Aging is characterized by progressive cellular dysfunction and increased susceptibility to chronic diseases. Enhancing autophagy, a key cellular clearance process, offers a promising strategy to combat aging. In this study, we investigated the autophagy-inducing and anti-aging properties of Salvia plebeia R. Br. ethanol extract (SPE) using in vitro and in vivo models. Our results showed that SPE enhanced autophagosome and autolysosome formation, elevated LC3-II and Beclin-1 levels, and reduced p62 expression in human foreskin fibroblasts (HFFs), confirming its autophagy-inducing activity. SPE also mitigated D-galactose (D-gal)-induced cellular senescence, reducing SA-β-gal staining, senescence markers (p16, p21), SASP factors, and γ-H2AX foci. These effects were Atg7-dependent, as Atg7 knockout abolished the benefits, highlighting autophagy's role in SPE's action. In vivo, SPE improved physical function, reversed cellular senescence, enhanced antioxidant defenses, and restored autophagic activity in D-gal-induced prematurely senescent mice. Furthermore, SPE alleviated age-related cognitive decline, reduced neuronal damage, increased synaptic density, and mitigated Tau accumulation. Notably, SPE demonstrated good tolerability over 12 weeks, with stable body weight, no apparent tissue injury, and unchanged serum ALT, AST, and creatinine. Chemical profiling identified rosmarinic acid (RA) as a major bioactive constituent that recapitulated key autophagy- and senescence-related effects in vitro. These findings suggest that SPE is a promising natural autophagy enhancer with potential to promote healthy aging, combat age-related diseases, and serve as a novel therapeutic strategy for cellular dysfunction in aging.
