Renal Aging: Causes and Consequences

Abstract

Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis-age-associated histologic changes in the kidneys. Recent studies have shown that the aged kidney undergoes a range of structural changes and has altered transcriptomic, hemodynamic, and physiologic behavior at rest and in response to renal insults. These changes impair the ability of the kidney to withstand and recover from injury, contributing to the high susceptibility of the aged population to AKI and their increased propensity to develop subsequent progressive CKD. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging in both experimental animal models and humans. We also discuss the potential for additional study to increase understanding of the aged kidney and lead to novel therapeutic strategies.

Keywords: Aging; glomerulosclerosis; kidney dysfunction; metabolism; molecular biology; progression of renal failure.

Figure 1.

Functional and structural changes in the aging kidney. With increasing age, there are alterations in the function of the kidney. These are accompanied by both macroscopic and microscopic changes and result in an alteration in the response of the kidney to diverse insults. GBM, glomerular basement membrane; T_x, transplant.

Figure 2.

Alterations in cellular and physiologic pathways in the aging kidney. Diverse physiologic, cellular, and gene expression alterations occur in the aging kidney, affecting homeostasis, function, and the response to renal injury.

Figure 3.

Cell cycle progression in the aged kidney. Cell cycle arrest in G1/S phase becomes more prevalent with age and results in p16^INK4a–positive senescent cells expressing multiple cytokines and promoting autocrine and paracrine changes in aged kidneys. Although studies are lacking in aged animals, increased G2/M cell cycle arrest in response to injury promotes maladaptive repair in murine kidney injury, with raised G2/M counts correlating with fibrosis.^, G2/M cell cycle arrest may have variable effects in different cell types, being profibrotic in renal tubular cells but preventing intimal hyperplasia in young smooth muscle cells. CTGF, connective tissue growth factor β; GROa, human growth regulated oncogene-α; CDK, cyclin-dependent kinase.

Figure 4.

Age-related pathways contributing to altered renal outcomes in the elderly. Multiple pathways interact to produce the changes of renal aging and ↓GFR. Black text indicates implicated upstream effectors of aging, whereas red text reports the functional and histologic changes found in the aged kidney. NO/AA/ANP, nitric oxide/amino acids/atrial natriuretic peptide; SA, senescence associated; TIMP, tissue inhibitors of metalloproteinases; TTKG, trans-tubular potassium gradient.

Figure 5.

Potential pathways and therapeutic targets for the treatment of renal aging. Proposed aging–associated pathways (left), and potential interventions to address them (right) coded by current use in patients (green), experimental use in models of renal disease/aging (orange), and potential for future study in the kidney (red). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.