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Inflammaging in the Aged Kidney


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Posted 18 September 2023 - 10:23 AM


With age, the immune system becomes simultaneously less capable (immunosenescence) and more active and inflammatory (inflammaging). This constant, low-grade, unresolved inflammatory activity is driven by a range of different mechanisms. For example, senescent cells energetically secrete pro-inflammatory signals, and their numbers grow with age in tissues throughout the body. Further, age-related issues in cell function can lead to fragments of DNA from mitochondria and the nucleus leaking into the cytoplasm, where they trigger innate immune mechanisms intended to detect pathogens. Constant, unresolved inflammation is harmful to cell and tissue function, as illustrated by this paper, focused on the kidney. Control of inflammation much be a part of any comprehensive toolkit of approaches to slowing and reversing degenerative aging.

Even during physiologic aging, the kidney experiences a loss of mass and a progressive functional decline. This is clinically relevant as it leads to an increased risk of acute and chronic kidney disease. The kidney tubular system plays an important role in the underlying aging process, but the involved cellular mechanisms remain largely elusive. Kidneys of 3-, 12- and 24-month-old male C57BL/6J mice were used for RNA sequencing, histological examination, immunostaining, and RNA-in-situ-hybridization. Single cell RNA sequencing data of differentially aged murine and human kidneys was analyzed to identify age-dependent expression patterns in tubular epithelial cells. Senescent and non-senescent primary tubular epithelial cells from mouse kidney were used for in vitro experiments.

During normal kidney aging, tubular cells adopt an inflammatory phenotype, characterized by the expression of MHC class II related genes. In our analysis of bulk and single cell transcriptional data we found that subsets of tubular cells show an age-related expression of Cd74, H2-Eb1 and H2-Ab1 in mice and CD74, HLA-DQB1 and HLADRB1 in humans. Expression of MHC class II related genes was associated with a phenotype of tubular cell senescence, and the selective elimination of senescent cells reversed the phenotype. Exposure to the Cd74 ligand MIF promoted a prosenescent phenotype in tubular cell cultures.

Together, these data suggest that during normal renal aging tubular cells activate a program of 'tubuloinflammaging', which might contribute to age-related phenotypical changes and to increased disease susceptibility.

Link: https://doi.org/10.3...mu.2023.1222339


View the full article at FightAging




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