20(S)-protopanaxadiol prolongs lifespan and enhances stress resistance in Caenorhabditis elegans via the insulin/IGF-1 signaling pathway.

Abstract

Aging is a progressive and irreversible process linked to a variety of diseases. Examination of the processes targeted by pharmacological treatments could potentially both extend lifespan and alleviate age-associated diseases. 20(S)-protopanaxadiol (20(S)-PPD), a primary ginsenoside metabolite, has many beneficial properties, although it`s anti-aging effects are unknown. Lifespan and behavioral assays were used to determine the effects of 20(S)-PPD on life span and healthy lifespan. Stress resistance was systematically determined under heat, oxidative, and chemical stress conditions. The target of 20(S)-PPD was identified by molecular docking and surface plasmon resonance. Investigation in mutant worms identified the signaling pathway and transcription factor mediating 20(S)-PPD-induced longevity. 20(S)-PPD could significantly extend Caenorhabditis elegans ( C. elegans ) lifespan without affecting food intake and reproductive output. It also improved healthspan in aging worms by ameliorating locomotor deficits and suppressing lipofuscin accumulation. Furthermore, 20(S)-PPD enhanced stress resistance and reduced age-associated reactive oxygen species (ROS) levels. Mechanistically, 20(S)-PPD bound dose-dependently to the insulin receptor (IR) with a KD value of 8.59 μM. The life-extending effects of 20(S)-PPD involved the DAF-2/insulin/IGF-1 signaling (IIS) pathway, rather than other conserved pathways. Treatment with 20(S)-PPD promoted DAF-16/FOXO activation and nuclear translocation, leading to upregulated transcription of several antioxidant and detoxification-related genes, including lys-7 , mtl-1 , hsp-12.6 , dod-3 , sod-3 , hsp-16.2 , gst-4 and sms-1 . 20(S)-PPD also upregulated the protein levels of SOD-3 and GST-4, known promoters of longevity in C. elegans . These findings demonstrate that IR is a molecular target of 20(S)-PPD and reveal a mechanism by which 20(S)-PPD promotes longevity and stress resistance, suggesting the potential of 20(S)-PPD in slowing aging and the development of age-associated disorders.