Podocyte Aging: Why and How Getting Old Matters

Abstract

The effects of healthy aging on the kidney, and how these effects intersect with superimposed diseases, are highly relevant in the context of the population's increasing longevity. Age-associated changes to podocytes, which are terminally differentiated glomerular epithelial cells, adversely affect kidney health. This review discusses the molecular and cellular mechanisms underlying podocyte aging, how these mechanisms might be augmented by disease in the aged kidney, and approaches to mitigate progressive damage to podocytes. Furthermore, we address how biologic pathways such as those associated with cellular growth confound aging in humans and rodents.

Keywords: RNA sequencing; aging; glomerulosclerosis; glomerulus; podocyte; senescence.

Figure 1.

Podocyte lifespan and healthspan. The length of time that an individual podocyte lives is its lifespan (green arrow). Lifespan is binary, where cells are either alive or lost due to death and/or detachment. Conversely, healthspan (orange arrow) is the part of the podocyte’s lifespan spent in good health. It is not binary as it changes dynamically throughout life (gradient orange-green arrow).

Figure 2.

Changes to podocytes in the aged human and rodent kidney. (A) Schema of the microcosm of cell types comprising a young glomerulus. (B) Glomerular size (hypertrophy) is increased in the aged kidney (ruler shown below). Podocytes detach, hypertrophy, efface, apoptose, and undergo pyroptosis. Parietal epithelial cells (PECs) become activated and decrease in number due to loss, mesangial cells are expanded, and glomerular endothelial cells become injured. Created with BioRender.com.

Figure 3.

Loss of autocrine and paracrine functions in aged podocytes. (A) In young human and rodent glomeruli, podocytes produce ligands (represented by circles, squares, and rectangles) that bind to receptors on podocytes for autocrine effects to maintain podocyte health. Likewise, podocyte ligands bind receptors on neighboring parietal epithelial cells and fenestrated glomerular endothelial cells for paracrine effects that maintain their health. (B) In the aged mouse kidney, data support a decrease in podocyte autocrine and paracrine functions, which adversely affects the health of podocytes, parietal epithelial cells, and glomerular endothelial cells. This is further compounded by an increased inflammatory and senescent-associated secretory phenotype (SASP), which in aged podocytes exert an injurious autocrine effect on podocytes and paracrine effect on neighboring parietal epithelial cells and glomerular endothelial cells. Created with BioRender.com.

Figure 4.

Summary of mechanisms and subsequent consequences in aged podocytes. Multiple mechanisms (listed in the red box) contribute to podocyte aging in humans and rodents. These molecular and cellular changes decrease the podocyte’s lifespan and healthspan each leading to physiologic and pathologic consequences. Created with BioRender.com.