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.

The Centers for Disease Control and Prevention predicts that 72 million Americans will be ages 65 years old or older by 2030, accounting for approximately 20% of the United States population.¹ Eurostat predicts that 28% of Europeans will be ages over 65 years old by 2060.² These increasing numbers of elderly individuals will inevitably lead to increasing diagnoses of age–related kidney impairment.

In renal aging, a complex interplay of genetics, environmental change, and cellular dysfunction leads to characteristic structural and functional changes.³ This review summarizes our current understanding of the factors driving age-associated changes in the kidney.

Clinical Features of Renal Aging in Humans

Structural Changes of Aging

With age, there is a decline in total nephron size and number, tubulointerstitial changes, glomerular basement membrane thickening, and increased glomerulosclerosis (Figure 1).^4,5 This age–related histologic appearance is frequently described as nephrosclerosis, and it describes a combination of two or more histologic features: any global glomerulosclerosis, tubular atrophy, interstitial fibrosis >5%, and any arteriosclerosis. A study of healthy kidney donors showed nephrosclerosis in only 2.7% of biopsies from donors <30 years old, 58% from donors 60–69 years old, and 73% from donors >70 years old.⁶ Cadaver studies estimate that the upper limit of normal glomerulosclerosis in aging exceeds 10%.⁷

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.

Nephrosclerosis remains a poorly understood observation, and its importance within an aging kidney is far from clear. We know that nephrosclerosis correlates with aging and mild hypertension in healthy living donor kidneys.⁸ Importantly, however, age-related decline in measured GFR does not correlate with the presence or absence of nephrosclerosis.⁹ In fact, nephrosclerosis does not correlate with urine albumin excretion, family history of ESRD, body mass index, serum cholesterol, glucose, or uric acid.⁶ It remains unclear then whether nephrosclerotic changes have any contribution to the functional changes seen in aging or are perhaps distinct and unrelated.^10,11

The Aging-CKD Spectrum

Our understanding of the pathways underlying renal aging is incomplete and derived from studies of healthy aging kidneys and extrapolation from experimental and clinical studies of CKD.

It is important to note the distinction between these conditions, with the mechanisms of progressive genetic–, immune–, or toxin–mediated injury seen in CKD distinct from the gradual, prevalent changes seen in the aging kidney. Throughout this review, we will focus on the changes seen in the healthy aged kidney, although due to the paucity of experimental and clinical data available in aging kidneys, at times, reference will be made to mechanisms in progressive CKD, which may also be of relevance to the uninjured but aged kidney. Processes discussed below, such as cellular senescence, fibrosis, vascular rarefaction, and glomerular loss, are common to both aging and CKD, despite differences in causation and natural history. Similarities are also seen in the behavior of the chronically damaged kidney and the aged kidney, including their heightened susceptibility to additional injury and deficient repair.¹²

Declining GFR

Population GFR declines with age, with longitudinal studies differing in their reported rates of decline.^13,14 Although the Modification of Diet in Renal Disease Study suggested renal function declined at a rate of 3.8 ml/min per year per 1.73 m², rates as low as 0.4 ml/min per year per 1.73 m² in The Netherlands have been described.^15–18 A Japanese cohort study suggests that the rate of GFR decline increases with advancing age.¹⁹

Studies of robustly phenotyped Kuna Indians with minimal prevalence of hypertension and cardiovascular disease show comparable declines in renal function over time, suggesting that there is a true age–related decline rather than the cumulative effects of cardiovascular disease.²⁰ How a significant minority of individuals apparently remains free of nephrosclerosis and GFR loss remains poorly understood and merits additional study.

