Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen, China.
J Gerontol A Biol Sci Med Sci. 2024 Nov 1;79(11). doi: 10.1093/gerona/glae221.
Aging triggers physiological changes in organisms that are tightly linked to metabolic changes. Senolytics targeting many fundamental aging processes are currently being developed. However, the host metabolic response to natural senescence and the molecular mechanism underlying the antiaging benefits of senolytics remain poorly understood. In this study, we investigated metabolic changes during natural senescence based on the Caenorhabditis elegans model and pinpointed potential biomarkers linked to the benefits of senolytics. These results suggest that age-dependent metabolic changes during natural aging occur in C elegans. Betaine was identified as a crucial metabolite in the natural aging process. We explored the metabolic effects of aging interventions by administering 3 antiaging drugs-metformin, quercetin, and minocycline-to nematodes. Notably, betaine expression significantly increased under the 3 antiaging drug treatments. Our findings demonstrated that betaine supplementation extends lifespan, primarily through pathways associated with the forkhead box transcription factor (FoxO) signaling pathway, the p38-mitogen-activated protein kinase (MAPK) signaling pathway, autophagy, the longevity regulating pathway, and the target of rapamycin (mTOR) signaling pathway. In addition, autophagy and free radicals are altered in betaine-treated nematodes. Overall, we found that betaine is a critical metabolite during natural aging and that senolytics extend the lifespan of nematodes by increasing betaine levels and promoting autophagy and antioxidant activity. This finding suggests that betaine could be a novel therapeutic target for promoting longevity.
衰老是触发生物体生理变化的一个原因，这些变化与代谢变化密切相关。目前正在开发针对许多基本衰老过程的衰老细胞清除剂。然而，宿主对自然衰老的代谢反应以及衰老细胞清除剂抗衰老益处的分子机制仍知之甚少。在这项研究中，我们基于秀丽隐杆线虫模型研究了自然衰老过程中的代谢变化，并确定了与衰老细胞清除剂益处相关的潜在生物标志物。这些结果表明，秀丽隐杆线虫在自然衰老过程中存在依赖年龄的代谢变化。甜菜碱被确定为自然衰老过程中的关键代谢物。我们通过给线虫施用 3 种抗衰老药物——二甲双胍、槲皮素和米诺环素，来探索衰老干预的代谢效应。值得注意的是，在这 3 种抗衰老药物的处理下，甜菜碱的表达显著增加。我们的研究结果表明，甜菜碱的补充可以延长寿命，主要是通过与 forkhead box 转录因子 (FoxO) 信号通路、p38-有丝分裂原激活蛋白激酶 (MAPK) 信号通路、自噬、长寿调控通路和雷帕霉素靶蛋白 (mTOR) 信号通路相关的途径。此外，在甜菜碱处理的线虫中，自噬和自由基发生改变。总的来说，我们发现甜菜碱是自然衰老过程中的关键代谢物，衰老细胞清除剂通过增加甜菜碱水平和促进自噬和抗氧化活性来延长线虫的寿命。这一发现表明，甜菜碱可能成为促进长寿的新的治疗靶点。
