Introduction

Aging is a constant and predictable sequence of events involving the growth and development of living organisms. Evolutionary Biology of Aging defines aging as ‘a persistent decline in the age-specific fitness components of an organism due to internal physiological deterioration’.1 Although aging is the consequence of ‘internal physiological deteriorations’, aging in humans is recognized as a multidimensional process encompassing physical, psychological and social alterations. For example, exercise capacity and reaction times diminish with age, whereas knowledge, experience and wisdom can be gained.

Aging is associated with a decline in physiological homeostasis. It is likely that aging-associated declines in organ function are not a homogenous sequence but represent a multidimensional process, as described above. In higher organisms, aging homeostasis is regulated by the interaction of multiple organs; age-mediated dysfunction in one organ can lead to a functional deficiency in multiple organs. The organs of an individual exhibit different rates of aging, which are influenced by several modifiable factors, including genetics, lifestyle choices and environmental exposures.

The kidneys are also affected by the aging process, which results in numerous effects on the renal system.2 Renal mass decreases between the ages of 30 and 80 years, with the steepest decline observed after age 50.3, 4 Fat and fibrosis scarring may replace some of the remaining functional parenchymal tissue.4, 5, 6 This scarring and loss of kidney parenchymal tissue occurs primarily in the renal cortex;6 therefore, scarring affects the nephrons that are important for maximal urine concentration. Even in normal aging kidneys, 30% of the glomeruli are destroyed and display diffuse glomerular sclerosis by age 75,7 and the remaining glomeruli exhibit impaired filtering ability. The results from aging studies in animals and humans suggest that diverse factors may contribute to the scarring process, such as tissue ischemia, injury, hypertension, metabolic defects and obesity.

Aging is an unavoidable process of life for all living creatures. However, the evidence from longitudinal studies suggests that one-third of all healthy individuals aged 23–97 years are essentially unaffected by changes in renal function throughout their lives.8 Recent evidence reveals that several anti-aging molecules are active in the human body and that these molecules are regulated by multiple factors through individual behaviors.9, 10 These results indicate that kidney aging could in fact be delayed and even reversed with the appropriate intervention.

In this review, we will discuss the general characteristics of renal aging and analyze potential interventional methods for aging kidneys.

Physiology of aged kidneys

At baseline, healthy normotensive older men exhibit 40% less renal plasma blood flow than young men.11 In older men, glomerular filtration is maintained and the filtration fraction is elevated12 by (1) enhanced hyperfiltration of the residual glomeruli by constriction of the efferent arteriole in comparison with the afferent arteriole13 and (2) a relative increase in the medullary blood flow due to a reduction in renal plasma blood flow in the renal cortex.3 Hyperfiltration in the glomeruli of the aging kidney can result in glomerulosclerosis by increasing intraglomerular pressure.

Aging kidneys exhibit increased vulnerability to stressful conditions and adrenergic activation.14 Under conditions of stress or illness associated with a reduction in the effective circulating volume, such as heart failure or dehydration, the levels of vasoconstrictive substances are markedly increased.15 Such vasoconstrictive substances in the elderly may further reduce the already compromised blood flow in the aging kidney.15 Under such conditions, renal circulation is highly dependent on the vasodilatory prostaglandins that can modulate excess vasoconstriction.15 The importance of prostaglandins in adrenergic activation has been demonstrated in experimental animal models.16 The function of aging kidneys can be preserved through vasodilation to compensate for the loss of vasculature,11, 17 because such a treatment can impair the renal response to maximal vasodilation. This prostaglandin-dependent homeostasis in the aging kidney is likely one of the reasons why older individuals exhibit a higher risk of non-steroidal anti-inflammatory drug-induced renal injury.18, 19 Some reports state that the inability of dopamine to affect creatinine clearance in the elderly may be responsible for the inability to respond to endogenous dopamine during times of physiologic stress, thereby resulting in an increased susceptibility to renal deficiency.20 How this dopamine insensitivity relates to the vasodilatory prostaglandin systems is unclear.

Nephron function

In general, the glomerular filtration rate in humans starts to decline by approximately 1 ml per year after approximately 30 years of age.21 By the time they reach 90 years of age, humans exhibit an inulin clearance rate of approximately 65 ml min−1.21 Creatinine clearance also decreases with age (7.5–10 ml min−1 per decade), although significant variability exists in the reported age-related decline in renal function in longitudinal studies;8 approximately one-third of patients exhibit no change in the glomerular filtration rate, another third exhibit a slight decline and the remaining third exhibit a more marked decline.8 In the elderly, the production of creatinine also decreases with age, whereas the secretion of creatinine from the tubules increases.22 Therefore, although the glomerular filtration rate declines in aging kidneys, the serum creatinine levels may remain stable,23 which further highlights the limitation of using relative insensitive serum creatinine levels as a marker of renal function.