Decreased Tubular Function

Aging is characterized by progressive tubular dysfunction, decreased sodium reabsorption, potassium excretion, and urine concentrating capacity potentially contributing to an increased susceptibility to AKI.^21–23 Elderly patients show decreased transtubular potassium gradients and fail to increase distal tubule potassium excretion when hyperkalemic or in response to fludrocortisone.²⁴ Decreased potassium excretion correlates with decreasing GFR and may reflect a degree of reduced sodium and chloride delivery to the distal convoluted tubule.²⁵

Vascular Changes

There are important changes to blood vessel structure and function in the aging kidney. There is increased extracellular matrix (ECM) deposition, increased intimal cell proliferation in preglomerular arterioles, and increased intrarenal shunting and capillary bypassing predominantly affecting the cortex.²⁶

Increased renal sympathetic tone increases vasoconstriction, whereas aortic baroreceptor attenuation of sympathetic tone decreases with age.^27,28 Renal vasodilators, such as atrial natriuretic peptide, nitric oxide (NO), and amino acids, become less effective.^29–31 Human studies show decreased NO production and platelet responsiveness,³² with accumulation of the NO synthase inhibitor asymmetric dimethylarginine in elderly individuals.³³ In particular, aging men become increasingly NO dependent to maintain renal plasma flow.³⁴

Biologic Processes and Mediators Implicated in Experimental Aging

Most rodent experimental models of renal disease are undertaken in young animals, potentially affecting their relevance to the aging kidney. There are limited or no data available regarding the response of the aged rodent kidney to experimental GN, AKI, ureteric obstruction, diabetic nephropathy, 5/6th nephrectomy, adriamycin nephropathy, or renal transplantation. Some aspects of renal aging may be studied in vitro, but others require study in vivo in aged mice or other experimental animals (Table 1).

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.

Studies have shown increased susceptibility of the aged kidney to ischemia-reperfusion injury (IRI) or toxic AKI.^35,36 Aged mice exhibit increased mortality, AKI severity, and chemokine/cytokine responses in a model of uterine sepsis.³⁷ Furthermore, aged mice exhibited increased mortality, prolonged injury, reduced regeneration, increased scarring, and microvascular rarefaction after renal IRI compared with young mice.³⁸

The biology of aging is complex, involving diverse changes to cells, tissues, organs, and the surrounding microenvironment (Figure 2). Many of these processes and mediators are discussed below, but the reader should appreciate that this list is not exhaustive.

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.

Signaling Pathways and Oxidative Stress in the Aging Kidney

Falling Klotho Levels

Klotho is a transmembrane protein strongly expressed in the kidney and a coreceptor for fibroblast growth factor-23 (FGF-23). Although its exact physiologic role in aging remains incompletely understood, Klotho has a role in modulating diverse aging–associated pathways. These include calcium and phosphate metabolism, with implications for vascular calcification, hypoxia, cellular regeneration, and senescence. Indeed, homozygous transgenic Klotho knockout mice show arteriosclerosis and vascular changes as part of their aging phenotype.³⁹ Similarly, FGF-23 knockout mice display high serum phosphate and increased renal phosphate reabsorption in addition to their aging-like phenotypes.^40,41 It may be that these vascular changes contribute directly to the aging phenotype that we observe.

Klotho’s effects on tissue function, autophagy, and fibrosis could contribute to abnormal healing and possibly, nephrosclerosis.^42,43 Importantly, Klotho-deficient mice exhibit reduced lifespan, skin and muscle atrophy, osteoporosis, and ectopic calcification.⁴⁴ Conversely, mice overexpressing Klotho have a longer mean lifespan.⁴²

Klotho decreases epithelial senescence in response to oxidative stress, reduces binding of NFκB, and increases cell survival in experimental uremia.⁴⁵ Klotho also represses insulin and IGF1 signaling, likely contributing to reduced oxidative stress in mice and in vitro models using Klotho overexpression.^42,44,46 Importantly, Klotho supplementation in a rat UUO model attenuated renal fibrosis.⁴⁷

Increasing Wnt Activation

Mechanisms for the antifibrotic effects of Klotho include suppression of FGF and modulation of Wnt signaling.^48–50 Wnt is a conserved signaling pathway activated postinjury that promotes profibrotic gene expression.⁵¹ As Klotho levels fall during aging, Wnt signaling increases, promoting fibrosis and vascular calcification,⁵² although additional experiments are required to clarify causality. Wnt activation promotes renal fibrosis in murine models and is a target for inhibition,^53,54 with antagonism of Wnt and its downstream targets ameliorating experimental renal fibrosis.^55,56 The interplay between potentially causative pathways is illustrated by studies showing that renin-angiotensin-aldosterone signaling is Wnt mediated, with experimental blockade protecting mice from postinjury fibrosis and proteinuria.⁵⁷

