Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4

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 modi-fied 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 mito-chondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription fac-tor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication be-tween 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.

Automated summary

The human population is aging, and there is a growing need for interventions to slow down age-related diseases. The repurposing of clinically used compounds, such as the anti-retroviral nucleoside reverse transcriptase inhibitor zidovudine, shows promising results in extending lifespan and health span in C. elegans. This effect is achieved through the modification of pyrimidine metabolism and proteostasis-related transcripts, as well as the activation of transcription factor 4 (ATF-4) and reduction of translation.