Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Cell Rep. 2023 Jan 31;42(1):111928. doi: 10.1016/j.celrep.2022.111928. Epub 2022 Dec 30.
The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.
人口老龄化，需要干预措施来减缓与年龄相关的疾病的进展（抗衰老干预）。重新利用已经在临床上使用的化合物，通常是在修改剂量的情况下，可以快速实施抗衰老药物。在这里，我们发现抗逆转录病毒核苷逆转录酶抑制剂（NRTI）齐多夫定可显著延长秀丽隐杆线虫的寿命和健康跨度，而不影响电子传递链损伤或 ROS 积累。相反，齐多夫定治疗可改变嘧啶代谢和与蛋白质稳态相关的转录本。测试线粒体应激和蛋白质稳态调节剂表明，寿命延长依赖于激活转录因子 4（ATF-4）。ATF-4 调节线粒体应激诱导的长寿，特别是线粒体和细胞质翻译之间的通讯。齐多夫定处理的蠕虫中的翻译减少，也依赖于 ATF-4。最后，我们显示另一种 NRTI 地丹诺辛诱导的 ATF-4 依赖性寿命延长。总之，我们的工作阐明了 NRTI 类药物（如齐多夫定）在体内通过降低翻译和 ATF-4 发挥抗衰老作用。