Declining Peroxisome Proliferator–Activated Receptor-γ Levels

Peroxisome proliferator–activated receptor-γ (PPARγ) is a nuclear receptor with activity that decreases with age in experimental rodent models, whereas PPARγ agonists increase Klotho expression.^58,59 The PPARγ pathway protects against oxidative stress and improves vascular function in vitro and in aging rats,^60–62 with PPARγ agonists protecting human fibroblasts against features of aging and oxidative stress in vitro.⁶³ PPARγ agonism by pioglitazone or baicalin improves age–related vascular oxidative stress or renal inflammation, respectively, providing a potential therapeutic strategy for elderly patients with reduced PPARγ activity.^59,64

Angiotensin II

Angiotensin II (AT2) is increased in aged rats compared with young controls,⁶⁵ driving increased fibrosis, glomerular cell growth and ECM accumulation,⁶⁶ altered mitochondrial redox function, and cytoplasmic oxidative stress in the aging kidney.^65,67,68 Angiotensin I receptor activation simulates the profibrotic β-catenin/Wnt pathway mentioned above.⁶⁹ Treating aging rats with captopril reduces TGF-β activity and attenuates renal fibrosis.^70,71 AT2 antagonism via ACEi/ARB improves mitochondrial number and function in rats, and additional studies are warranted.⁷²

Oxidative Stress

A balance exists in tissues between reactive oxygen species (ROS) generation and oxidant scavenging and defense mechanisms. When this balance is disturbed by increased generation of ROS, decreased detoxification, or both, then oxidative stress may occur. It has been hypothesized that oxidative stress leads to tissue damage and contributes to the aging phenotype. Certainly, there is evidence in murine and human studies of both increased ROS generation and altered oxidant removal in aging.^73–75

There is a continuous generation of oxidative species through various mechanisms, including mitochondrial oxidative phosphorylation, which increases within the aging kidney.^75,76 Studies in aged rat kidneys support the theory that there is also reduced oxidant defense showing decreased antioxidative capacity and reduced levels of Cu/Zn-SOD, catalase, and GSH reductase.^77,78 This overall increased oxidative load may contribute to chronic cellular stress and mitochondrial injury⁷⁶ as well as apoptosis and possibly, may induce tubular cell damage.^79,80

Contributing to this increased oxidative stress, it has been noted that sirtuins (important antioxidant molecules) are diminished with age. Sirtuins protect against renal inflammation, fibrosis, and apoptosis while improving autophagy.^81,82 Thus, defective ability to respond to cell stress in aged kidneys may contribute to the aged phenotype.⁸³ Mouse models of reduced SIRT-1 expression show increased apoptosis and fibrosis after UUO.⁸⁴ Additional Sirtuin functions include histone deacetylation and regulation of transcription factors controlling cellular stress and survival.^85,86 Altered Sirtuin levels in aging may contribute to aging phenotypes by altering the kidneys capacity to respond to oxidative stress and thus, suffering increased oxidative DNA damage.^87,88 Interestingly, AT2 downregulates SIRT-3 in vitro, suggesting that the damaging effects of raised AT2 levels and low Sirtuin levels may be related in the aging kidney.⁸⁹

Cell Cycle Progression in the Aged Kidney

Aged animals have reduced proliferative responses after experimental IRI. Tubular epithelial cells in aged mice express higher levels of zinc-α-(2)-glycoprotein (AZGP1), limiting proliferation after IRI.⁹⁰ Although reduced proliferation might be expected to delay recovery, AZGP1 knockout mice displayed worsened fibrosis after IRI, with AZGP1 administration being protective, implicating control of proliferation as a mechanism-limiting fibrosis with aging.⁹¹ Studies in several CKD models show that G2/M arrest in tubular epithelial cells promotes renal fibrosis, but no studies have examined G2/M arrest in aging kidneys.⁹²

Cellular senescence, defined as a state of permanent cell cycle arrest, is a key antiproliferative response to aging and injury. This crucial process shuts down damaged cells, protects against malignant transformation, and limits excess fibrosis at both baseline and after injury.⁹³

Senescence may occur as a result of repeated cell division and telomere shortening (replicative senescence) or after factors, such as oxidative stress or genotoxic injury (stress–induced premature senescence) (Figure 3).⁹⁴ Increased numbers of senescent cells accumulate in multiple organs, including the kidney with advancing age (identified by p16^INK4a or senescence–associated β-galactosidase expression).

