Atypical Tetracyclines Promote Longevity and Ferroptotic Neuroprotection via Translation Attenuation.

Reducing protein synthesis extends lifespan across taxa, but pharmacological strategies to safely attenuate translation remain limited. Tetracyclines are clinically used antibiotics long observed to exert beneficial effects in age-associated diseases and extend lifespan in model organisms, though the underlying mechanisms remain unclear. Here, we systematically profiled commercially available tetracyclines and show that translation attenuation is a general property of the tetracycline class. Importantly, we identify the atypical tetracyclines 4-epiminocycline and 12-aminominocycline, which attenuate translation independently of antibiotic activity and integrated stress response (ISR) activation. These compounds extend lifespan in C. elegans, attenuate translation in human induced neurons, reduce hippocampal protein synthesis in vivo, and protect neurons from ferroptotic stress. Together, our results demonstrate that pharmacological attenuation of translation is sufficient to promote longevity and establish translation attenuation as a druggable longevity mechanism in mammals.