Abstract
Background: Aging is characterized by cellular senescence, inflammation, and physiological decline. Currently available antiaging therapies often have limitations due to their toxicity and off-target effects. However, natural compounds derived from Chinese herbal medicine, such as Rhapontigenin (Rhap), have shown potential as safer antiaging agents. Purpose: This study aimed to evaluate the potential of Rhap to be used as an antiaging agent by investigating its effects on cellular senescence, physical function, immune modulation, and autophagy in both in vitro and in vivo aging models. Methods: NIH3T3 and IMR90 cells were subjected to oxidative or genotoxic stress to induce senescence and then treated with Rhap. Senescence markers, cell viability, and autophagy-related protein levels were assessed. Aged mice were treated with Rhap for 8 weeks, and physical performance, immune modulation, and organ health were evaluated. Mechanistic studies were conducted to determine the role of Sirt1 in mediating the effects of Rhap. Results: Rhap treatment significantly reduced cellular senescence marker (p16 and p21) levels and senescence-associated β-galactosidase (SA-β-Gal) activity in stressed cells. In aged mice, Rhap improved physical performance, such as grip strength and motor coordination, and reduced depressive-like behaviors. Rhap also decreased liver senescence, lipid accumulation, and fibrosis and increased immune function by reducing proinflammatory cytokine production and enhancing T-cell homeostasis. Mechanistically, Rhap upregulated Sirt1 and promoted autophagy, both of which contributed to its antiaging effects. Sirt1 knockdown attenuated the effects of Rhap on autophagy and senescence, indicating the importance of Sirt1 in mediating these beneficial effects. Conclusion: Rhap is a promising candidate for mitigating age-related cellular and physiological decline by reducing cellular senescence, promoting autophagy, and modulating immune function. However, further work is needed to fully elucidate the precise molecular mechanisms of Rhap's action and its pharmacokinetic profile to assess its translational potential in humans.