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Renal Aging: Causes and Consequences


Eoin D. O’Sullivan,* Jeremy Hughes,*† and David A. Ferenbach*†‡§
*Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; †MRC Centre for
Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and

Renal and §Biomedical Engineering Divisions, Brigham and Women’s Hospital, Department of Medicine, Harvard
Medical School, Boston, Massachusetts

ABSTRACT
Individuals age .65 years old are the fastest expanding population demographic of nephrosclerosis.9 In fact, nephrosclerosis
throughout the developed world. Consequently, more aged patients than before does not correlate with urine albumin ex-
are receiving diagnoses of impaired renal function and nephrosclerosis—age–associated cretion, family history of ESRD, body mass
histologic changes in the kidneys. Recent studies have shown that the aged kidney index, serum cholesterol, glucose, or uric
undergoes a range of structural changes and has altered transcriptomic, hemodynamic, acid.6 It remains unclear then whether
and physiologic behavior at rest and in response to renal insults. These changes impair nephrosclerotic changes have any contribu-
the ability of the kidney to withstand and recover from injury, contributing to the high tion to the functional changes seen in aging
susceptibility of the aged population to AKI and their increased propensity to develop or are perhaps distinct and unrelated.10,11
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 The Aging-CKD Spectrum
changes observed with aging in both experimental animal models and humans. We also Our understanding of the pathways un-
discuss the potential for additional study to increase understanding of the aged kidney derlying renal aging is incomplete and
and lead to novel therapeutic strategies. derived from studies of healthy aging kid-
neys and extrapolation from experimen-
J Am Soc Nephrol 28: ccc–ccc, 2016. doi: 10.1681/ASN.2015121308
tal and clinical studies of CKD.
It is important to note the distinction
between these conditions, with the mech-
The Centers for Disease Control and Pre- changes, glomerular basement mem-
anisms of progressive genetic–, immune–,
vention predicts that 72 million Americans brane thickening, and increased glomer-
or toxin–mediated injury seen in CKD dis-
will be ages 65 years old or older by 2030, ulosclerosis (Figure 1).4,5 This age–related
tinct from the gradual, prevalent changes
accounting for approximately 20% of the histologic appearance is frequently de-
seen in the aging kidney. Throughout this
United States population.1 Eurostat pre- scribed as nephrosclerosis, and it describes
review, we will focus on the changes seen
dicts that 28% of Europeans will be ages a combination of two or more histologic
in the healthy aged kidney, although due to
over 65 years old by 2060.2 These increas- features: any global glomerulosclerosis, tu-
the paucity of experimental and clinical
ing numbers of elderly individuals will in- bular atrophy, interstitial fibrosis .5%, data available in aging kidneys, at times,
evitably lead to increasing diagnoses of and any arteriosclerosis. A study of healthy
reference will be made to mechanisms
age–related kidney impairment. kidney donors showed nephrosclerosis in
in progressive CKD, which may also be
In renal aging, a complex interplay of only 2.7% of biopsies from donors ,30
of relevance to the uninjured but aged
genetics, environmental change, and cel- years old, 58% from donors 60–69 years
kidney. Processes discussed below, such
lular dysfunction leads to characteristic old, and 73% from donors .70 years
as cellular senescence, fibrosis, vascular
structural and functional changes.3 This old.6 Cadaver studies estimate that the up-
rarefaction, and glomerular loss, are
review summarizes our current understand- per limit of normal glomerulosclerosis in
ing of the factors driving age-associated aging exceeds 10%.7
changes in the kidney. Nephrosclerosis remains a poorly un-
Published online ahead of print. Publication date
derstood observation, and its importance available at www.jasn.org.
CLINICAL FEATURES OF RENAL within an aging kidney is far from clear. We
Correspondence: Dr. Eoin D. O’Sullivan, Department
AGING IN HUMANS know that nephrosclerosis correlates with
of Renal Medicine, Royal Infirmary of Edinburgh, 51
aging and mild hypertension in healthy liv- Little France Cres, EH16 4SA Edinburgh, United King-
Structural Changes of Aging ing donor kidneys.8 Importantly, however, dom. Email: eoindosullivan@gmail.com
With age, there is a decline in total neph- age-related decline in measured GFR does Copyright © 2016 by the American Society of
ron size and number, tubulointerstitial not correlate with the presence or absence Nephrology

