Lang, LaurineFuente, RocíoLópez, José ManuelPastor Arroyo, Eva MaríaSeebeck, PetraShcherbakov, DimitriBöttger, ErikBrennan, LorraineWagner, Carsten A.Rubio Aliaga, Isabel2025-07-172025-07-172025Lang, L., Fuente, R., López, J. M., Pastor‐Arroyo, E., Seebeck, P., Shcherbakov, D., Böttger, E., Brennan, L., Wagner, C. A., & Rubio‐Aliaga, I. (2025). Signs of premature kidney aging in mice with error‐prone protein synthesis. The FASEB Journal, 39(12), e70725. https://doi.org/10.1096/fj.202500723R1530-68600892-6638https://hdl.handle.net/11268/16031Chronic kidney disease (CKD) is more prevalent with increasing age. The incidence of CKD is rising due to the widespread nature of its risk factors, hypertension and diabetes, and because aging causes a gradual decline in kidney function. This decline is a consequence of structural, molecular, and metabolic changes occurring in aging kidneys. Understanding the mechanisms that accelerate kidney aging may help manage CKD and promote healthy aging. Recently, it has been shown that protein translation errors accelerate aging in mammals. Mice heterozygous for the ribosomal ambiguity mutation Rps9D95N, which results in genome-wide error-prone translation, have reduced life span, increased macroscopic signs of aging, and exhibit a neuropathological phenotype resembling early signs of Alzheimer disease. Here, using deep phenotyping, we investigated the kidneys of Rps9D95N/+ mice and showed that genome-wide error-prone translation is also associated with signs of premature kidney aging. These mice have renal amyloidosis, an altered glomerular basement membrane, reduced autophagy in kidney tissue, and renal fibrosis compared to age-matched aged mice. These alterations in kidney tissue were accompanied by signs of kidney dysfunction such as albuminuria and elevated levels of Kim-1, a marker of kidney injury and kidney disease progression. In addition, lipid metabolism is altered, as shown by RNAseq and targeted metabolomic analysis, suggesting increased lipid deposition as lipid droplets in the Rps9D95N knock-in mice. Only mild changes in systemic phosphate metabolism were observed. Our findings provide insights into premature kidney aging, likely due to accelerated loss of proteostasis caused by genome-wide translation errors.engEnfermedad renalProteostasisExperimentación animaljournal article10.1096/fj.202500723Ropen accessEnfermedadCiencias médicasMétodo experimentalGoal 3: Ensure healthy lives and promote well-being for all at all ages