You are on page 1of 14

BRIEF REVIEW www.jasn.


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

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
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:
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




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 BRIEF REVIEW

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
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
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
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
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

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

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 BRIEF REVIEW

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

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,

J Am Soc Nephrol 28: ccc–ccc, 2016 Renal Aging: Causes and Consequences 5

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

6 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016 BRIEF REVIEW

cytokines detectable in the serum correlat-

ing with age–related renal disease.155,156


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

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-

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
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.

8 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016 BRIEF REVIEW

REFERENCES assessment of the natural rate of decline in in elderly volunteers. Am J Kidney Dis 22:
renal function with age. J Nephrol 27: 635– 538–544, 1993
641, 2014 30. Fuiano G, Sund S, Mazza G, Rosa M,
1. Centers for Disease Control and Prevention:
17. Wetzels JFM, Kiemeney LALM, Swinkels Caglioti A, Gallo G, Natale G, Andreucci M,
The State of Aging and Healthy in America,
DW, Willems HL, den Heijer M: Age- and Memoli B, De Nicola L, Conte G: Renal he-
Atlanta, GA, Createspace Independent Pub-
gender-specific reference values of esti- modynamic response to maximal vasodilating
lisher, 2013
mated GFR in Caucasians: The Nijmegen stimulus in healthy older subjects. Kidney Int
2. European Commission: The 2015 ageing
biomedical study. Kidney Int 72: 632–637, 59: 1052–1058, 2001
report. Eur Econ 3: 424, 2015
2007 31. Fliser D, Zeier M, Nowack R, Ritz E: Renal
3. Zhou XJ, Rakheja D, Yu X, Saxena R, Vaziri
18. Sarnak MJ, Poindexter A, Wang S-R, Beck functional reserve in healthy elderly sub-
ND, Silva FG: The aging kidney. Kidney Int
GJ, Kusek JW, Marcovina SM, Greene T, jects. J Am Soc Nephrol 3: 1371–1377,
74: 710–720, 2008
Levey AS: Serum C-reactive protein and 1993
4. Newbold KM, Sandison A, Howie AJ:
leptin as predictors of kidney disease pro- 32. Sverdlov AL, Ngo DTM, Chan WPA, Chirkov
Comparison of size of juxtamedullary and
gression in the modification of diet in renal YY, Horowitz JD: Aging of the nitric oxide
outer cortical glomeruli in normal adult kidney.
disease study. Kidney Int 62: 2208–2215, system: Are we as old as our NO? J Am
Virchows Arch A Pathol Anat Histopathol 420:
2002 Heart Assoc 3: e000973, 2014
127–129, 1992
19. Imai E, Horio M, Yamagata K, Iseki K, Hara S, 33. Kielstein JT, Bode-Böger SM, Frölich JC,
5. Nyengaard JR, Bendtsen TF: Glomerular
Ura N, Kiyohara Y, Makino H, Hishida A, Ritz E, Haller H, Fliser D: Asymmetric di-
number and size in relation to age, kidney
Matsuo S: Slower decline of glomerular fil- methylarginine, blood pressure, and renal
weight, and body surface in normal man.
tration rate in the Japanese general pop- perfusion in elderly subjects. Circulation
Anat Rec 232: 194–201, 1992
ulation: A longitudinal 10-year follow-up 107: 1891–1895, 2003
6. Rule AD, Amer H, Cornell LD, Taler SJ,
study. Hypertens Res 31: 433–441, 2008 34. Ahmed SB, Fisher NDL, Hollenberg NK:
Cosio FG, Kremers WK, Textor SC, Stegall
20. Hollenberg NK, Rivera A, Meinking T, Gender and the renal nitric oxide synthase
MD: The association between age and Martinez G, McCullough M, Passan D, system in healthy humans. Clin J Am Soc
nephrosclerosis on renal biopsy among Preston M, Taplin D, Vicaria-Clement M: Nephrol 2: 926–931, 2007
healthy adults. Ann Intern Med 152: 561– Age, renal perfusion and function in island- 35. Ferenbach DA, Nkejabega NCJ, McKay J,
567, 2010 dwelling indigenous Kuna Amerinds of Choudhary AK, Vernon MA, Beesley MF,
7. Chan KW, Leung CY, Chan CW: Age-related Panama. Nephron 82: 131–138, 1999 Clay S, Conway BC, Marson LP, Kluth DC,
glomerular sclerosis: Baseline values in 21. Sands JM: Urine concentrating and diluting Hughes J: The induction of macrophage
Hong Kong. Pathology 22: 177–180, 1990 ability during aging. J Gerontol A Biol Sci hemeoxygenase-1 is protective during
8. Denic A, Alexander MP, Kaushik V, Lerman Med Sci 67: 1352–1357, 2012 acute kidney injury in aging mice. Kidney Int
LO, Lieske JC, Stegall MD, Larson JJ, 22. Mimran A, Ribstein J, Jover B: Aging and 79: 966–976, 2011
Kremers WK, Vrtiska TJ, Chakkera HA, sodium homeostasis. Kidney Int Suppl 37: 36. Nath KA, Grande JP, Farrugia G, Croatt AJ,
Poggio ED, Rule AD: Detection and clinical S107–S113, 1992 Belcher JD, Hebbel RP, Vercellotti GM,
patterns of nephron hypertrophy and 23. Michelis MF: Hyperkalemia in the elderly. Katusic ZS: Age sensitizes the kidney to
nephrosclerosis among apparently healthy Am J Kidney Dis 16: 296–299, 1990 heme protein-induced acute kidney injury.
adults. Am J Kidney Dis 68: 58–67, 2016 24. Mc Greevy C, Horan J, Jones D, Biswas K, Am J Physiol Renal Physiol 304: F317–F325,
9. Rule AD, Cornell LD, Poggio ED: Senile O’Meara YM, Mulkerrin EC: A study of tu- 2013
nephrosclerosis–does it explain the decline bular potassium secretory capacity in older 37. Maddens B, Vandendriessche B, Demon D,
in glomerular filtration rate with aging? patients with hyperkalaemia. J Nutr Health Vanholder R, Chiers K, Cauwels A, Meyer E:
Nephron Physiol 119[Suppl l]: 6–11, 2011 Aging 12: 152–155, 2008 Severity of sepsis-induced acute kidney in-
10. Meyrier A: Nephrosclerosis: A term in quest 25. Musso C, Liakopoulos V, Stefanidis I, De jury in a novel mouse model is age de-
of a disease. Nephron 129: 276–282, 2015 Miguel R, Imperiali N, Algranati L: Correla- pendent. Crit Care Med 40: 2638–2646,
11. Meyrier A: Nephrosclerosis: Update on a tion between creatinine clearance and 2012
centenarian. Nephrol Dial Transplant 30: transtubular potassium concentration gra- 38. Clements ME, Chaber CJ, Ledbetter SR,
1833–1841, 2015 dient in old people and chronic renal dis- Zuk A: Increased cellular senescence and
12. Ferenbach DA, Bonventre JV: Mechanisms ease patients. Saudi J Kidney Dis Transpl 18: vascular rarefaction exacerbate the pro-
of maladaptive repair after AKI leading to 551–555, 2007 gression of kidney fibrosis in aged mice
accelerated kidney ageing and CKD. Nat 26. Takazakura E, Sawabu N, Handa A, Takada following transient ischemic injury. PLoS
Rev Nephrol 11: 264–276, 2015 A, Shinoda A, Takeuchi J: Intrarenal vascular One 8: e70464, 2013
13. Rowe JW, Andres R, Tobin JD, Norris AH, changes with age and disease. Kidney Int 2: 39. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H,
Shock NW: The effect of age on creatinine 224–230, 1972 Suga T, Utsugi T, Ohyama Y, Kurabayashi
clearance in men: A cross-sectional and 27. Hajduczok G, Chapleau MW, Johnson SL, M, Kaname T, Kume E, Iwasaki H, Iida A,
longitudinal study. J Gerontol 31: 155–163, Abboud FM: Increase in sympathetic activ- Shiraki-Iida T, Nishikawa S, Nagai R,
1976 ity with age. I. Role of impairment of arterial Nabeshima YI: Mutation of the mouse klotho
14. Lindeman RD, Tobin J, Shock NW: Longi- baroreflexes. Am J Physiol 260: H1113– gene leads to a syndrome resembling age-
tudinal studies on the rate of decline in renal H1120, 1991 ing. Nature 390: 45–51, 1997
function with age. J Am Geriatr Soc 33: 28. Jerkic M, Vojvodic S, López-Novoa JM: The 40. Shimada T, Kakitani M, Yamazaki Y, Hasegawa
278–285, 1985 mechanism of increased renal susceptibility H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka
15. Baba M, Shimbo T, Horio M, Ando M, to toxic substances in the elderly. Part I. The K, Yamashita T: Targeted ablation of Fgf23
Yasuda Y, Komatsu Y, Masuda K, Matsuo S, role of increased vasoconstriction. Int Urol demonstrates an essential physiological role of
Maruyama S: Longitudinal study of the de- Nephrol 32: 539–547, 2001 FGF23 in phosphate and vitamin D metabo-
cline in renal function in healthy subjects. 29. Mulkerrin EC, Brain A, Hampton D, Penney lism. J Clin Invest 113: 561–568, 2004
PLoS One 10: e0129036, 2015 MD, Sykes DA, Williams JD, Coles GA, 41. Razzaque MS, Sitara D, Taguchi T, St-Arnaud
16. Cohen E, Nardi Y, Krause I, Goldberg E, Woodhouse KW: Reduced renal hemody- R, Lanske B: Premature aging-like pheno-
Milo G, Garty M, Krause I: A longitudinal namic response to atrial natriuretic peptide type in fibroblast growth factor 23 null mice

