Brochard Thomas, McIntyre Rebecca L, Houtkooper Riekelt H, Seluanov Andrei, Gorbunova Vera, Janssens Georges E
Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
Ageing Res Rev. 2023 Dec;92:102132. doi: 10.1016/j.arr.2023.102132. Epub 2023 Nov 19.
Repurposing drugs already approved in the clinic to be used off-label as geroprotectors, compounds that combat mechanisms of aging, are a promising way to rapidly reduce age-related disease incidence in society. Several recent studies have found that a class of drugs-nucleoside reverse transcriptase inhibitors (NRTIs)-originally developed as treatments for cancers and human immunodeficiency virus (HIV) infection, could be repurposed to slow the aging process. Interestingly, these studies propose complementary mechanisms that target multiple hallmarks of aging. At the molecular level, NRTIs repress LINE-1 elements, reducing DNA damage, benefiting the hallmark of aging of 'Genomic Instability'. At the organellar level, NRTIs inhibit mitochondrial translation, activate ATF-4, suppress cytosolic translation, and extend lifespan in worms in a manner related to the 'Loss of Proteostasis' hallmark of aging. Meanwhile, at the cellular level, NRTIs inhibit the P2X7-mediated activation of the inflammasome, reducing inflammation and improving the hallmark of aging of 'Altered Intercellular Communication'. Future development of NRTIs for human aging health will need to balance out toxic side effects with the beneficial effects, which may occur in part through hormesis.
将已在临床上获批的药物用于非标签用途，作为老年保护剂，即对抗衰老机制的化合物，是一种有望在社会上迅速降低与年龄相关疾病发病率的方法。最近的几项研究发现，一类最初开发用于治疗癌症和人类免疫缺陷病毒（HIV）感染的药物——核苷逆转录酶抑制剂（NRTIs），可以重新用于延缓衰老过程。有趣的是，这些研究提出了针对衰老多个标志的互补机制。在分子水平上，NRTIs抑制LINE-1元件，减少DNA损伤，有益于“基因组不稳定”这一衰老标志。在细胞器水平上，NRTIs抑制线粒体翻译，激活ATF-4，抑制胞质翻译，并以与衰老的“蛋白质稳态丧失”标志相关的方式延长蠕虫的寿命。同时，在细胞水平上，NRTIs抑制P2X7介导的炎性小体激活，减少炎症并改善“细胞间通讯改变”这一衰老标志。NRTIs用于人类衰老健康的未来发展需要在毒副作用与有益效果之间取得平衡，有益效果可能部分通过应激适应发生。