J Am Soc Nephrol 28: ccc–ccc, 2016 ISSN : 1046-6673/2802-ccc 1


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BIOLOGIC PROCESSES AND


MEDIATORS IMPLICATED IN
EXPERIMENTAL AGING

Most rodent experimental models of


renal disease are undertaken in young
animals, potentially affecting their rele-
vance to the aging kidney. There are lim-
ited or no data available regarding the
response of the aged rodent kidney to
experimental GN, AKI, ureteric obstruc-
tion, diabetic nephropathy, 5/6th ne-
phrectomy, adriamycin nephropathy,
or renal transplantation. Some aspects
of renal aging may be studied in vitro,
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
but others require study in vivo in aged
and microscopic changes and result in an alteration in the response of the kidney to diverse mice or other experimental animals
insults. GBM, glomerular basement membrane; Tx, transplant. (Table 1).
Studies have shown increased suscepti-
common to both aging and CKD, despite urine concentrating capacity potentially bility of the aged kidney to ischemia-
differences in causation and natural his- contributing to an increased susceptibil- reperfusion injury (IRI) or toxic AKI.35,36
tory. Similarities are also seen in the be- ity to AKI.21–23 Elderly patients show Aged mice exhibit increased mortality,
havior of the chronically damaged kidney decreased transtubular potassium gra- AKI severity, and chemokine/cytokine
and the aged kidney, including their dients and fail to increase distal tubule responses in a model of uterine sepsis.37
heightened susceptibility to additional potassium excretion when hyperkalemic Furthermore, aged mice exhibited in-
injury and deficient repair.12 or in response to fludrocortisone.24 De- creased mortality, prolonged injury, re-
creased potassium excretion correlates duced regeneration, increased scarring,
Declining GFR with decreasing GFR and may reflect a and microvascular rarefaction after renal
Population GFR declines with age, with degree of reduced sodium and chloride IRI compared with young mice.38
longitudinal studies differing in their re- delivery to the distal convoluted tu- The biology of aging is complex, involv-
ported rates of decline.13,14 Although the bule.25 ing diverse changes to cells, tissues, organs,
Modification of Diet in Renal Disease and the surrounding microenvironment
Study suggested renal function declined Vascular Changes (Figure 2). Many of these processes and
at a rate of 3.8 ml/min per year per There are important changes to blood mediators are discussed below, but the
1.73 m2, rates as low as 0.4 ml/min per vessel structure and function in the aging reader should appreciate that this list is
year per 1.73 m 2 in The Netherlands kidney. There is increased extracellular not exhaustive.
have been described.15–18 A Japanese co- matrix (ECM) deposition, increased in-
hort study suggests that the rate of GFR timal cell proliferation in preglomerular Signaling Pathways and Oxidative
decline increases with advancing age.19 arterioles, and increased intrarenal Stress in the Aging Kidney
Studies of robustly phenotyped Kuna shunting and capillary bypassing pre- Falling Klotho Levels
Indians with minimal prevalence of hy- dominantly affecting the cortex.26 Klotho is a transmembrane protein
pertension and cardiovascular disease show Increased renal sympathetic tone in- strongly expressed in the kidney and a
comparable declines in renal function over creases vasoconstriction, whereas aortic coreceptor for fibroblast growth factor-
time, suggesting that there is a true age– baroreceptor attenuation of sympathetic 23 (FGF-23). Although its exact physio-
related decline rather than the cumulative tone decreases with age.27,28 Renal vaso- logic role in aging remains incompletely
effects of cardiovascular disease.20 How a dilators, such as atrial natriuretic pep- understood, Klotho has a role in modulat-
significant minority of individuals appar- tide, nitric oxide (NO), and amino acids, ing diverse aging–associated pathways.
ently remains free of nephrosclerosis and become less effective.29–31 Human stud- These include calcium and phosphate me-
GFR loss remains poorly understood and ies show decreased NO production and tabolism, with implications for vascular
merits additional study. platelet responsiveness,32 with accumu- calcification, hypoxia, cellular regenera-
lation of the NO synthase inhibitor tion, and senescence. Indeed, homozygous
Decreased Tubular Function asymmetric dimethylarginine in elderly transgenic Klotho knockout mice show ar-
Aging is characterized by progressive tu- individuals.33 In particular, aging men teriosclerosis and vascular changes as part
bular dysfunction, decreased sodium re- become increasingly NO dependent to of their aging phenotype.39 Similarly, FGF-
absorption, potassium excretion, and maintain renal plasma flow.34 23 knockout mice display high serum