J Am Soc Nephrol 28: ccc–ccc, 2016 Renal Aging: Causes and Consequences 9

is a vitamin D mediated process. FASEB J ameliorates proteinuria and kidney injury. J Caballero C, Iglesias MC, Rodríguez-Puyol
20: 720–722, 2006 Am Soc Nephrol 22: 90–103, 2011 M, Rodríguez-Puyol D: Age-related increase
42. Kurosu H, Yamamoto M, Clark JD, Pastor 57. Zhou L, Li Y, Hao S, Zhou D, Tan RJ, Nie J, in expression of TGF-beta1 in the rat kidney:
JV, Nandi A, Gurnani P, McGuinness OP, Hou FF, Kahn M, Liu Y: Multiple genes of the Relationship to morphologic changes. J Am
Chikuda H, Yamaguchi M, Kawaguchi H, renin-angiotensin system are novel targets Soc Nephrol 9: 782–791, 1998
Shimomura I, Takayama Y, Herz J, Kahn CR, of Wnt/b-catenin signaling. J Am Soc Nephrol 71. Cruz CI, Ruiz-Torres P, del Moral RG,
Rosenblatt KP, Kuro-o M: Suppression of 26: 107–120, 2015 Rodríguez-Puyol M, Rodríguez-Puyol D:
aging in mice by the hormone Klotho. Sci- 58. Iemitsu M, Miyauchi T, Maeda S, Tanabe T, Age-related progressive renal fibrosis in rats
ence 309: 1829–1833, 2005 Takanashi M, Irukayama-Tomobe Y, Sakai S, and its prevention with ACE inhibitors and
43. John GB, Cheng C-Y, Kuro-o M: Role of Ohmori H, Matsuda M, Yamaguchi I: Aging- taurine. Am J Physiol Renal Physiol 278:
Klotho in aging, phosphate metabolism, induced decrease in the PPAR-alpha level in F122–F129, 2000
and CKD. Am J Kidney Dis 58: 127–134, hearts is improved by exercise training. Am 72. de Cavanagh EMV, Piotrkowski B, Basso N,
2011 J Physiol Heart Circ Physiol 283: H1750– Stella I, Inserra F, Ferder L, Fraga CG: Enalapril
44. Kuro-o M: Klotho as a regulator of oxidative H1760, 2002 and losartan attenuate mitochondrial dys-
stress and senescence. Biol Chem 389: 59. Wang P, Li B, Cai G, Huang M, Jiang L, Pu J, function in aged rats. FASEB J 17: 1096–
233–241, 2008 Li L, Wu Q, Zuo L, Wang Q, Zhou P: Acti- 1098, 2003
45. Sopjani M, Rinnerthaler M, Kruja J, vation of PPAR-g by pioglitazone attenuates 73. Vlassara H, Torreggiani M, Post JB, Zheng F,
Dermaku-Sopjani M: Intracellular signaling oxidative stress in aging rat cerebral arteries Uribarri J, Striker GE: Role of oxidants/in-
of the aging suppressor protein Klotho. through upregulating UCP2. J Cardiovasc flammation in declining renal function in
Curr Mol Med 15: 27–37, 2015 Pharmacol 64: 497–506, 2014 chronic kidney disease and normal aging.
46. Yang H, Fogo AB: Cell senescence in the 60. Zhang H, Li Y, Fan Y, Wu J, Zhao B, Guan Y, Kidney Int Suppl 114: S3–S11, 2009
aging kidney. J Am Soc Nephrol 21: 1436– Chien S, Wang N: Klotho is a target gene 74. Simão S, Gomes P, Pinto V, Silva E, Amaral
1439, 2010 of PPAR-gamma. Kidney Int 74: 732–739, JS, Igreja B, Afonso J, Serrão MP, Pinho MJ,
47. Liu Q-F, Ye J-M, Deng Z-Y, Yu L-X, Sun Q, Li 2008 Soares-da-Silva P: Age-related changes in
S-S: Ameliorating effect of Klotho on en- 61. Zhang R, Zheng F: PPAR-gamma and aging: renal expression of oxidant and antioxidant
doplasmic reticulum stress and renal fibrosis One link through klotho? Kidney Int 74: enzymes and oxidative stress markers in
induced by unilateral ureteral obstruction. 702–704, 2008 male SHR and WKY rats. Exp Gerontol 46:
Iran J Kidney Dis 9: 291–297, 2015 62. Sung B, Park S, Yu BP, Chung HY: Modula- 468–474, 2011
48. Kuro-o M: Klotho as a regulator of fibroblast tion of PPAR in aging, inflammation, and 75. Miyazawa M, Ishii T, Yasuda K, Noda S,
growth factor signaling and phosphate/ calorie restriction. J Gerontol A Biol Sci Onouchi H, Hartman PS, Ishii N: The role of
calcium metabolism. Curr Opin Nephrol Med Sci 59: 997–1006, 2004 mitochondrial superoxide anion (O2(-)) on
Hypertens 15: 437–441, 2006 63. Briganti S, Flori E, Bellei B, Picardo M: physiological aging in C57BL/6J mice.
49. Zhou L, Li Y, Zhou D, Tan RJ, Liu Y: Loss of Modulation of PPARg provides new insights J Radiat Res (Tokyo) 50: 73–83, 2009
