ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1657436
20(S)-protopanaxadiol prolongs lifespan and enhances stress resistance in Caenorhabditis elegans via the insulin/IGF-1 signaling pathway
Provisionally accepted
- 1Jilin Medical College for Health Staff, Jilin, China
- 2Changchun University of Chinese Medicine, Changchun, China
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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. Here, it was found that 20(S)-PPD could significantly extend Caenorhabditis elegans (C. elegans) lifespan without affecting food intake and reproductive output. 20(S)-PPD enhanced the health of aging worms, reversing locomotory deficits and neurological degeneration, and inhibiting lipofuscin accumulation. In addition, 20(S)-PPD improved resistance to stress and reduced ROS levels associated with aging. Algorithm analysis and surface plasmon resonance identified 20(S)-PPD dose-dependently bound to insulin receptor (IR) with KD value of 8.59 μM. Investigation in mutant worms showed that the life-extending effects of 20(S)-PPD involved the DAF-2/insulin/IGF-1 signaling (IIS) pathway, rather than other conserved pathways. Moreover, 20(S)-PPD activated DAF-16/FOXO, leading to its nuclear translocation to regulate transcription of lys-7, mtl-1, hsp-12.6, dod-3, sod-3, hsp-16.2, gst-4 and sms-1, described as antioxidant and detoxification-associated genes. 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.
Keywords: Caenorhabditis elegans, 20(S)-Protopanaxadiol, Longevity, Insulin/IGF-1 signaling pathway, DAF-16/FOXO
Received: 01 Jul 2025; Accepted: 26 Sep 2025.
Copyright: © 2025 Song, Yan, Xu, Lou, Wang, Ren, Liu and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Fangbing Liu, liufb@ccucm.edu.cn
Shuai Zhang, zhangs530@nenu.edu.cn
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