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.^92,194 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.¹⁹⁵ CTGF, connective tissue growth factor β; GROa, human growth regulated oncogene-α; CDK, cyclin-dependent kinase.

Cell senescence limits fibroblast proliferation in tissue wounds; however, there is increasing interest in the role of the Senescence–Associated Secretory Phenotype (SASP) in promoting fibrosis.⁹³ SASP promotes fibrosis and organ dysfunction in aging via release of factors, including IL-6, IL-8, Wnt16B, and GROα.^95–97 Studies in murine renal transplantation showed that renal p16^INK4a deletion reduced pathologic changes and interstitial fibrosis post-IRI, supporting clinical findings that cellular senescence contributes to adverse long–term allograft outcomes.⁹⁸ Cell stress is known to induce stress–induced premature senescence, and consistent with this, porcine models have shown that renal p16^INK4a expression increases after IRI.⁹⁹ Interestingly, p16^INK4a knockout mice exposed to experimental renal injury show improved recovery after IRI but worsened fibrosis after UUO.^100,101 These superficially inconsistent findings may reflect the different pathologic processes at play, with p16^INK4a deficiency leading to less cell death and enhanced regenerative proliferation in AKI but the lack of p16^INK4a-induced senescence inducing an exaggerated, maladaptive fibroblast response to ongoing injury in UUO.

Recent seminal studies used transgenic animals to induce specific depletion of p16^INK4a expressing senescent cells and showed reduced markers of aging in multiple organs, including the kidney, and increased overall lifespan.¹⁰² Other work has used Bcl2/xL inhibitors to deplete senescent cells in nontransgenic animals.¹⁰³ Although these findings open up exciting new therapeutic avenues for the selective targeting of senescent cells to prolong healthy lifespan, additional studies focusing on the aging kidney are required.

Telomere Shortening

Telomeres are nucleotide sequences that act as a defensive cap, limiting activation of DNA repair pathways, protecting genetic material, and minimizing background cellular stress response.^104,105 Although telomere length declines with age, it remains controversial whether this is a primary process or a byproduct of aging.^104,106 As telomeres shorten with aging and oxidative stress, chromosome instability ensues, leading to cellular instability, senescence, and subsequent apoptosis.¹⁰⁷

Increased telomere shortening in telomerase-deficient mice is associated with increased tubular injury and reduced tubular proliferation after renal IRI, with reduced tubular cell autophagy implicated in the limited regenerative response.^108,109 This implies a potential causal role for telomere shortening in some of the vulnerability of aging kidneys to injury, and it is noteworthy that experimental elongation of shortened telomeres resulted in partial reversal of aged organ degeneration.¹¹⁰

Hypoxic Damage and Disordered Repair

Under physiologic conditions, the kidney is supported by a network of resident mononuclear phagocytes and pericytes contributing to tissue homeostasis and vascular stability. Renal oxygen delivery and the functional status of resident and recruited cells in the kidney have been shown to alter in aged and injured experimental animals.