Klotho contributes to kidney injury by de- in a stress induced premature senescence 76. Nath KA: The role of Sirt1 in renal re-
repression of Wnt/b-catenin signaling. J Am model. PLoS One 9: e104045, 2014 juvenation and resistance to stress. J Clin
Soc Nephrol 24: 771–785, 2013 64. Lim HA, Lee EK, Kim JM, Park MH, Kim DH, Invest 120: 1026–1028, 2010
50. Zhang X, Chen X, Hong Q, Lin H, Zhu H, Liu Choi YJ, Ha YM, Yoon J-H, Choi JS, Yu BP, 77. Akçetin Z, Erdemli G, Brömme HJ: Experi-
Q, Wang J, Xie Y, Shang X, Shi S, Lu Y, Yin Z: Chung HY: PPARg activation by baicalin mental study showing a diminished cyto-
TIMP-1 promotes age-related renal fibrosis suppresses NF-kB-mediated inflammation solic antioxidative capacity in kidneys of
through upregulating ICAM-1 in human in aged rat kidney. Biogerontology 13: aged rats. Urol Int 64: 70–73, 2000
TIMP-1 transgenic mice. J Gerontol A Biol 133–145, 2012 78. Martin R, Fitzl G, Mozet C, Martin H, Welt K,
Sci Med Sci 61: 1130–1143, 2006 65. Sangaralingham SJ, Wang BH, Huang L, Wieland E: Effect of age and hypoxia/re-
51. Tan RJ, Zhou D, Zhou L, Liu Y: Wnt/b-catenin Kumfu S, Ichiki T, Krum H, Burnett JC Jr. : oxygenation on mRNA expression of anti-
signaling and kidney fibrosis. Kidney Int Cardiorenal fibrosis and dysfunction in ag- oxidative enzymes in rat liver and kidneys.
Suppl (2011) 4: 84–90, 2014 ing: Imbalance in mediators and regulators Exp Gerontol 37: 1481–1487, 2002
52. Bian A, Neyra JA, Zhan M, Hu MC: Klotho, of collagen. Peptides 76: 108–114, 2016 79. Qiao X, Chen X, Wu D, Ding R, Wang J,
stem cells, and aging. Clin Interv Aging 10: 66. Fogo AB: The role of angiotensin II and Hong Q, Shi S, Li J, Xie Y, Lu Y, Wang Z:
1233–1243, 2015 plasminogen activator inhibitor-1 in pro- Mitochondrial pathway is responsible for
53. Brack AS, Conboy MJ, Roy S, Lee M, Kuo gressive glomerulosclerosis. Am J Kidney aging-related increase of tubular cell apo-
CJ, Keller C, Rando TA: Increased Wnt sig- Dis 35: 179–188, 2000 ptosis in renal ischemia/reperfusion injury.
naling during aging alters muscle stem cell 67. Vajapey R, Rini D, Walston J, Abadir P: The J Gerontol A Biol Sci Med Sci 60: 830–839,
fate and increases fibrosis. Science 317: impact of age-related dysregulation of the 2005
807–810, 2007 angiotensin system on mitochondrial redox 80. Small DM, Bennett NC, Roy S, Gabrielli BG,
54. Maarouf OH, Aravamudhan A, Rangarajan balance. Front Physiol 5: 439, 2014 Johnson DW, Gobe GC: Oxidative stress
D, Kusaba T, Zhang V, Welborn J, Gauvin D, 68. Benigni A, Cassis P, Remuzzi G: Angiotensin and cell senescence combine to cause
Hou X, Kramann R, Humphreys BD: Para- II revisited: New roles in inflammation, im- maximal renal tubular epithelial cell dys-
crine Wnt1 drives interstitial fibrosis without munology and aging. EMBO Mol Med 2: function and loss in an in vitro model of
inflammation by tubulointerstitial cross-talk. 247–257, 2010 kidney disease. Nephron Exp Nephrol 122:
J Am Soc Nephrol 27: 781–790, 2016 69. Cuevas CA, Gonzalez AA, Inestrosa NC, Vio 123–130, 2012
55. Hao S, He W, Li Y, Ding H, Hou Y, Nie J, Hou CP, Prieto MC: Angiotensin II increases fi- 81. Kitada M, Kume S, Takeda-Watanabe A,
FF, Kahn M, Liu Y: Targeted inhibition of bronectin and collagen I through the b-catenin- Kanasaki K, Koya D: Sirtuins and renal dis-
b-catenin/CBP signaling ameliorates renal dependent signaling in mouse collecting eases: Relationship with aging and diabetic
interstitial fibrosis. J Am Soc Nephrol 22: duct cells. Am J Physiol Renal Physiol 308: nephropathy. Clin Sci (Lond) 124: 153–164,
1642–1653, 2011 F358–F365, 2015 2013
56. He W, Kang YS, Dai C, Liu Y: Blockade of 70. Ruiz-Torres MP, Bosch RJ, O’Valle F, Del 82. Yeung F, Hoberg JE, Ramsey CS, Keller MD,
Wnt/b-catenin signaling by paricalcitol Moral RG, Ramírez C, Masseroli M, Pérez- Jones DR, Frye RA, Mayo MW: Modulation

