The Role And Mechanism Of Ginsenosides In Regulating The SIRT3/FOXO3 Pathway To Alleviate Vascular Aging

Objective: As our country gradually enters into an aging society,various diseases caused by aging as well as the decline of body functions have become a major crisis in national health.Total Ginsenosides(TGS)have anti-aging effects.Previous studies have found that middle age is the best time window for ginsenoside anti-aging intervention,and it has significant anti-vascular aging efficacy,this paper will systematically explain its inner mechanism.Methods: Twelve-month-old mice were used as a mouse model of middle age,and after three months of treatment with TGS,the effects of TGS on aging-related phenotypes,such as grip strength,fatigue resistance,cognitive index,cardiac function,adiposity,and gait pattern,were evaluated by applying grip dynamometer,rotating fatigue bar,SMART3.0,small-animal ultrasonography,small-animal nuclear magnetic resonance,and gait analysis system at the beginning of the 15-month age of the mice.HE staining was applied to detect the morphological changes of various tissues in mice,Masson staining to detect collagen deposition in mouse aorta,EVG staining to detect the morphology of elastic fibers in mouse aorta,γ-H2 AX immunofluorescence staining was applied to evaluate the effect of TGS on DNA damage in the organs,and immunohistochemistry and immunofluorescence were further applied to evaluate the effect of TGS on the aorta and the key aging-related regulatory factors in the tissues,p21,SIRT3 and FOXO3 expression.Subsequently,several aging cell models were applied to detect the components of TGS into blood by combined MS to clarify the main ginsenoside monomers active components.Finally,the regulatory relationship between ginsenosides,SIRT3/FOXO3 pathway and vascular aging was clarified by overexpression and silencing of SIRT3.Results: TGS significantly enhanced grip strength,fatigue resistance,cognitive index,ejection fraction,and short-axis shortening in 15-month-old mice.Reduced fat content and improved insulin sensitivity;ginsenosides were specific for the improvement of brain,heart,skeletal muscle,adipose and other important organ functions in aging mice.Reduced intima-media thickness in the aorta of senescent mice;reduced collagen deposition and DNA damage in the aorta;and inhibited aortic elastic fiber alignment disorders;Subsequent molecular biology experiments revealed that TGS attenuated ROS in aortic endothelial cells,mainly through the promotion of the expression of SIRT3 and FOXO3;and facilitated their cell cycle;Finally,we conducted validation experiments for SIRT3 and found that silencing of SIRT3 counteracted most of the anti-vascular aging efficacy of TGS and was mainly ginsenoside Rc.Conclusion: Ginsenosides given to mice in middle-aged elevated the health status of naturally aging mice and significantly attenuated vascular aging,the mechanism of which may be that ginsenoside Rc attenuates ROS and DNA damage in aging aortic endothelial cells and slows down vascular aging by modulating the SIRT3/FOXO3 pathway.