Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4
Rebecca L. McIntyre,
Marte Molenaars,
Bauke V. Schomakers,
Arwen W. Gao,
Rashmi Kamble,
Aldo Jongejan,
Michel van Weeghel,
André B.P. van Kuilenburg,
Richard Possemato,
Riekelt H. Houtkooper,
Georges E. Janssens
Affiliations
Rebecca L. McIntyre
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Marte Molenaars
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
Bauke V. Schomakers
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Arwen W. Gao
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Rashmi Kamble
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Aldo Jongejan
Bioinformatics Laboratory, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Michel van Weeghel
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
André B.P. van Kuilenburg
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Richard Possemato
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
Riekelt H. Houtkooper
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Georges E. Janssens
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Corresponding author
Summary: 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.