10 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016 BRIEF REVIEW

of NF-kappaB-dependent transcription and 96. Kuilman T, Michaloglou C, Vredeveld LCW, 108. Westhoff JH, Schildhorn C, Jacobi C,
cell survival by the SIRT1 deacetylase. Douma S, van Doorn R, Desmet CJ, Aarden Hömme M, Hartner A, Braun H, Kryzer C,
EMBO J 23: 2369–2380, 2004 LA, Mooi WJ, Peeper DS: Oncogene-induced Wang C, von Zglinicki T, Kränzlin B, Gretz N,
83. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, senescence relayed by an interleukin- Melk A: Telomere shortening reduces re-
Isshiki K, Araki S, Sugimoto T, Haneda M, dependent inflammatory network. Cell 133: generative capacity after acute kidney in-
Kashiwagi A, Koya D: Calorie restriction 1019–1031, 2008 jury. J Am Soc Nephrol 21: 327–336, 2010
enhances cell adaptation to hypoxia through 97. Binet R, Ythier D, Robles AI, Collado M, 109. Cheng H, Fan X, Lawson WE, Paueksakon P,
Sirt1-dependent mitochondrial autophagy in Larrieu D, Fonti C, Brambilla E, Brambilla C, Harris RC: Telomerase deficiency delays renal
mouse aged kidney. J Clin Invest 120: 1043– Serrano M, Harris CC, Pedeux R: WNT16B recovery in mice after ischemia-reperfusion
1055, 2010 is a new marker of cellular senescence that re- injury by impairing autophagy. Kidney Int
84. He W, Wang Y, Zhang M-Z, You L, Davis LS, gulates p53 activity and the phosphoinositide 88: 85–94, 2015
Fan H, Yang H-C, Fogo AB, Zent R, Harris 3-kinase/AKT pathway. Cancer Res 69: 9183– 110. Jaskelioff M, Muller FL, Paik J-H, Thomas E,
RC, Breyer MD, Hao C-M: Sirt1 activation 9191, 2009 Jiang S, Adams AC, Sahin E, Kost-Alimova
protects the mouse renal medulla from ox- 98. Braun H, Schmidt BMW, Raiss M, Baisantry M, Protopopov A, Cadiñanos J, Horner JW,
idative injury. J Clin Invest 120: 1056–1068, A, Mircea-Constantin D, Wang S, GrossM-L, Maratos-Flier E, Depinho RA: Telomerase
2010 Serrano M, Schmitt R, Melk A: Cellular reactivation reverses tissue degeneration in
85. Sauve AA, Wolberger C, Schramm VL, senescence limits regenerative capacity and aged telomerase-deficient mice. Nature
Boeke JD: The biochemistry of sirtuins. allograft survival. J Am Soc Nephrol 23: 1467– 469: 102–106, 2011
Annu Rev Biochem 75: 435–465, 2006 1473, 2012 111. Ballermann BJ, Obeidat M: Tipping the
86. Longo VD, Kennedy BK: Sirtuins in aging 99. Chkhotua AB, Abendroth D, Froeba G, balance from angiogenesis to fibrosis in
and age-related disease. Cell 126: 257– Schelzig H: Up-regulation of cell cycle CKD. Kidney Int Suppl (2011) 4: 45–52,
268, 2006 regulatory genes after renal ischemia/ 2014
87. Radak Z, Koltai E, Taylor AW, Higuchi M, reperfusion: Differential expression of 112. Tanaka T, Kato H, Kojima I, Ohse T, Son D,
Kumagai S, Ohno H, Goto S, Boldogh I: p16(INK4a), p21(WAF1/CIP1) and p27(Kip1) Tawakami T, Yatagawa T, Inagi R, Fujita T,
Redox-regulating sirtuins in aging, caloric cyclin-dependent kinase inhibitor genes Nangaku M: Hypoxia and expression of
restriction, and exercise. Free Radic Biol depending on reperfusion time. Transpl hypoxia-inducible factor in the aging kid-
Med 58: 87–97, 2013 Int 19: 72–77, 2006 ney. J Gerontol A Biol Sci Med Sci 61: 795–
88. Park S, Mori R, Shimokawa I: Do sirtuins 100. Lee DH, Wolstein JM, Pudasaini B, Plotkin 805, 2006
promote mammalian longevity? A critical M: INK4a deletion results in improved kid- 113. Kang DH, Anderson S, Kim YG, Mazzalli M,
review on its relevance to the longevity ef- ney regeneration and decreased capillary Suga S, Jefferson JA, Gordon KL, Oyama
fect induced by calorie restriction. Mol Cells rarefaction after ischemia-reperfusion in- TT, Hughes J, Hugo C, Kerjaschki D,
35: 474–480, 2013 jury. Am J Physiol Renal Physiol 302: F183– Schreiner GF, Johnson RJ: Impaired angio-
89. Benigni A, Corna D, Zoja C, Sonzogni A, F191, 2012 genesis in the aging kidney: Vascular endo-
Latini R, Salio M, Conti S, Rottoli D, Longaretti 101. Wolstein JM, Lee DH, Michaud J, Buot V, thelial growth factor and thrombospondin-1
L, Cassis P, Morigi M, Coffman TM, Remuzzi Stefanchik B, Plotkin MD: INK4a knockout in renal disease. Am J Kidney Dis 37: 601–
G: Disruption of the Ang II type 1 receptor mice exhibit increased fibrosis under nor- 611, 2001
promotes longevity in mice. J Clin Invest 119: mal conditions and in response to unilateral 114. Kramann R, Tanaka M, Humphreys BD:
524–530, 2009 ureteral obstruction. Am J Physiol Renal Fluorescence microangiography for quan-
90. Schmitt R, Marlier A, Cantley LG: Zag ex- Physiol 299: F1486–F1495, 2010 titative assessment of peritubular capillary
pression during aging suppresses prolifera- 102. Baker DJ, Childs BG, Durik M, Wijers ME, changes after AKI in mice. J Am Soc
tion after kidney injury. J Am Soc Nephrol 19: Sieben CJ, Zhong J, Saltness RA, Jeganathan Nephrol 25: 1924–1931, 2014
2375–2383, 2008 KB, Verzosa GC, Pezeshki A, Khazaie K, Miller 115. Sebastián C, Espia M, Serra M, Celada A,
91. Sörensen-Zender I, Bhayana S, Susnik N, JD, van Deursen JM: Naturally occurring p16- Lloberas J: MacrophAging: A cellular and
Rolli V, Batkai S, Baisantry A, Bahram S, Sen positive cells shorten healthy lifespan. Nature molecular review. Immunobiology 210:
P, Teng B, Lindner R, Schiffer M, Thum T, 530: 184–189, 2016 121–126, 2005
Melk A, Haller H, Schmitt R: Zinc-a2- 103. Chang J, Wang Y, Shao L, Laberge RM, 116. Costa E, Fernandes J, Ribeiro S, Sereno J,
Glycoprotein exerts antifibrotic effects in Demaria M, Campisi J, Janakiraman K, Garrido P, Rocha-Pereira P, Coimbra S,
kidney and heart. J Am Soc Nephrol 26: Sharpless NE, Ding S, Feng W, Luo Y, Wang Catarino C, Belo L, Bronze-da-Rocha E, Vala
2659–2668, 2015 X, Aykin-Burns N, Krager K, Ponnappan U, H, Alves R, Reis F, Santos-Silva A: Aging is
92. Yang L, Besschetnova TY, Brooks CR, Shah Hauer-Jensen M, Meng A, Zhou D: Clear- associated with impaired renal function,
JV, Bonventre JV: Epithelial cell cycle arrest ance of senescent cells by ABT263 rejuve- INF-gamma induced inflammation and with
in G2/M mediates kidney fibrosis after in- nates aged hematopoietic stem cells in alterations in iron regulatory proteins gene
jury. Nat Med 16: 535–543, 2010 mice. Nat Med 22: 78–83, 2016 expression. Aging Dis 5: 356–365, 2013
93. Jun J-I, Lau LF: The matricellular protein 104. Aubert G, Lansdorp PM: Telomeres and 117. Song F, Ma Y, Bai X-Y, Chen X: The ex-
CCN1 induces fibroblast senescence and aging. Physiol Rev 88: 557–579, 2008 pression changes of inflammasomes in the
restricts fibrosis in cutaneous wound heal- 105. d’Adda di Fagagna F, Reaper PM, Clay-Farrace aging rat kidneys. J Gerontol A Biol Sci Med
ing. Nat Cell Biol 12: 676–685, 2010 L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Sci 71: 747–756, 2015
94. van Deursen JM: The role of senescent cells Carter NP, Jackson SP: A DNA damage 118. Stranks AJ, Hansen AL, Panse I, Mortensen M,
in ageing. Nature 509: 439–446, 2014 checkpoint response in telomere-initiated Ferguson DJP, Puleston DJ, Shenderov K,
95. Yang G, Rosen DG, Zhang Z, Bast RC Jr., senescence. Nature 426: 194–198, 2003 Watson AS, Veldhoen M, Phadwal K, Cerundolo
Mills GB, Colacino JA, Mercado-Uribe I, Liu 106. Mikhelson VM, Gamaley IA: Telomere short- V, Simon AK: Autophagy controls acquisition
J: The chemokine growth-regulated onco- ening is a sole mechanism of aging in mam- of aging features in macrophages. J Innate
gene 1 (Gro-1) links RAS signaling to the se- mals. Curr Aging Sci 5: 203–208, 2012 Immun 7: 375–391, 2015
nescence of stromal fibroblasts and ovarian 107. Wills LP, Schnellmann RG: Telomeres and 119. Zheng F, Cheng Q-L, Plati A-R, Ye SQ,
tumorigenesis. Proc Natl Acad Sci USA 103: telomerase in renal health. J Am Soc Nephrol Berho M, Banerjee A, Potier M, Jaimes EA,
16472–16477, 2006 22: 39–41, 2011 Yu H, Guan Y-F, Hao C-M, Striker LJ, Striker

