Inhibiting NLRP3 Signaling in Aging Podocytes Improves Their Life- and Health-Span | Aging-US



August 7, 2023

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  • Aging-US published this research paper on July 23, 2023 in Volume 15, Issue 14, entitled, “Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span" by researchers from the Division of Nephrology, University of Washington, Seattle, WA; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH; Department of Medicine, Division of Nephrology, National University Hospital, Singapore; Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA; Department of Chemistry, University of Washington, Seattle, WA; Division of Nephrology, University of Michigan, Ann Arbor, MI; Department of Physiology and Biophysics, University of Washington, Seattle, WA; Department of Pathology, University of Chicago, Chicago, IL; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA. DOI - Corresponding authors - Oliver Wessely -, and Stuart J. Shankland - Abstract The decrease in the podocyte’s lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1β IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. Together, these results suggest a critical role for the NLRP3 inflammasome in podocyte and liver aging. Sign up for free Altmetric alerts about this article - Subscribe for free publication alerts from Aging - Keywords - aging, kidney, podocyte, NLRP3 inflammasome, reporter About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at​​ and connect with us: SoundCloud - Facebook - Twitter - Instagram - YouTube - LinkedIn - Pinterest - Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

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