Dioscin extends lifespan and ameliorates aging associated phenotypes in association with the endoplasmic reticulum unfolded protein response.

Dioscin, a naturally occurring steroidal saponin isolated from various kinds of herbs with pleiotropic pharmacological properties, remains mechanistically undefined regarding its mammalian aging modulation. This study discovered that dioscin extended the lifespan of Caenorhabditis elegans. Concurrently, dioscin improved the motor function of C. elegans and reduced age pigment accumulation, while having no effect on the reproductive performance of the C. elegans. By pathway screening, we identified that dioscin extends healthspan via the endoplasmic reticulum unfolded protein response (UPRER) transcription factor XBP-1. Moreover, lifespan assays conducted on nematode mutants that the UPRER key effectors (PERK, IRE1α and ATF6) demonstrated that dioscin influences the lifespan of C. elegans through all three of these key effectors. These findings provide a foundation for further investigation into its mechanism of action in regulating mammalian aging. In this study, we used naturally aged C57BL/6 J mice in a 6-month intervention study and found that dioscin significantly reduced expression of senescence markers (p21, p16) in hepatic and skeletal muscle tissues. Furthermore, dioscin maintains proteostasis through coordinated activation of the endoplasmic reticulum unfolded protein response (UPRER) key effectors (PERK, IRE1α, ATF6, and s-XBP1). Our study provides preclinical evidence supporting dioscin as a novel intervention that ameliorates aging-associated phenotypes and highlights the pivotal role of UPRER in lifespan extension and aging suppression.