Hypoxia

Although the healthy kidney has areas of low oxygen tension, reduced capillary density and increased hypoxia are recognized as potential drivers of CKD, and the role in normal aging is being explored. In experimental CKD, the expected angiogenic response to hypoxia fails, instead resulting in fibrosis.¹¹¹ Increased renal hypoxia has also been shown throughout aged rat kidneys, most prominently in the cortical zones, as detected by use of the hypoxia–sensitive marker pimonidazole.¹¹² Aged rat kidneys show decreased VEGF globally and increased antiangiogenic thrombospondin-1, resulting in capillary loss with increased glomerular sclerosis.¹¹³ Recently reported techniques to quantify subtle changes in the renal vasculature have potential to yield new information on the evolution of renal circulatory changes and hypoxia with advancing age.¹¹⁴

Leukocytes

Changes in leukocyte function promoting inflammatory activation occur with aging, although whether this is a cause or effect of aging remains unclear.¹¹⁵ Increased inflammatory signaling and macrophage infiltration¹¹⁶ with alterations in inflammasome components, such as NOD–like receptor P3, NLRC4, procaspase-1, NFκB, and cytokines, including IL-1β and IL-18, occur in aging.¹¹⁷ Aged murine macrophages show impaired autophagy and reduced nitrate release and phagocytosis.¹¹⁸ Healthy aged mice have increased glomerular macrophage numbers with increased macrophage infiltration evident postinjury, with renal IRI models showing an increased influx of macrophage and T lymphocytes.^38,119 Additionally, aged mice show defective upregulation of the cytoprotective enzyme hemoxygenase-1 after IRI, with pharmacologic macrophage hemoxygenase-1 induction protecting against subsequent IRI.³⁵ Finally, aged macrophages express reduced anti–inflammatory IL-10 during tissue repair in nonrenal injury models.¹²⁰ Given the importance of IL-10 and the negative prognostic role of macrophage infiltrates in human renal disease, these aging-associated changes potentially contribute to the increased rates of injury and maladaptive repair seen in aged kidneys.

Additional evidence for the importance of the aging immune system in renal aging comes from young-old bone marrow transplant studies showing that aged animals receiving bone marrow transplants from young mice exhibited reduced renal fibrosis and cellular senescence.¹²¹

Pericytes

Although important for microvascular health, pericytes are also recognized as key cells in renal fibrosis.^122,123 In aged mice, renal pericytes decline in number and adopt a profibrotic phenotype,¹²⁴ implicating them in aging–related fibrotic changes. Pericyte-endothelial detachment under pathologic conditions and their differentiation into myofibroblasts promote microvascular rarefaction, hypoxia, and fibrosis.^125,126 Proposed mediators of this pericyte-endothelial crosstalk include VEGF and PDGF,¹²⁷ and blocking this pericyte-endothelial interaction attenuates microvascular damage and interstitial fibrosis.^128,129

Disordered Repair

The normal enzymatic equilibrium is disturbed in aging, and the balance of metalloproteinases (MMPs) shifts toward fibrosis, potentially via upregulation of tissue inhibitor of MMP1 and increased leukocyte recruitment,⁵⁰ a pattern likely to result in increased collagen deposition. Longitudinal studies of aging mice show increased Collagen I, Collagen III, and TGF-β1,⁵⁰ whereas aging rat kidneys exhibit increased ECM deposition and TGF-β3 expression and decreased MMP1 activity, suggesting altered collagen production and processing.¹³⁰ Additional noninflammatory pathways may contribute to the histologic changes seen, including pathways driven by Wnt and AT2 as mentioned.⁵⁴

The Aging Human Kidney

The clinical implications of renal aging in humans extend beyond changes in glomerular and tubular function. Although data generated by animal studies implicate multiple pathways of potential importance for human renal aging (Figure 4), data supporting their involvement in humans are currently sparse, with additional studies required.

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.

Signaling Pathways and Oxidative Stress in the Aging Kidney

Falling Klotho Levels

Klotho and FGF-23 are present in human kidneys.¹³¹ Klotho levels decline with age and are implicated in accelerated age–related CKD and atherosclerosis.^132,133 Conversely, patients with increased functional Klotho expression are reported to have increased lifespan.¹³⁴ As Klotho falls, FGF-23 levels increase and alter phosphate and calcium homeostasis. Clinical studies in patients on dialysis and patients with CKD show that higher FGF-23 levels associate with increased mortality.¹³⁵

Increasing Wnt Activation

Although direct evidence of Wnt activation in human aging is lacking, several Wnt antagonists are now undergoing phase 1 clinical trials for cancer therapy in humans.¹³⁶ If effective, these agents offer new therapeutic options for aging–associated or fibrotic renal disease.