J Am Soc Nephrol 28: ccc–ccc, 2016 Renal Aging: Causes and Consequences 11

GE: The glomerulosclerosis of aging in fe- 131. Lim K, Groen A, Molostvov G, Lu T, Lilley with diabetic kidney disease. Clin J Am Soc
males: Contribution of the proinflammatory KS, Snead D, James S, Wilkinson IB, Ting S, Nephrol 10: 759–766, 2015
mesangial cell phenotype to macrophage Hsiao L-L, Hiemstra TF, Zehnder D: a-klotho 144. Halloran PF, Melk A, Barth C: Rethinking
infiltration. Am J Pathol 165: 1789–1798, expressison in human tissues. J Clin Endo- chronic allograft nephropathy: The concept
2004 crinol Metab 100: E1308–E1318, 2015 of accelerated senescence. J Am Soc Nephrol
120. Zhang B, Bailey WM, Braun KJ, Gensel JC: 132. Keles N, Caliskan M, Dogan B, Keles NN, 10: 167–181, 1999
Age decreases macrophage IL-10 expres- Kalcik M, Aksu F, Kostek O, Aung SM, 145. Melk A, Schmidt BMW, Vongwiwatana A,
sion: Implications for functional recovery Isbilen B, Oguz A: Low serum level of klotho Rayner DC, Halloran PF: Increased expres-
and tissue repair in spinal cord injury. Exp is an early predictor of atherosclerosis. sion of senescence-associated cell cycle
Neurol 273: 83–91, 2015 Tohoku J Exp Med 237: 17–23, 2015 inhibitor p16INK4a in deteriorating renal
121. Yang H-C, Rossini M, Ma L-J, Zuo Y, Ma J, 133. Xu Y, Sun Z: Molecular basis of klotho: From transplants and diseased native kidney. Am
Fogo AB: Cells derived from young bone gene to function in aging. Endocr Rev 36: J Transplant 5: 1375–1382, 2005
marrow alleviate renal aging. J Am Soc 174–193, 2015 146. Verzola D, Gandolfo MT, Gaetani G,
Nephrol 22: 2028–2036, 2011 134. Arking DE, Krebsova A, Macek M Sr., Ferraris A, Mangerini R, Ferrario F, Villaggio
122. Kramann R, Schneider RK, DiRocco DP, Macek M Jr., Arking A, Mian IS, Fried L, B, Gianiorio F, Tosetti F, Weiss U, Traverso
Machado F, Fleig S, Bondzie PA, Henderson Hamosh A, Dey S, McIntosh I, Dietz HC: P, Mji M, Deferrari G, Garibotto G: Accelera-
JM, Ebert BL, Humphreys BD: Perivascular Association of human aging with a func- ted senescence in the kidneys of patients
Gli1+ progenitors are key contributors to tional variant of klotho. Proc Natl Acad Sci with type 2 diabetic nephropathy. Am J
injury-induced organ fibrosis. Cell Stem Cell USA 99: 856–861, 2002 Physiol Renal Physiol 295: F1563–F1573,
16: 51–66, 2015 135. Nitta K, Nagano N, Tsuchiya K: Fibroblast 2008
123. Humphreys BD, Lin S-L, Kobayashi A, growth factor 23/klotho axis in chronic kid- 147. Sis B, Tasanarong A, Khoshjou F, Dadras F,
Hudson TE, Nowlin BT, Bonventre JV, ney disease. Nephron Clin Pract 128: 1–10, Solez K, Halloran PF: Accelerated expres-
Valerius MT, McMahon AP, Duffield JS: 2014 sion of senescence associated cell cycle
Fate tracing reveals the pericyte and not 136. Takebe N, Miele L, Harris PJ, Jeong W, inhibitor p16INK4A in kidneys with glo-
epithelial origin of myofibroblasts in kidney Bando H, Kahn M, Yang SX, Ivy SP: Tar- merular disease. Kidney Int 71: 218–226,
fibrosis. Am J Pathol 176: 85–97, 2010 geting notch, hedgehog, and Wnt path- 2007
124. Stefanska A, Eng D, Kaverina N, Duffield JS, ways in cancer stem cells: Clinical update. 148. Melk A, Schmidt BMW, Takeuchi O,
Pippin JW, Rabinovitch P, Shankland SJ: Nat Rev Clin Oncol 12: 445–464, 2015 Sawitzki B, Rayner DC, Halloran PF: Ex-
Interstitial pericytes decrease in aged 137. Speeckaert MM, Vanfraechem C, Speeckaert R, pression of p16INK4a and other cell cycle
mouse kidneys. Aging (Albany, NY) 7: 370– Delanghe JR: Peroxisome proliferator-activated regulator and senescence associated genes
382, 2015 receptor agonists in a battle against the in aging human kidney. Kidney Int 65: 510–
125. Gomez IG, Duffield JS: The FOXD1 lineage aging kidney. Ageing Res Rev 14: 1–18, 520, 2004
of kidney perivascular cells and myofibro- 2014 149. Melk A, Ramassar V, Helms LM, Moore R,
blasts: Functions and responses to injury. 138. Liu J, Wang LN: Peroxisome proliferator- Rayner D, Solez K, Halloran PF: Telomere
Kidney Int Suppl (2011) 4: 26–33, 2014 activated receptor gamma agonists for shortening in kidneys with age. J Am Soc
126. Schrimpf C, Teebken OE, Wilhelmi M, preventing recurrent stroke and other vas- Nephrol 11: 444–453, 2000
Duffield JS: The role of pericyte detachment cular events in patients with stroke or tran- 150. Raschenberger J, Kollerits B, Titze S,
in vascular rarefaction. J Vasc Res 51: 247– sient ischaemic attack. Cochrane Database Köttgen A, Bärthlein B, Ekici AB, Forer L,
258, 2014 Syst Rev 1: CD010693, 2014 Schönherr S, Weissensteiner H, Haun M,
127. Rojas A, Chang F-C, Lin S-L, Duffield JS: The 139. Duggan J, Kilfeather S, O’Brien E, Wanner C, Eckardt K-U, Kronenberg F;
role played by perivascular cells in kidney O’Malley K, Nussberger J: Effects of GCKD study Investigators: Association of
interstitial injury. Clin Nephrol 77: 400–408, aging and hypertension on plasma an- relative telomere length with cardiovascular
2012 giotensin II and platelet angiotensin II disease in a large chronic kidney disease
128. Lin S-L, Chang F-C, Schrimpf C, Chen Y-T, receptor density. Am J Hypertens 5: 687– cohort: The GCKD study. Atherosclerosis
Wu C-F, Wu V-C, Chiang W-C, Kuhnert F, 693, 1992 242: 529–534, 2015
Kuo CJ, Chen Y-M, Wu K-D, Tsai T-J, 140. Yoon HE, Choi BS: The renin-angiotensin 151. Raschenberger J, Kollerits B, Ritchie J, Lane
Duffield JS: Targeting endothelium-pericyte system and aging in the kidney. Korean J B, Kalra PA, Ritz E, Kronenberg F: Associa-
cross talk by inhibiting VEGF receptor Intern Med 29: 291–295, 2014 tion of relative telomere length with pro-
signaling attenuates kidney microvascular 141. Panickar KS, Jewell DE: The beneficial role gression of chronic kidney disease in two
rarefaction and fibrosis. Am J Pathol 178: of anti-inflammatory dietary ingredients in cohorts: Effect modification by smoking
911–923, 2011 attenuating markers of chronic low-grade and diabetes. Sci Rep 5: 11887, 2015
129. Chen Y-T, Chang F-C, Wu C-F, Chou Y-H, inflammation in aging. Horm Mol Biol Clin 152. Boxall MC, Goodship THJ, Brown AL, Ward
Hsu H-L, Chiang W-C, Shen J, Chen Y-M, Investig 23: 59–70, 2015 MC, von Zglinicki T: Telomere shortening
Wu K-D, Tsai T-J, Duffield JS, Lin S-L: 142. Vlassara H, Uribarri J, Ferrucci L, Cai W, and haemodialysis. Blood Purif 24: 185–
Platelet-derived growth factor receptor Torreggiani M, Post JB, Zheng F, Striker GE: 189, 2006
signaling activates pericyte-myofibroblast Identifying advanced glycation end prod- 153. Epstein FH, Prasad P: Effects of furosemide
transition in obstructive and post-ischemic ucts as a major source of oxidants in aging: on medullary oxygenation in younger and
kidney fibrosis. Kidney Int 80: 1170–1181, Implications for the management and/or older subjects. Kidney Int 57: 2080–2083,
2011 prevention of reduced renal function in 2000
130. Gagliano N, Arosio B, Santambrogio D, elderly persons. Semin Nephrol 29: 594– 154. Kasiske BL: Relationship between vascular
Balestrieri MR, Padoani G, Tagliabue J, 603, 2009 disease and age-associated changes in the
Masson S, Vergani C, Annoni G: Age- 143. Yubero-Serrano EM, Woodward M, human kidney. Kidney Int 31: 1153–1159,
dependent expression of fibrosis-related Poretsky L, Vlassara H, Striker GE; AGE-less 1987
genes and collagen deposition in rat kidney Study Group: Effects of sevelamer carbon- 155. Sarkar D, Fisher PB: Molecular mechanisms
cortex. J Gerontol A Biol Sci Med Sci 55: ate on advanced glycation end products of aging-associated inflammation. Cancer
B365–B372, 2000 and antioxidant/pro-oxidant status in patients Lett 236: 13–23, 2006

