Salvianolic acids are natural senolytics and increase lifespan in old age

Abstract Cellular senescence plays a critical role in chronological aging and is implicated in the onset and progression of multiple age-related disorders. Targeting senescent cells represents a promising strategy to reduce disease burden and improve healthspan. Here we report the senotherapeutic properties of salvianolic acid (SA) family members, specifically A (SAA), B (SAB) and E (SAE). From a natural medicinal agent library, we identified selective cytotoxicity of these SA compounds against senescent cells across diverse senescence types and cell lineages. Mechanistically, SAA, SAB and SAE enhance ROS production and target glutathione S-transferase Pi1 (GSTP1), a redox homeostasis modulator, inducing both apoptosis and ferroptosis in senescent cells. Incorporation of SAs into chemotherapeutic regimens enhanced anticancer efficacy and prolonged post-treatment survival. Intermittent SA administration improved physical function and increased healthspan and lifespan in aged mice. Collectively, our study establishes SAs as an emerging class of natural senolytics (phenolic acids) with the capacity to delay aging and alleviate age-related pathologies in advanced life. Competing Interest Statement The authors have declared no competing interest. Data availability Experimental data supporting the plots within this article and other findings from this study are available from the corresponding author upon reasonable request. The RNA-seq data generated in the present study have been deposited in the Gene Expression Omnibus database under accession code GSE216218, GSE279345, GSE275945. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository iProX 99 with the dataset identifier PXD056831. All data that support the findings of this study are available within the article and Supplementary Information. Source data are provided with this paper. A reporting summary for this article is available in the Supplementary Information.