2 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016
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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 Reduced in mice with age.107 Impaired Reduced with age, oxidative stress,
length of passage. Critical regeneration after IRI108 CKD, and HD.149,151 Risk factor for
shortening leads to CVD150
senescence105
Klotho signaling Klotho opposes signaling of IGF1 Klotho deficiency decreases lifespan.44 Reduced with age.131 Reduction
and insulin42 in cell lines in vitro Overexpression reduces IGF1 and Wnt associated with calcification and
signaling and increases lifespan42 vascular disease135
Wnt signaling Promotes profibrotic genes (e.g., Levels increase with injury and in response Increases seen in CKD and linked to
Snail, PAI1, and MMP7)51 to falling Klotho with aging.52 Mediates organ fibrosis196
renal RAAS signaling57
PPARg levels Reduces oxidative stress/ Reduced activity with age.58,59 Agonists Studies of PPARg agonists suggest
senescence in human reduce renal inflammation/injury64 reduction in rates of proteinuria in
fibroblasts63 patients with diabetes137
Antioxidant capacity Aged rats have reduced renal antioxidant Higher levels of oxidative stress in
capacity and enhanced renal injury.78 human aging and CKD.73 AGE
Reduced oxidative stress lessens renal accumulates with age141
injury197
Fibrosis AT2 promotes fibrosis of Collagens I and III and TGF-b are Nephrosclerosis is a feature of aging
glomerular cells and promotes upregulated in aging mice50 and rats.65 and of hypertensive renal
reduction of SIRT-389 G2/M arrest is implicated in postinjury disease.10,11 Fibrosis and AT2
renal fibrosis92 hypersensitivity seen in aged
kidneys140
Senescence/G1 arrest Human and animal cells undergo p16INK4a and SA-b-galactosidase are Increased numbers of senescent renal
senescence in vitro in response markers for senescent cells and cells correlate with increased injury
to stress or prolonged culture.94 increased in aged animals and and reduced transplant
p16INK4a KO epithelial cells postinjury. G2/M arrest seen in scarred function145,146
convert to mesenchyme more kidneys in response to injury92
readily101
Vascular changes Aged mice aortas have increased Reduced renal capillary density in aged Increased renal vascular tone and
G2/M–phase cell cycle arrest in mice124 and in response to severe vascular stiffening with age.199 Loss
vitro198 IRI114 of efficacy of vasodilators200
Pericyte behavior Pericytes (but not myofibroblasts) Reduction of interstitial pericytes with Comparative studies in aged humans
stabilize endothelial cell cultures aging.124 Increased myofibroblasts in (with or without CKD) have not been
in vitro173 response to UUO and IRI201 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, XXX; RAAS, XXX; AGE, XXX; SIRT-3, XXX; KO, knockout; SA, XXX; UUO, XXX.

phosphate and increased renal phosphate insulin and IGF1 signaling, likely contrib- to clarify causality. Wnt activation pro-
reabsorption in addition to their aging-like uting to reduced oxidative stress in mice motes renal fibrosis in murine models
phenotypes.40,41 It may be that these vas- and in vitro models using Klotho overex- and is a target for inhibition,53,54 with
cular changes contribute directly to the ag- pression.42,44,46 Importantly, Klotho supple- antagonism of Wnt and its downstream
ing phenotype that we observe. mentation in a rat UUO model attenuated targets ameliorating experimental renal
Klotho’s effects on tissue function, auto- renal fibrosis.47 fibrosis.55,56 The interplay between po-
phagy, and fibrosis could contribute to abnor- tentially causative pathways is illustrated
mal healing and possibly, nephrosclerosis.42,43 Increasing Wnt Activation by studies showing that renin-angiotensin-
Importantly, Klotho-deficient mice exhibit Mechanisms for the antifibrotic effects of aldosterone signaling is Wnt mediated,
reduced lifespan, skin and muscle atrophy, Klotho include suppression of FGF and with experimental blockade protecting
osteoporosis, and ectopic calcification.44 modulation of Wnt signaling.48–50 Wnt mice from postinjury fibrosis and pro-
Conversely, mice overexpressing Klotho is a conserved signaling pathway activated teinuria.57
have a longer mean lifespan.42 postinjury that promotes profibrotic gene
Klotho decreases epithelial senescence in expression.51 As Klotho levels fall during Declining Peroxisome Proliferator–Activated
response to oxidative stress, reduces binding aging, Wnt signaling increases, promoting Receptor-g Levels
of NFkB, and increases cell survival in ex- fibrosis and vascular calcification,52 al- Peroxisome proliferator–activated receptor-g
perimental uremia.45 Klotho also represses though additional experiments are required (PPARg) is a nuclear receptor with activity