12 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016 BRIEF REVIEW

156. Costello-White R, Ryff CD, Coe CL: Aging AJ, Lee RT: Growth differentiation factor M, Tanaka T, Li G, Johnson AD, Gierman
and low-grade inflammation reduce renal 11 is a circulating factor that reverses age- HJ, Feitosa M, Hwang S-J, Atkinson EJ,
function in middle-aged and older adults in related cardiac hypertrophy. Cell 153: Lohman K, Cornelis MC, Johansson Å,
Japan and the USA. Age (Dordr) 37: 9808, 828–839, 2013 Tönjes A, Dehghan A, Chouraki V, Holliday
2015 166. Smith SC, Zhang X, Zhang X, Gross P, EG, Sorice R, Kutalik Z, Lehtimäki T, Esko T,
157. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur Starosta T, Mohsin S, Franti M, Gupta P, Deshmukh H, Ulivi S, Chu AY, Murgia F,
NK, Childs BG, van de Sluis B, Kirkland JL, Hayes D, Myzithras M, Kahn J, Tanner J, Trompet S, Imboden M, Kollerits B, Pistis
van Deursen JM: Clearance of p16Ink4a- Weldon SM, Khalil A, Guo X, Sabri A, Chen G, Harris TB, Launer LJ, Aspelund T,
positive senescent cells delays ageing- X, MacDonnell S, Houser SR: GDF11 does Eiriksdottir G, Mitchell BD, Boerwinkle E,
associated disorders. Nature 479: 232–236, not rescue aging-related pathological hy- Schmidt H, Cavalieri M, Rao M, Hu FB,
2011 pertrophy. Circ Res 117: 926–932, 2015 Demirkan A, Oostra BA, de Andrade M,
158. Baker DJ, Jeganathan KB, Cameron JD, 167. Rodgers BD, Eldridge JA: Reduced circu- Turner ST, Ding J, Andrews JS, Freedman
Thompson M, Juneja S, Kopecka A, Kumar lating GDF11 is unlikely responsible for BI, Koenig W, Illig T, Döring A, Wichmann
R, Jenkins RB, de Groen PC, Roche P, van age-dependent changes in mouse heart, H-E, Kolcic I, Zemunik T, Boban M, Minelli
Deursen JM: BubR1 insufficiency causes muscle, and brain. Endocrinology 156: C, Wheeler HE, Igl W, Zaboli G, Wild SH,
early onset of aging-associated phenotypes 3885–3888, 2015 Wright AF, Campbell H, Ellinghaus D,
and infertility in mice. Nat Genet 36: 744– 168. Brun CE, Rudnicki MA: GDF11 and the Nöthlings U, Jacobs G, Biffar R, Endlich K,
749, 2004 mythical fountain of youth. Cell Metab 22: Ernst F, Homuth G, Kroemer HK, Nauck M,
159. Conboy IM, Conboy MJ, Wagers AJ, Girma 54–56, 2015 Stracke S, Völker U, Völzke H, Kovacs P,
ER, Weissman IL, Rando TA: Rejuvenation 169. Egerman MA, Cadena SM, Gilbert JA, Stumvoll M, Mägi R, Hofman A, Uitterlinden
of aged progenitor cells by exposure to a Meyer A, Nelson HN, Swalley SE, Mallozzi AG, Rivadeneira F, Aulchenko YS, Polasek
young systemic environment. Nature 433: C, Jacobi C, Jennings LL, Clay I, Laurent G, O, Hastie N, Vitart V, Helmer C, Wang JJ,
760–764, 2005 Ma S, Brachat S, Lach-Trifilieff E, Ruggiero D, Bergmann S, Kähönen M,
160. Ruckh JM, Zhao J-W, Shadrach JL, van Shavlakadze T, Trendelenburg A-U, Brack Viikari J, Nikopensius T, Province M, Ketkar
Wijngaarden P, Rao TN, Wagers AJ, AS, Glass DJ: GDF11 increases with age S, Colhoun H, Doney A, Robino A, Giulianini
Franklin RJM: Rejuvenation of regeneration and inhibits skeletal muscle regeneration. F, Krämer BK, Portas L, Ford I, Buckley BM,
in the aging central nervous system. Cell Cell Metab 22: 164–174, 2015 Adam M, Thun G-A, Paulweber B, Haun M,
Stem Cell 10: 96–103, 2012 170. Diep CQ, Ma D, Deo RC, Holm TM, Naylor Sala C, Metzger M, Mitchell P, Ciullo M, Kim
161. Villeda SA, Luo J, Mosher KI, Zou B, RW, Arora N, Wingert RA, Bollig F, SK, Vollenweider P, Raitakari O, Metspalu A,
Britschgi M, Bieri G, Stan TM, Fainberg N, Djordjevic G, Lichman B, Zhu H, Ikenaga T, Palmer C, Gasparini P, Pirastu M, Jukema
Ding Z, Eggel A, Lucin KM, Czirr E, Park J-S, Ono F, Englert C, Cowan CA, Hukriede NA, JW, Probst-Hensch NM, Kronenberg F,
Couillard-Després S, Aigner L, Li G, Peskind Handin RI, Davidson AJ: Identification of Toniolo D, Gudnason V, Shuldiner AR,
ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, adult nephron progenitors capable of kid- Coresh J, Schmidt R, Ferrucci L, Siscovick
