Table 1.

Studies of putative aging pathways in vitro, in vivo, and in human

Aging Factor	In Vitro Studies	Experimental Studies	Human Studies
Telomere shortening	Shown in cells to reduce with length of passage. Critical shortening leads to senescence105	Reduced in mice with age.107 Impaired regeneration after IRI108	Reduced with age, oxidative stress, CKD, and HD.149,151 Risk factor for CVD150
Klotho signaling	Klotho opposes signaling of IGF1 and insulin42 in cell lines in vitro	Klotho deficiency decreases lifespan.44 Overexpression reduces IGF1 and Wnt signaling and increases lifespan42	Reduced with age.131 Reduction associated with calcification and vascular disease135
Wnt signaling	Promotes profibrotic genes (e.g., Snail, PAI1, and MMP7)51	Levels increase with injury and in response to falling Klotho with aging.52 Mediates renal RAAS signaling57	Increases seen in CKD and linked to organ fibrosis196
PPARγ levels	Reduces oxidative stress/senescence in human fibroblasts63	Reduced activity with age.58,59 Agonists reduce renal inflammation/injury64	Studies of PPARγ agonists suggest reduction in rates of proteinuria in patients with diabetes137
Antioxidant capacity		Aged rats have reduced renal antioxidant capacity and enhanced renal injury.78 Reduced oxidative stress lessens renal injury197	Higher levels of oxidative stress in human aging and CKD.73 AGE accumulates with age141
Fibrosis	AT2 promotes fibrosis of glomerular cells and promotes reduction of SIRT-389	Collagens I and III and TGF-β are upregulated in aging mice50 and rats.65 G2/M arrest is implicated in postinjury renal fibrosis92	Nephrosclerosis is a feature of aging and of hypertensive renal disease.10,11 Fibrosis and AT2 hypersensitivity seen in aged kidneys140
Senescence/G1 arrest	Human and animal cells undergo senescence in vitro in response to stress or prolonged culture.94 p16INK4a KO epithelial cells convert to mesenchyme more readily101	p16INK4a and SA-β-galactosidase are markers for senescent cells and increased in aged animals and postinjury. G2/M arrest seen in scarred kidneys in response to injury92	Increased numbers of senescent renal cells correlate with increased injury and reduced transplant function145,146
Vascular changes	Aged mice aortas have increased G2/M–phase cell cycle arrest in vitro198	Reduced renal capillary density in aged mice124 and in response to severe IRI114	Increased renal vascular tone and vascular stiffening with age.199 Loss of efficacy of vasodilators200
Pericyte behavior	Pericytes (but not myofibroblasts) stabilize endothelial cell cultures in vitro173	Reduction of interstitial pericytes with aging.124 Increased myofibroblasts in response to UUO and IRI201	Comparative studies in aged humans (with or without CKD) have not been undertaken

Changes in activity of various signaling pathways and mechanisms implicated in the response of kidney to increasing age. Column 2 indicates cellular changes observed in vitro, column 3 reports effects seen in experimental models of renal aging and injury, and column 4 shows any reported effects in human aging and renal disease. HD, hemodialysis; CVD, cardiovascular disease; PAI1, plasminogen activator inhibitor 1, RAAS, renin-angiotensin-aldosterone system; SIRT-3, sirtuin-3; KO, knockout; SA, senescence associated; UUO, unilateral ureteral obstruction.