J Am Soc Nephrol 28: ccc–ccc, 2016 Renal Aging: Causes and Consequences 3
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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


Figure 2. Alterations in cellular and physiologic pathways in the aging kidney. Diverse Kidney
physiologic, cellular, and gene expression alterations occur in the aging kidney, affecting Aged animals have reduced proliferative
homeostasis, function, and the response to renal injury. responses after experimental IRI. Tubu-
lar epithelial cells in aged mice express
higher levels of zinc-a-(2)-glycoprotein
that decreases with age in experimental detoxification, or both, then oxidative (AZGP1), limiting proliferation after
rodent models, whereas PPARg agonists stress may occur. It has been hypothe- IRI.90 Although reduced proliferation
increase Klotho expression. 58,59 The sized that oxidative stress leads to tissue might be expected to delay recovery,
PPARg pathway protects against oxida- damage and contributes to the aging phe- AZGP1 knockout mice displayed wors-
tive stress and improves vascular func- notype. Certainly, there is evidence in ened fibrosis after IRI, with AZGP1 ad-
tion in vitro and in aging rats,60–62 with murine and human studies of both in- ministration being protective, implicating
PPARg agonists protecting human fibro- creased ROS generation and altered ox- control of proliferation as a mechanism-
blasts against features of aging and oxi- idant removal in aging.73–75 limiting fibrosis with aging.91 Studies in
dative stress in vitro.63 PPARg agonism There is a continuous generation of several CKD models show that G2/M
by pioglitazone or baicalin improves oxidative species through various mech- arrest in tubular epithelial cells promotes
age–related vascular oxidative stress or anisms, including mitochondrial oxida- renal fibrosis, but no studies have exam-
renal inflammation, respectively, pro- tive phosphorylation, which increases ined G2/M arrest in aging kidneys.92
viding a potential therapeutic strategy within the aging kidney.75,76 Studies in Cellular senescence, defined as a state
for elderly patients with reduced PPARg aged rat kidneys support the theory that of permanent cell cycle arrest, is a key anti-
activity.59,64 there is also reduced oxidant defense proliferative response to aging and injury.
showing decreased antioxidative capac- This crucial process shuts down damaged
Angiotensin II ity and reduced levels of Cu/Zn-SOD, cells, protects against malignant transfor-
Angiotensin II (AT2) is increased in aged catalase, and GSH reductase.77,78 This mation, and limits excess fibrosis at both
rats compared with young controls,65 overall increased oxidative load may baseline and after injury.93
driving increased fibrosis, glomerular contribute to chronic cellular stress and Senescence may occur as a result of
cell growth and ECM accumulation,66 mitochondrial injury76 as well as apo- repeated cell division and telomere
altered mitochondrial redox function, ptosis and possibly, may induce tubular shortening (replicative senescence) or af-
and cytoplasmic oxidative stress in the cell damage.79,80 ter factors, such as oxidative stress or gen-
aging kidney.65,67,68 Angiotensin I recep- Contributing to this increased oxida- otoxic injury (stress–induced premature
tor activation simulates the profibrotic tive stress, it has been noted that sirtuins senescence) (Figure 3). 94 Increased
b-catenin/Wnt pathway mentioned (important antioxidant molecules) are numbers of senescent cells accumulate
above.69 Treating aging rats with capto- diminished with age. Sirtuins protect in multiple organs, including the kidney
pril reduces TGF-b activity and attenu- against renal inflammation, fibrosis, with advancing age (identified by p16INK4a
ates renal fibrosis.70,71 AT2 antagonism and apoptosis while improving auto- or senescence–associated b-galactosidase
via ACEi/ARB improves mitochondrial phagy.81,82 Thus, defective ability to re- expression).
number and function in rats, and addi- spond to cell stress in aged kidneys may Cell senescence limits fibroblast pro-
tional studies are warranted.72 contribute to the aged phenotype. 83 liferation in tissue wounds; however,
Mouse models of reduced SIRT-1 ex- there is increasing interest in the role of
Oxidative Stress pression show increased apoptosis and the Senescence–Associated Secretory
A balance exists in tissues between reac- fibrosis after UUO.84 Additional Sirtuin Phenotype (SASP) in promoting fibro-
tive oxygen species (ROS) generation and functions include histone deacetylation sis.93 SASP promotes fibrosis and organ
oxidant scavenging and defense mecha- and regulation of transcription factors dysfunction in aging via release of fac-
nisms. When this balance is disturbed by controlling cellular stress and sur- tors, including IL-6, IL-8, Wnt16B, and
increased generation of ROS, decreased vival.85,86 Altered Sirtuin levels in aging GROa. 95–97 Studies in murine renal

