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

• Published in: Cell reports (Cambridge) Vol. 42; no. 1; p. 111928
• Main Authors: McIntyre, Rebecca L., Molenaars, Marte, Schomakers, Bauke V., Gao, Arwen W., Kamble, Rashmi, Jongejan, Aldo, van Weeghel, Michel, van Kuilenburg, André B.P., Possemato, Richard, Houtkooper, Riekelt H., Janssens, Georges E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31-01-2023; Elsevier
• Subjects: Activating Transcription Factor 4; aging; Animals; ATF-4; Caenorhabditis elegans - physiology; CP: Metabolism; CP: Molecular biology; geroprotector; HIV Infections - drug therapy; Humans; lifespan; Longevity; nucleoside reverse transcriptase inhibitor; Retroviridae; Reverse Transcriptase Inhibitors - pharmacology; Reverse Transcriptase Inhibitors - therapeutic use; translation; Zidovudine; Zidovudine - pharmacology; Zidovudine - therapeutic use; geroprotector; ATF-4; CP: Metabolism; lifespan; nucleoside reverse transcriptase inhibitor; translation; CP: Molecular biology; aging; Zidovudine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111928

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.
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•The anti-retroviral zidovudine extends healthy longevity in C. elegans•Lifespan extension with NRTIs zidovudine and didanosine depends on ATF-4•Zidovudine alters pyrimidine metabolism and reduces cytosolic translation•ATF-4 regulates reduced translation upon zidovudine treatment
McIntyre et al. report on the longevity-extending effects of the anti-retroviral pharmaceutical zidovudine in the worm C. elegans. Zidovudine reduces translation in treated worm populations, and both this reduced translation and the lifespan extension are dependent on the transcription factor ATF-4.