Aging is an intricate biological process that unfolds gradually over time, leading to progressive deterioration in the structural and functional integrity of cells [1]. This gradual decline not only reduces quality of life but also increases susceptibility to mortality as individuals age. Research indicates that between 1990 and 2017, the primary driver of the global increase in deaths was population aging. Ischemic heart disease and stroke, both of which are prevalent among the elderly, were significant contributors to this trend [2]. This highlights the link between the growing elderly population and the rise in age-related diseases, resulting in higher mortality rates. Aging is also a key factor in the development of various disorders, particularly neurodegenerative diseases(NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) [3]. Currently, the global population of individuals aged 65 and older is growing at an unprecedented rate, projected to reach 1.6 billion by 2050 [4]. This demographic shift is accompanied by a higher prevalence of chronic conditions, which increases the risk of both physical and cognitive impairments in older adults. Consequently, it is crucial to develop strategies that promote healthy aging and mitigate the progression of age-related diseases.

The autophagy–lysosomal pathway is a critical and conserved cellular degradation process responsible for removing damaged organelles and pathological proteins. It maintains cellular homeostasis and ensures a steady supply of essential molecules, such as amino acids, under normal physiological conditions [5]. However, growing evidence suggests that autophagic activity declines with age across various organisms, and autophagy dysfunction has now been recognized as one of the twelve hallmarks of aging [6]. Studies in Caenorhabditis elegans, rodents, and human cells have shown that aging is associated with reduced expression of key autophagy-related genes, such as ATG5, ATG7, and BECN1, which are essential for autophagy initiation and function [7]. As a result, enhancing autophagic activity is emerging as a promising strategy to delay aging and mitigate age-related conditions. Numerous studies have highlighted the anti-aging effects of compounds that enhance autophagy. For instance, rapamycin, which inhibits mTOR activity to activate autophagy, has been shown to extend lifespan and improve healthspan in mice [8]. Similarly, metformin enhances autophagy via the AMPK/mTOR pathway, promoting the degradation of age-related proteins and alleviating cellular senescence [9,10]. Therefore, autophagy enhancers are becoming promising candidates for aging interventions, prompting extensive efforts to identify safe and effective drugs.

Natural medicine, particularly Traditional Chinese Medicine (TCM), has gained attention for promoting healthy aging due to its holistic principles and long-standing use. In this study, we employed the GFP-RFP-LC3 U87 cell line as a tool to monitor autophagic flux, enabling rapid screening of diverse natural resources—including crude extracts, fractions, and monomeric compounds—for autophagy-enhancing activity. This screening identified Salvia plebeia R. Br. (SP, “Li-Zhi-Cao”) as a novel autophagy inducer. SP is widely distributed across China, Iran, Japan, South Korea, India, and Australia [11] and has been traditionally used to treat inflammatory conditions such as nephritis, bronchitis, colds, flu, and rheumatoid arthritis. Beyond medicinal use, SP possesses antioxidative, antibacterial, and antiviral properties [12] and is also consumed as a nutritional supplement or herbal tea, highlighting its dietary relevance. Previous studies demonstrated that the ethanol extract of SP (SPE) protects against UVB-induced photoaging, with homoplantaginin (Hom) identified as an active component capable of alleviating vascular senescence [[13], [14], [15]]. In the present study, we employed multiple aging models to further investigate the molecular mechanisms and anti-aging effects of SPE. We show that SPE induces autophagy in primary human foreskin fibroblasts (HFFs) and mitigates cellular senescence via Atg7-dependent autophagy activation. In a d-galactose (d-gal)-induced premature aging mouse model, SPE supplementation enhanced physiological and cognitive functions, promoting healthy aging in vivo. Finally, we identified rosmarinic acid (RA) as the primary bioactive compound responsible for autophagy induction and senescence delay. RA is a polyphenolic caffeic acid ester, abundant in Lamiaceae family plants (e.g., Perilla frutescens, Rosmarinus officinalis, and Melissa officinalis) that are widely used as foods, teas, and herbs, highlighting its dual nutritional and medicinal relevance [16]. Collectively, our study highlights SP and RA as promising nutritionally relevant anti-aging agents that enhance autophagy and alleviate age-related dysfunction, providing a foundation for further mechanistic studies and translational development.