Rando TA, Wyss-Coray T: The ageing sys- ney regeneration in zebrafish. Nature 470: DS, van Duijn CM, Borecki I, Kardia SLR, Liu
temic milieu negatively regulates neuro- 95–100, 2011 Y, Curhan GC, Rudan I, Gyllensten U, Wilson
genesis and cognitive function. Nature 477: 171. Sander V, Davidson AJ: Kidney injury and JF, Franke A, Pramstaller PP, Rettig R,
90–94, 2011 regeneration in zebrafish. Semin Nephrol Prokopenko I, Witteman JCM, Hayward C,
162. Smith LK, He Y, Park J-S, Bieri G, Snethlage 34: 437–444, 2014 Ridker P, Parsa A, Bochud M, Heid IM,
CE, Lin K, Gontier G, Wabl R, Plambeck KE, 172. McKee RA, Wingert RA: Zebrafish renal Goessling W, Chasman DI, Kao WHL, Fox
Udeochu J, Wheatley EG, Bouchard J, pathology: Emerging models of acute kid- CS; CARDIoGRAM Consortium; ICBP Con-
Eggel A, Narasimha R, Grant JL, Luo J, ney injury. Curr Pathobiol Rep 3: 171–181, sortium; CARe Consortium; Wellcome Trust
Wyss-Coray T, Villeda SA: b2-microglobulin 2015 Case Control Consortium 2 (WTCCC2):
is a systemic pro-aging factor that impairs 173. Schrimpf C, Xin C, Campanholle G, Gill SE, Genome-wide association and functional
cognitive function and neurogenesis. Nat Stallcup W, Lin S-L, Davis GE, Gharib SA, follow-up reveals new loci for kidney func-
Med 21: 932–937, 2015 Humphreys BD, Duffield JS: Pericyte TIMP3 tion. PLoS Genet 8: e1002584, 2012
163. Katsimpardi L, Litterman NK, Schein PA, and ADAMTS1 modulate vascular stability 176. Köttgen A, Glazer NL, Dehghan A, Hwang
Miller CM, Loffredo FS, Wojtkiewicz GR, after kidney injury. J Am Soc Nephrol 23: S-J, Katz R, Li M, Yang Q, Gudnason V,
Chen JW, Lee RT, Wagers AJ, Rubin LL: 868–883, 2012 Launer LJ, Harris TB, Smith AV, Arking DE,
Vascular and neurogenic rejuvenation of 174. Zhu Y, Tchkonia T, Pirtskhalava T, Gower A, Astor BC, Boerwinkle E, Ehret GB, Ruczinski
the aging mouse brain by young sys- Ding H, Giorgadze N, Palmer AK, Ikeno Y, I, Scharpf RB, Chen Y-DI, de Boer IH,
temic factors. Science 344: 630–634, Borden G, Lenburg M, O’Hara SP, LaRusso Haritunians T, Lumley T, Sarnak M, Siscovick
2014 NF, Miller JD, Roos CM, Verzosa GC, D, Benjamin EJ, Levy D, Upadhyay A,
164. Sinha M, Jang YC, Oh J, Khong D, Wu EY, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Aulchenko YS, Hofman A, Rivadeneira F,
Manohar R, Miller C, Regalado SG, Loffredo Stout MB, McGowan SJ, Fuhrmann-Stroissnigg Uitterlinden AG, van Duijn CM, Chasman DI,
FS, Pancoast JR, Hirshman MF, Lebowitz J, H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro Paré G, Ridker PM, Kao WHL, Witteman JC,
Shadrach JL, Cerletti M, Kim M-J, Serwold A, Ling YY, Barghouthy AS, Navarro DC, Coresh J, Shlipak MG, Fox CS: Multiple loci
T, Goodyear LJ, Rosner B, Lee RT, Wagers Sano T, Robbins PD, Niedernhofer LJ, associated with indices of renal function and
AJ: Restoring systemic GDF11 levels re- Kirkland JL: The achilles’ heel of senescent chronic kidney disease. Nat Genet 41: 712–
verses age-related dysfunction in mouse cells: From transcriptome to senolytic drugs. 717, 2009
skeletal muscle. Science 344: 649–652, Aging Cell 14: 644–658, 2015 177. Gorski M, Tin A, Garnaas M, McMahon GM,
2014 175. Pattaro C, Köttgen A, Teumer A, Garnaas Chu AY, Tayo BO, Pattaro C, Teumer A,
165. Loffredo FS, Steinhauser ML, Jay SM, Gannon M, Böger CA, Fuchsberger C, Olden M, Chasman DI, Chalmers J, Hamet P,
J, Pancoast JR, Yalamanchi P, Sinha M, Chen M-H, Tin A, Taliun D, Li M, Gao X, Tremblay J, Woodward M, Aspelund T,
Dall’Osso C, Khong D, Shadrach JL, Miller CM, Gorski M, Yang Q, Hundertmark C, Foster Eiriksdottir G, Gudnason V, Harris TB,
Singer BS, Stewart A, Psychogios N, Gerszten MC, O’Seaghdha CM, Glazer N, Isaacs A, Launer LJ, Smith AV, Mitchell BD,
RE, Hartigan AJ, Kim M-J, Serwold T, Wagers Liu C-T, Smith AV, O’Connell JR, Struchalin O’Connell JR, Shuldiner AR, Coresh J, Li M,