4 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016
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transplantation showed that renal p16INK4a kidney, and increased overall life- IRI, with reduced tubular cell autophagy
deletion reduced pathologic changes span.102 Other work has used Bcl2/xL implicated in the limited regenerative re-
and interstitial fibrosis post-IRI, sup- inhibitors to deplete senescent cells in sponse.108,109 This implies a potential
porting clinical findings that cellular nontransgenic animals. 103 Although causal role for telomere shortening in
senescence contributes to adverse long– these findings open up exciting new some of the vulnerability of aging kid-
term allograft outcomes.98 Cell stress is therapeutic avenues for the selective tar- neys to injury, and it is noteworthy that
known to induce stress–induced prema- geting of senescent cells to prolong experimental elongation of shortened
ture senescence, and consistent with this, healthy lifespan, additional studies fo- telomeres resulted in partial reversal of
porcine models have shown that renal cusing on the aging kidney are required. aged organ degeneration.110
p16 INK4a expression increases after
IRI.99 Interestingly, p16INK4a knockout Telomere Shortening Hypoxic Damage and Disordered
mice exposed to experimental renal in- Telomeres are nucleotide sequences that Repair
jury show improved recovery after IRI act as a defensive cap, limiting activation Under physiologic conditions, the kid-
but worsened fibrosis after UUO.100,101 of DNA repair pathways, protecting ge- ney is supported by a network of resident
These superficially inconsistent findings netic material, and minimizing back- mononuclear phagocytes and pericytes
may reflect the different pathologic ground cellular stress response.104,105 contributing to tissue homeostasis and
processes at play, with p16INK4a defi- Although telomere length declines with vascular stability. Renal oxygen delivery
ciency leading to less cell death and en- age, it remains controversial whether and the functional status of resident and
hanced regenerative proliferation in AKI this is a primary process or a byproduct recruited cells in the kidney have been
but the lack of p16INK4a-induced senes- of aging.104,106 As telomeres shorten with shown to alter in aged and injured exper-
cence inducing an exaggerated, maladap- aging and oxidative stress, chromosome imental animals.
tive fibroblast response to ongoing injury instability ensues, leading to cellular in-
in UUO. stability, senescence, and subsequent Hypoxia
Recent seminal studies used trans- apoptosis.107 Although the healthy kidney has areas of
genic animals to induce specific deple- Increased telomere shortening in low oxygen tension, reduced capillary
tion of p16INK4a expressing senescent telomerase-deficient mice is associated density and increased hypoxia are recog-
cells and showed reduced markers of ag- with increased tubular injury and re- nized as potential drivers of CKD, and the
ing in multiple organs, including the duced tubular proliferation after renal role in normal aging is being explored. In
experimental CKD, the expected angio-
genic 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 promot-
Figure 3. Cell cycle progression in the aged kidney. Cell cycle arrest in G1/S phase be-
ing inflammatory activation occur with
comes more prevalent with age and results in p16INK4a–positive senescent cells expressing
aging, although whether this is a cause or
multiple cytokines and promoting autocrine and paracrine changes in aged kidneys. Al-
though studies are lacking in aged animals, increased G2/M cell cycle arrest in response to effect of aging remains unclear.115 In-
injury promotes maladaptive repair in murine kidney injury, with raised G2/M counts cor- creased inflammatory signaling and
relating with fibrosis.92,194 G2/M cell cycle arrest may have variable effects in different cell macrophage infiltration116 with alter-
types, being profibrotic in renal tubular cells but preventing intimal hyperplasia in young ations in inflammasome components,
smooth muscle cells.195 CTGF, XXX; GROa, XXX; INK CDK, XXX. such as NOD–like receptor P3, NLRC4,

