Structure−activity relationship of ginsenoside derivatives with different glycosides and double bond position on anti-aging bioactivities

Aging is a complex and inevitable biological process that involves the decline of function in multiple systems and organs, and it is possible to delay aging process and improve health conditions through diet. Ginsenosides, the major active compounds in Panax ginseng Meyer, exhibit anti-oxidant, anti-cancer, and anti-aging properties. However, the relationship between bioactivities and structures of ginsenoside derivatives with same molecular formula remain unclear. Using Caenorhabditis elegans (C. elegans) model, we evaluated the anti-aging activities of 4 ginsenoside derivatives (Rg5, Rg6, Rk1, and F4), which differ in glycoside composition and double bond position. Their effects on lifespan, physiological functions, locomotion ability, lipofuscin accumulation, stress resistance, and acetylcholinesterase (AChE) activity were assessed. Four ginsenoside derivatives showed different activities of delaying aging by improving muscle function, enhancing anti-oxidant stress, and reducing AChE activity in C. elegans. Particularly, Rg5 and Rk1, which contain two glucose residues, demonstrated superior activity compared to Rg6 and F4, which possess glucose-(2-1)-rhamnose residues. Meanwhile, Rg5 and F4, with a double bond at Δ20(22) had better effects than Rk1 and Rg6 with a double bond at Δ20(21). Molecular docking analysis showed that Rg5 and Rk1 formed more hydrogen bonds and hydrophobic interactions with amino acid residues at the AChE active site compared to Rg6 and F4, Rg5 exhibited the most favorable binding energy, while Rg6 formed only a hydrogen bond and F4 showed no hydrogen bonding; both had the same binding energy. These findings suggest that glycoside types and double bond position are key structural determinants of the anti-aging activities of ginsenoside derivatives. This provides a theoretical foundation for the development of ginsenoside-based therapeutics for aging and aging-related chronic diseases.