Novel 18-norspirostane steroidal saponins: Extending lifespan and mitigating neurodegeneration through promotion of mitophagy and mitochondrial biogenesis in Caenorhabditis elegans

• Published in: Mechanisms of ageing and development Vol. 218; p. 111901
• Main Authors: Wu, An-Guo, Yong, Yuan-Yuan, He, Chang-Long, Li, Ya-Ping, Zhou, Xing-Yue, Yu, Lu, Chen, Qi, Lan, Cai, Liu, Jian, Yu, Chong-Lin, Qin, Da-Lian, Wu, Jian-Ming, Zhou, Xiao-Gang
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.04.2024
• Subjects: Animals; Anti-aging; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Deoxytrillenoside CA; Epitrillenoside CA; Longevity; Mitochondrial biogenesis; Mitophagy; Organelle Biogenesis; Parkinson Disease; Saponins - pharmacology; Rap; C. elegans; AD; Anti-aging; 6-OHDA; TTM; polyQ40; Mitophagy; ETCA; Deoxytrillenoside CA; DTCA; HSPs; GFP; Epitrillenoside CA; DCFH-DA; TCMs; Mitochondrial biogenesis; PD; NGM; L-Dopa; HD; NDs; FUDR; α-synuclein
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2024.111901

Pharmacological strategies to delay aging and combat age-related diseases are increasingly promising. This study explores the anti-aging and therapeutic effects of two novel 18-norspirostane steroidal saponins from Trillium tschonoskii Maxim, namely deoxytrillenoside CA (DTCA) and epitrillenoside CA (ETCA), using Caenorhabditis elegans (C. elegans). Both DTCA and ETCA significantly extended the lifespan of wild-type N2 worms and improved various age-related phenotypes, including muscle health, motility, pumping rate, and lipofuscin accumulation. Furthermore, these compounds exhibited notable alleviation of pathology associated with Parkinson's disease (PD) and Huntington's disease (HD), such as the reduction of α-synuclein and poly40 aggregates, improvement in motor deficits, and mitigation of neuronal damage. Meanwhile, DTCA and ETCA improved the lifespan and healthspan of PD- and HD-like C. elegans models. Additionally, DTCA and ETCA enhanced the resilience of C. elegans against heat and oxidative stress challenges. Mechanistic studies elucidated that DTCA and ETCA induced mitophagy and promoted mitochondrial biogenesis in C. elegans, while genetic mutations or RNAi knockdown affecting mitophagy and mitochondrial biogenesis effectively eliminated their capacity to extend lifespan and reduce pathological protein aggregates. Together, these compelling findings highlight the potential of DTCA and ETCA as promising therapeutic interventions for delaying aging and preventing age-related diseases. •DTCA and ETCA prolong lifespan and mitigate age-related degeneration in C. elegans.•DTCA and ETCA alleviate PD-and HD pathology in C. elegans.•DTCA and ETCA induce mitophagy and promote mitochondrial biogenesis in C. elegans.•DTCA and ETCA extend lifespan by modulating mitophagy and mitochondrial biogenesis.