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procaspase-1, NFkB, and cytokines, in- metalloproteinases (MMPs) shifts toward Declining PPARg Levels
cluding IL-1b and IL-18, occur in ag- fibrosis, potentially via upregulation of tis- Agonists of PPARg are used clinically as
ing.117 Aged murine macrophages show sue inhibitor of MMP1 and increased leu- antidiabetic agents. Retrospective reviews
impaired autophagy and reduced nitrate kocyte recruitment,50 a pattern likely to of renal outcomes in clinical practice
release and phagocytosis. 118 Healthy result in increased collagen deposition. suggest that augmented PPARg activity
aged mice have increased glomerular Longitudinal studies of aging mice show opposes proteinuria in these patients.137
macrophage numbers with increased increased Collagen I, Collagen III, and A meta-analysis of PPARg use has also
macrophage infiltration evident postin- TGF-b1,50 whereas aging rat kidneys shown that they associate with reduced
jury, with renal IRI models showing an exhibit increased ECM deposition and rates of cerebrovascular disease, sup-
increased influx of macrophage and T TGF-b3 expression and decreased porting a role in delaying age–associated
lymphocytes. 38,119 Additionally, aged MMP1 activity, suggesting altered collagen pathology.138 There is a need for pro-
mice show defective upregulation of production and processing.130 Additional spective trials assessing their effects on
the cytoprotective enzyme hemoxyge- noninflammatory pathways may contrib- renal function.
nase-1 after IRI, with pharmacologic ute to the histologic changes seen, includ-
macrophage hemoxygenase-1 induction ing pathways driven by Wnt and AT2 as AT2
protecting against subsequent IRI.35 Fi- mentioned.54 Despite decreased plasma renin activity
nally, aged macrophages express reduced in the elderly, serum AT2 levels do not
anti–inflammatory IL-10 during tissue fall, and hypersensitivity to AT2 develops
repair in nonrenal injury models. 120 THE AGING HUMAN KIDNEY in the renal vasculature.139,140 Although
Given the importance of IL-10 and the ACEi and ARB drugs are in widespread
negative prognostic role of macrophage The clinical implications of renal aging in use, there is a lack of human data on the
infiltrates in human renal disease, these humans extend beyond changes in glo- effect of AT2 blocking treatments on
aging-associated changes potentially merular and tubular function. Although normal renal aging and outcomes at
contribute to the increased rates of in- data generated by animal studies impli- present.
jury and maladaptive repair seen in aged cate multiple pathways of potential im-
kidneys. portance for human renal aging (Figure Oxidative Stress
Additional evidence for the impor- 4), data supporting their involvement in As discussed, oxidative stress represents a
tance of the aging immune system in renal humans are currently sparse, with addi- disruption of the balance of oxidant han-
aging comes from young-old bone marrow tional studies required. dling in tissues. In humans, longitudinal
transplant studies showing that aged ani- studies show increased oxidative stress in
mals receiving bone marrow transplants Signaling Pathways and Oxidative normal aging and CKD.73,141 Research
from young mice exhibited reduced renal Stress in the Aging Kidney has focused on advanced glycation end
fibrosis and cellular senescence.121 Falling Klotho Levels products as drivers of oxidative stress in
Klotho and FGF-23 are present in human aging. These molecules accumulate with
Pericytes kidneys.131 Klotho levels decline with age and are associated with increased ar-
Although important for microvascular age and are implicated in accelerated age– terial stiffness, inflammation, oxidative
health, pericytes are also recognized as related CKD and atherosclerosis.132,133 stress, and declining renal function.142
key cells in renal fibrosis.122,123 In aged Conversely, patients with increased func- One pharmacologic attempt to modify
mice, renal pericytes decline in number tional Klotho expression are reported to antioxidant status in patients with dia-
and adopt a profibrotic phenotype,124 have increased lifespan.134 As Klotho betic nephropathy showed no effect on
implicating them in aging–related fibrotic falls, FGF-23 levels increase and alter proteinuria, despite increased circulating
changes. Pericyte-endothelial detachment phosphate and calcium homeostasis. antioxidant levels.143 Whether an alterna-
under pathologic conditions and their dif- Clinical studies in patients on dialysis tive, longer–term treatment approach in
ferentiation into myofibroblasts promote and patients with CKD show that higher the healthy aged population might have ef-
microvascular rarefaction, hypoxia, and FGF-23 levels associate with increased ficacy remains untested.
fibrosis.125,126 Proposed mediators of this mortality.135
pericyte-endothelial crosstalk include Cell Cycle Progression in the Aged
VEGF and PDGF,127 and blocking this Increasing Wnt Activation Kidney
pericyte-endothelial interaction attenuates Although direct evidence of Wnt activa- The presence of increased numbers of
microvascular damage and interstitial tion in human aging is lacking, several senescent cells has been noted in chronic
fibrosis.128,129 Wnt antagonists are now undergoing allograft nephropathy and proposed as
phase 1 clinical trials for cancer therapy drivers of the progressive fibrosis
Disordered Repair in humans.136 If effective, these agents seen.144 Recent advances in our under-
The normal enzymatic equilibrium is offer new therapeutic options for aging– standing of the roles of aging and stress
disturbed in aging, and the balance of associated or fibrotic renal disease. in inducing the detrimental SASP phenotype