Declining PPARγ Levels

Agonists of PPARγ are used clinically as antidiabetic agents. Retrospective reviews of renal outcomes in clinical practice suggest that augmented PPARγ activity opposes proteinuria in these patients.¹³⁷ A meta-analysis of PPARγ use has also shown that they associate with reduced rates of cerebrovascular disease, supporting a role in delaying age–associated pathology.¹³⁸ There is a need for prospective trials assessing their effects on renal function.

AT2

Despite decreased plasma renin activity in the elderly, serum AT2 levels do not fall, and hypersensitivity to AT2 develops in the renal vasculature.^139,140 Although ACEi and ARB drugs are in widespread use, there is a lack of human data on the effect of AT2 blocking treatments on normal renal aging and outcomes at present.

Oxidative Stress

As discussed, oxidative stress represents a disruption of the balance of oxidant handling in tissues. In humans, longitudinal studies show increased oxidative stress in normal aging and CKD.^73,141 Research has focused on advanced glycation end products as drivers of oxidative stress in aging. These molecules accumulate with age and are associated with increased arterial stiffness, inflammation, oxidative stress, and declining renal function.¹⁴² One pharmacologic attempt to modify antioxidant status in patients with diabetic nephropathy showed no effect on proteinuria, despite increased circulating antioxidant levels.¹⁴³ Whether an alternative, longer–term treatment approach in the healthy aged population might have efficacy remains untested.

Cell Cycle Progression in the Aged Kidney

The presence of increased numbers of senescent cells has been noted in chronic allograft nephropathy and proposed as drivers of the progressive fibrosis seen.¹⁴⁴ Recent advances in our understanding of the roles of aging and stress in inducing the detrimental SASP phenotype add to the importance of senescence cells found in both aged and disease–affected human renal biopsies.^145–147 In humans, senescence is maximal in the medulla, potentially reflecting increased oxidative and cellular stress and relative hypoxia resulting from the vascular changes discussed previously.¹⁴⁸

Telomeres

Telomeres shorten in human kidneys at a rate of 0.25% length per year.¹⁴⁹ Although telomere shortening provides an elegant explanation of cellular aging, currently, no data exist to link shorter telomeres to any histologic or functional measure of renal aging. Shorter telomeres associate with CKD and worse cardiovascular outcomes and are shorter in diabetic nephropathy, where they associate with rates of disease progression.^150,151 Furthermore, studies of patients on hemodialysis show increased rates of telomere attrition, suggesting that they shorten in response to the physiologic stress.¹⁵² Although intriguing, the importance of telomere shortening in human aging remains to be elucidated.

Hypoxia, Inflammation, and Nephrosclerosis in the Aged Kidney

Because of the inherent risks of renal biopsy, samples of healthy aged kidney are seldom available for assessment of levels of nephrosclerosis, and there are no time course studies available to chart the temporal relationships of the histologic findings in the aged kidney. Ongoing progress in imaging technology should enable serial noninvasive assessment of renal perfusion, vascular resistance, hypoxia, inflammation, and atrophy in healthy young and aged volunteers.

Renal Hypoxia

The clinical use of BOLD MRI imaging has shown a lower Po₂ in older kidneys compared with younger subjects.¹⁵³ Because intrarenal vascular disease contributes to increased glomerular sclerosis in aged biopsies, it is possible that subclinical disease leads to hypoxia before marked macroscopic changes occur.¹⁵⁴

Inflammation

Inflammation is increased within the aging kidney in humans, with proinflammatory cytokines detectable in the serum correlating with age–related renal disease.^155,156

Future Research

Reviewing the current evidence base in clinical and experimental renal aging, it is clear that more work is required to understand which pathways are dispensable and which represent master regulators of the aging phenotype. Studies in aged animals should allow characterization of both the importance and interdependence of factors predisposing aged kidneys to injury, fibrosis, and maladaptive repair, with subsequent validation in humans. Because of the time and cost constraints inherent in using aged animals, establishing whether models of genetically accelerated aging, such as the BubR1 progeroid mouse, represent useful models of renal aging will be of value.¹⁵⁷ BubR1 mice have a shortened lifespan and exhibit a variety of age-related phenotypes, including sarcopenia, cataracts, fat loss, cardiac arrhythmias, arterial wall stiffening, and impaired wound healing. Specific to kidney research, BubR1-deficient mice also show higher senescence–associated β-galactosidase activity in kidney sections than aged matched controls.¹⁵⁸ Whether they truly manifest a renal aging phenotype has yet to be determined.