J Am Soc Nephrol 28: ccc–ccc, 2016 Renal Aging: Causes and Consequences 13

Freudenberger P, Hofer E, Schmidt H, Davis RW, Higgins J, Owen AB, Kim SK: A from acute kidney injury. Nephrol Dial
Schmidt R, Holliday EG, Mitchell P, Wang transcriptional profile of aging in the human Transplant 30: 575–583, 2015
JJ, de Boer IH, Li G, Siscovick DS, Kutalik Z, kidney. PLoS Biol 2: e427, 2004 195. Hariri RJ, Hajjar DP, Coletti D, Alonso DR,
Corre T, Vollenweider P, Waeber G, Gupta 184. Broer L, van Duijn CM: GWAS and meta- Weksler ME, Rabellino E: Aging and arte-
J, Kanetsky PA, Hwang S-J, Olden M, Yang analysis in aging/longevity. Adv Exp Med riosclerosis. Cell cycle kinetics of young and
Q, de Andrade M, Atkinson EJ, Kardia SLR, Biol 847: 107–125, 2015 old arterial smooth muscle cells. Am J
Turner ST, Stafford JM, Ding J, Liu Y, 185. Plomin R, Haworth CMA, Davis OSP: Com- Pathol 131: 132–136, 1988
Barlassina C, Cusi D, Salvi E, Staessen JA, mon disorders are quantitative traits. Nat 196. Rong S, Zhao X, Jin X, Zhang Z, Chen L, Zhu
Ridker PM, Grallert H, Meisinger C, Müller- Rev Genet 10: 872–878, 2009 Y, Yuan W: Vascular calcification in chronic
Nurasyid M, Krämer BK, Kramer H, Rosas 186. Tan Q, Zhao JH, Li S, Kruse TA, Christensen kidney disease is induced by bone mor-
SE, Nolte IM, Penninx BW, Snieder H, K: Power assessment for genetic associa- phogenetic protein-2 via a mechanism in-
Fabiola Del Greco M, Franke A, Nöthlings tion study of human longevity using offspring volving the Wnt/b-catenin pathway. Cell
U, Lieb W, Bakker SJL, Gansevoort RT, van of long-lived subjects. Eur J Epidemiol 25: Physiol Biochem 34: 2049–2060, 2014
der Harst P, Dehghan A, Franco OH, 501–506, 2010 197. Yonekura Y, Fujii H, Nakai K, Kono K, Goto
Hofman A, Rivadeneira F, Sedaghat S, 187. Shi H, Belbin O, Medway C, Brown K, S, Shinohara M, Nishi S: Anti-oxidative ef-
Uitterlinden AG, Coassin S, Haun M, Kalsheker N, Carrasquillo M, Proitsi P, fect of the b-blocker carvedilol on diabetic
Kollerits B, Kronenberg F, Paulweber B, Powell J, Lovestone S, Goate A, Younkin S,
Aumann N, Endlich K, Pietzner M, Völker U, nephropathy in non-obese type 2 diabetic
Passmore P, Morgan K, Craig D, Johnston J, rats [published online ahead of print July
Rettig R, Chouraki V, Helmer C, Lambert Mcguinness B, Todd S, Kehoe PG, Hooper
J-C, Metzger M, Stengel B, Lehtimäki T, 14, 2015]. Clin Exp Pharmacol Physiol
NM, Vardy ERLC, Mann DM, Smith AD,
Lyytikäinen L-P, Raitakari O, Johnson A, 10.1111/1440-1681.12447
Wilcock G, Warden D; Genetic and Envi- 198. Bianchessi V, Badi I, Bertolotti M, Nigro P,
Parsa A, Bochud M, Heid IM, Goessling W,
ronmental Risk for Alzheimer’s Disease
Köttgen A, Kao WHL, Fox CS, Böger CA: D’Alessandra Y, Capogrossi MC, Zanobini
Consortium; Alzheimer’s Research UK
Genome-wide association study of kidney M, Pompilio G, Raucci A, Lauri A: The mi-
Consortium: Genetic variants influencing
function decline in individuals of European tochondrial lncRNA ASncmtRNA-2 is in-
human aging from late-onset Alzheimer’s
descent. Kidney Int 87: 1017–1029, 2015 duced in aging and replicative senescence
disease (LOAD) genome-wide association
178. Johnson SC, Dong X, Vijg J, Suh Y: Genetic in Endothelial Cells. J Mol Cell Cardiol 81:
studies (GWAS). Neurobiol Aging 33: 1849.
evidence for common pathways in human 62–70, 2015
e5–1849.e18, 2012
age-related diseases. Aging Cell 14: 809– 199. London G, Covic A, Goldsmith D, Wiecek A,
188. Rando TA, Chang HY: Aging, rejuvenation,
817, 2015 Suleymanlar G, Ortiz A, Massy Z, Lindholm
179. Tampe B, Zeisberg M: Contribution of ge- and epigenetic reprogramming: Resetting
B, Martinez-Castelao A, Fliser D, Agarwal R,
netics and epigenetics to progression of the aging clock. Cell 148: 46–57, 2012
Jager KJ, Dekker FW, Blankestijn PJ,
kidney fibrosis. Nephrol Dial Transplant 29 189. Dwivedi RS, Herman JG, McCaffrey TA, Raj
Zoccali C; for EUropean REnal and CArdio-
[Suppl 4]: iv72–iv79, 2014 DSC: Beyond genetics: Epigenetic code in
vascular Medicine working group of the
180. Noordmans GA, Hillebrands J-L, van Goor chronic kidney disease. Kidney Int 79: 23–
32, 2011 European Renal Association–European Di-
H, Korstanje R: A roadmap for the genetic
190. Reddy MA, Natarajan R: Epigenetics in di- alysis and Transplant Association (ERA–
analysis of renal aging. Aging Cell 14: 725–
abetic kidney disease. J Am Soc Nephrol EDTA): Arterial aging and arterial disease:
733, 2015
22: 2182–2185, 2011 Interplay between central hemodynamics,
181. Wolf I, Levanon-Cohen S, Bose S, Ligumsky
191. Smyth LJ, McKay GJ, Maxwell AP, cardiac work, and organ flow-implications
H, Sredni B, Kanety H, Kuro-o M, Karlan B,
McKnight AJ: DNA hypermethylation and for CKD and cardiovascular disease. Kidney
Kaufman B, Koeffler HP, Rubinek T: Klotho:
A tumor suppressor and a modulator of the DNA hypomethylation is present at differ- Int Suppl (2011) 1: 10–12, 2011
IGF-1 and FGF pathways in human breast ent loci in chronic kidney disease. Epige- 200. Zeng Y, Wang P-H, Zhang M, Du J-R: Aging-
cancer. Oncogene 27: 7094–7105, 2008 netics 9: 366–376, 2014 related renal injury and inflammation are
182. Bartke A: Long-lived klotho mice: New in- 192. Trionfini P, Benigni A, Remuzzi G: Micro- associated with downregulation of Klotho
sights into the roles of IGF-1 and insulin in RNAs in kidney physiology and disease. Nat and induction of RIG-I/NF-kB signaling
aging. Trends Endocrinol Metab 17: 33–35, Rev Nephrol 11: 23–33, 2015 pathway in senescence-accelerated mice.
2006 193. Ben-Avraham D: Epigenetics of aging. Adv Aging Clin Exp Res 28: 69–76, 2015
183. Rodwell GEJ, Sonu R, Zahn JM, Lund J, Exp Med Biol 847: 179–191, 2015 201. Ren S, Duffield JS: Pericytes in kidney fi-
Wilhelmy J, Wang L, Xiao W, Mindrinos M, 194. Canaud G, Bonventre JV: Cell cycle arrest brosis. Curr Opin Nephrol Hypertens 22:
Crane E, Segal E, Myers BD, Brooks JD, and the evolution of chronic kidney disease 471–480, 2013

14 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016