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cytokines detectable in the serum correlat-


ing 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 un-
derstand which pathways are dispensable
and which represent master regulators of
the aging phenotype. Studies in aged an-
imals should allow characterization of
both the importance and interdepen-
dence of factors predisposing aged kid-
neys to injury, fibrosis, and maladaptive
repair, with subsequent validation in hu-
mans. Because of the time and cost con-
straints inherent in using aged animals,
establishing whether models of geneti-
cally accelerated aging, such as the
BubR1 progeroid mouse, represent use-
Figure 4. Age-related pathways contributing to altered renal outcomes in the elderly. Multiple
ful models of renal aging will be of
pathways interact to produce the changes of renal aging and ↓GFR. Black text indicates im-
value.157 BubR1 mice have a shortened
plicated upstream effectors of aging, whereas red text reports the functional and histologic
changes found in the aged kidney. NO/AA/ANP, XXX; SA, XXX; TIMP, XXX; TTKG, XXX. lifespan and exhibit a variety of age-
related phenotypes, including sarcopenia,
cataracts, fat loss, cardiac arrhythmias,
add to the importance of senescence cells Hypoxia, Inflammation, and arterial wall stiffening, and impaired
found in both aged and disease–affected Nephrosclerosis in the Aged Kidney wound healing. Specific to kidney research,
human renal biopsies.145–147 In humans, Because of the inherent risks of renal BubR1-deficient mice also show higher
senescence is maximal in the medulla, po- biopsy, samples of healthy aged kidney senescence–associated b-galactosidase
tentially reflecting increased oxidative and are seldom available for assessment of activity in kidney sections than aged
cellular stress and relative hypoxia result- levels of nephrosclerosis, and there are matched controls.158 Whether they truly
ing from the vascular changes discussed no time course studies available to chart manifest a renal aging phenotype has yet
previously.148 the temporal relationships of the histo- to be determined.
logic findings in the aged kidney. Ongo-
Telomeres ing progress in imaging technology should Circulating Factors
Telomeres shorten in human kidneys at a enable serial noninvasive assessment of re- Heterochronic parabiosis with aged and
rate of 0.25% length per year. 149 Al- nal perfusion, vascular resistance, hypoxia, young mice sharing a common circula-
though telomere shortening provides inflammation, and atrophy in healthy tion has provided evidence in nonrenal
an elegant explanation of cellular aging, young and aged volunteers. modelsthatcirculatingfactorsmaymodulate
currently, no data exist to link shorter features of aging, including impaired regen-
telomeres to any histologic or functional Renal Hypoxia eration and increased fibrosis.159–161 Pro-
measure of renal aging. Shorter telomeres The clinical use of BOLD MRI imaging posed factors include b2-microglobulin
associate with CKD and worse cardiovas- has shown a lower PO2 in older kidneys and growth differentiation factor 11, and
cular outcomes and are shorter in diabetic compared with younger subjects.153 Be- reversal of changes in the brain, cardiac,
nephropathy, where they associate with cause intrarenal vascular disease contrib- and skeletal muscle has been shown.162–164
rates of disease progression.150,151 Further- utes to increased glomerular sclerosis in Debate continues as to the significance of
more, studies of patients on hemodialysis aged biopsies, it is possible that subclinical individual factors.165–169 Whether such
show increased rates of telomere attrition, disease leads to hypoxia before marked factors affect the function of the aged kid-
suggesting that they shorten in response macroscopic changes occur.154 ney remains completely unknown.
to the physiologic stress.152 Although
intriguing, the importance of telomere Inflammation Novel Experimental Species
shortening in human aging remains to Inflammation is increased within the aging Undertaking studies of experimental renal
be elucidated. kidney in humans, with proinflammatory disease in aged mice is challenging, and