Circulating Factors

Heterochronic parabiosis with aged and young mice sharing a common circulation has provided evidence in nonrenal models that circulating factors may modulate features of aging, including impaired regeneration and increased fibrosis.^159–161 Proposed factors include β2-microglobulin and growth differentiation factor 11, and reversal of changes in the brain, cardiac, and skeletal muscle has been shown.^162–164 Debate continues as to the significance of individual factors.^165–169 Whether such factors affect the function of the aged kidney remains completely unknown.

Novel Experimental Species

Undertaking studies of experimental renal disease in aged mice is challenging, and other organisms may be of use. Zebrafish have been used as a model for AKI and nephron regeneration and exhibit aging-associated abnormalities.^170–172 Thus, the use of genetically manipulated zebrafish in renal aging studies may be informative.

Novel Therapeutic Strategies

Many pathways implicated in the aging process are the target of interventions to improve the aging phenotype in experimental mice (Figure 5). Klotho agonists are under investigation via repurposing of established agents, including PPARγ agonists and ACEi and ARB drugs. The importance of maintaining a normal renal microvasculature and pericyte pool is increasingly understood,¹⁷³ and developing strategies to quantify microvascular function and promote endothelial and pericyte health are a pressing clinical need.¹¹⁴

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.

Drugs targeting cellular senescence (senolytics) include siRNA therapies, the experimental agent navitoclax, and the licensed drugs dasatinib and quercetin.¹⁷⁴ In experiments, these agents show selective toxicity to senescent cells, and their potential utility in animal models and humans merits additional study.

Genetics

Genome–wide association studies (GWASs) have identified upregulation of several genes with aging. Although cumulative damage may well influence much of the elderly genetic milieu, candidate genes have declared themselves as being consistently highly expressed in aged kidneys.^175–177 Despite the utility of GWAS in identifying disease-specific pathways, it has proved difficult to discover any canonical aging pathways with GWAS.¹⁷⁸

The most promising genes encode for modulators of the glomerular filtration barrier, fibrosis, and inflammatory mediators, although difficulty arises when identified candidate genes do not match the experimental observations or models.^179,180 Transcriptomic analysis identified 427 genes strongly associated with renal aging, including mortalin-2, a heat shock protein that may counteract cell senescence, and IGF receptor, a target of Klotho.^181–183

GWAS remains, however, a promising tool, because whole-genome analyses of GWAS data suggest that over 80% of the heritability of aging is explained by common genetic variants.¹⁸⁴ Future GWASs will continue to generate meaningful results as more advanced statistical techniques develop and researchers increase statistical power by increasing samples number, combining studies using meta-analytic techniques, using multicenter collaborations, and including more extreme phenotypes in the data.^184–187

Epigenetics

Epigenetics is the study of genome changes that do not alter DNA sequence. Epigenetic changes in aging include methylation and deacetylation of histone lysine residues, chromatin changes, and increased transcriptional noise.^178,188 Interestingly, similar changes in DNA methylation and histones are associated with CKD disease progression.^189–191 The role of microRNA expression in modifying gene expression and nephrosclerosis is of interest,¹⁹² with data in other organs suggesting an influence on aging.¹⁹³

Conclusion

Renal aging is complex and remains incompletely understood. Decreased protective factors, hypoxia, and microenvironmental stress drive increasingly disordered inflammation and renal fibrosis. The resulting fibrosis, senescence, and microvascular rarefaction exacerbate damage and promote progression. The future of treating renal aging is likely in understanding the key initiating events and the common downstream pathways present in kidney aging that may be shared with CKD. This knowledge should allow the development of therapies capable of arresting the key mechanisms early to preserve kidney function throughout life.

Disclosures

None.