient or postbiotic formulation for high-altitude adaptation, metabolic anti-aging interventions, and gut-targeted nutritional strategies.