J Am Soc Nephrol 28: ccc–ccc, 2016 Renal Aging: Causes and Consequences 7
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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 zebra-
fish in renal aging studies may be infor-
mative.

Novel Therapeutic Strategies


Many pathways implicated in the aging
process are the target of interventions to
improve the aging phenotype in experi-
mental mice (Figure 5). Klotho agonists
are under investigation via repurposing
of established agents, including PPARg
agonists and ACEi and ARB drugs. The
importance of maintaining a normal re-
nal microvasculature and pericyte pool
Figure 5. Potential pathways and therapeutic targets for the treatment of renal aging. Pro-
is increasingly understood,173 and devel-
posed aging–associated pathways (left), and potential interventions to address them (right)
oping strategies to quantify microvascu-
coded by current use in patients (green), experimental use in models of renal disease/aging
lar function and promote endothelial (orange), and potential for future study in the kidney (red). ACEi, XXX; ARB, XXX.
and pericyte health are a pressing clinical
need.114
Drugs targeting cellular senescence shock protein that may counteract cell CONCLUSION
(senolytics) include siRNA therapies, senescence, and IGF receptor, a target
the experimental agent navitoclax, and of Klotho.181–183 Renal aging is complex and remains incom-
the licensed drugs dasatinib and querce- GWAS remains, however, a promising pletely understood. Decreased protective
tin. 174 In experiments, these agents tool, because whole-genome analyses of factors, hypoxia, and microenvironmental
show selective toxicity to senescent cells, GWAS data suggest that over 80% of the stress drive increasingly disordered inflam-
and their potential utility in animal heritability of aging is explained by com- mation and renal fibrosis. The resulting
models and humans merits additional mon genetic variants.184 Future GWASs fibrosis, senescence, and microvascular rar-
study. will continue to generate meaningful results efaction exacerbate damage and promote
as more advanced statistical techniques de- progression. The future of treating renal
Genetics velop and researchers increase statistical aging is likely in understanding the key ini-
Genome–wide association studies power by increasing samples number, com- tiating events and the common down-
(GWASs) have identified upregulation bining studies using meta-analytic tech- stream pathways present in kidney aging
of several genes with aging. Although cu- niques, using multicenter collaborations, that may be shared with CKD. This know-
mulative damage may well influence and including more extreme phenotypes ledge should allow the development of
much of the elderly genetic milieu, can- in the data.184–187 therapies capable of arresting the key
didate genes have declared themselves as mechanisms early to preserve kidney
being consistently highly expressed in Epigenetics function throughout life.
aged kidneys.175–177 Despite the utility Epigenetics is the study of genome
of GWAS in identifying disease-specific changes that do not alter DNA sequence.
pathways, it has proved difficult to dis- Epigenetic changes in aging include
cover any canonical aging pathways with methylation and deacetylation of his- ACKNOWLEDGMENTS
GWAS.178 tone lysine residues, chromatin changes,
The most promising genes encode for and increased transcriptional noise.178,188 J.H. is supported by Cunningham Trust CT13/
modulators of the glomerular filtration Interestingly, similar changes in DNA 16, the Mrs. A.E. Hogg Charitable Trust, and
barrier, fibrosis, and inflammatory me- methylation and histones are associated Kidney Research UK. D.A.F. is supported by
diators, although difficulty arises when with CKD disease progression. 189–191 Intermediate Clinical Fellowship WT100171MA
identified candidate genes do not match The role of microRNA expression in from the Wellcome Trust.
the experimental observations or mod- modifying gene expression and nephro-
els.179,180 Transcriptomic analysis iden- sclerosis is of interest,192 with data in
tified 427 genes strongly associated with other organs suggesting an influence on DISCLOSURES
renal aging, including mortalin-2, a heat aging.193 None.

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