In general, electrolyte and fluid homeostasis is relatively well maintained during normal aging. In a steady-state condition, older individuals can maintain balanced sodium levels. However, under stressful conditions, the ability to maximally dilute the urine is impaired, and the excreted water load is compromised.24 For instance, aging kidneys exhibit a significant impairment in the reduction of urinary sodium excretion in response to dietary sodium chloride deprivation compared with young individuals.24 The mean lithium clearance, an indicator of proximal tubular function, is significantly decreased in older individuals when compared with healthy, young individuals.25 In the elderly, the fractional proximal sodium reabsorption is significantly higher than it is in young individuals, but this elevation is offset by the lower distal fractional reabsorption of sodium.

In contrast, potassium handling in aging kidneys is negatively affected by aging. Older individuals are susceptible to developing hyperkalemia when using certain drugs, such as inhibitors of the renin–angiotensin system. Urine potassium is derived from active transtubular transport in the distal nephron and collecting duct, and is associated with the reabsorption of sodium by the aldosterone-modulated Na-K ATPase transporters. Impaired potassium secretion, which is directly associated with disorders in sodium reabsorption, may occur in aging kidneys due to tubular atrophy and tubular interstitial scarring. Hyporeninemic or normoreninemic hypoaldosteronism and volume depletion-related suppression of water and sodium delivery into the distal nephron is also associated with potassium secretion disorders in aging kidneys.26 This tubular dysfunction results in the inability to maximally concentrate and dilute the urine; older individuals may exhibit a higher rate of nocturia and a predisposition to dehydration and volume-dependent hyper- or hyponatremia.27, 28

One of the clinically important issues in aging kidneys is the increased susceptibility to drug-induced nephrotoxicity.29 In older individuals, the metabolism and clearance of administered drugs are compromised due to the decline in hepatic metabolism and the reduction in the excretory capacity of the kidneys. Therefore, aging kidneys often suffer from the effects of sustained elevated concentrations of drugs because of the altered pharmacokinetics of these drugs. Drug pharmacodynamics are also altered in older individuals through the modulation of drug sensitivity and the physiological response to drug actions, regardless of changes in kidney condition. The combination of altered pharmacodynamics and pharmacokinetics in older individuals with multiple comorbidities that require medication results in an increased probability of drug toxicities and associated complications. It is therefore reasonable to start therapy at the lowest drug dosage required and gradually increase the dose over time.

Other important functional alterations in the kidneys include a deficiency in urine acidification and acid excretion. The ability of aging kidneys to recover from acute damage is also compromised,30, 31, 32 and they are vulnerable to ischemic damage, exhibiting increased apoptosis following ischemic damage.32 In addition, the tubular cells of aging kidneys exhibit disorders in their ability to repopulate following acute ischemic damage.32

Endocrine function

The reduction in renal function is associated with the decreased production of erythropoietin (EPO),33 resulting in an increased incidence of anemia.34 Healthy elderly individuals exhibit relatively high serum EPO levels, which suggests a compensatory response to age-related subclinical blood loss, increased erythrocyte turnover or increased EPO resistance.35 EPO levels are, however, unexpectedly suppressed in anemic elderly patients when compared with anemic young individuals, which suggests a blunted response to low hemoglobin levels.36, 37, 38

Older women with osteoporosis and mild renal dysfunction exhibit lower calcium absorption rates and lower serum 1,25-dihydroxyvitamin D levels despite normal serum 25-hydroxyvitamin D levels, indicating a deficiency in the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the aging kidneys.39 Mild renal dysfunction (creatinine clearance less than 65 ml min−1) is an independent risk factor for falls and their associated fractures in older patients with osteoporosis.40 Calcitriol therapy has been shown to reduce the number of falls in elderly patients by 50%, perhaps due to the increase in serum 1,25-dihydroxyvitamin D levels with the upregulation of vitamin D receptors in muscle tissue, resulting in improved muscle strength.39

Approximately 50% of insulin in the peripheral circulation is removed by the kidneys.41 The kidneys filter insulin from the glomeruli, after which it is taken up in the proximal tubules and subsequently degraded. Renal function deficiencies in older individuals result in reduced insulin clearance. These renal dysfunction-associated insulin clearance disorders are partially offset by diminished glucose tolerance secondary to age-induced defective insulin secretion and action. Chronic renal insufficiency-associated parathyroid hormone excess has been shown to result in impaired insulin secretion and impaired glucose tolerance in humans.42 Similarly, an analysis in an experimental animal model suggested that impaired insulin secretion in aging rats might be the result of aging-associated chronic renal insufficiency and excess parathyroid hormone.43 Glucose intolerance in healthy older patients is due to a decrease in both insulin secretion and insulin resistance.44 Therefore, even though the total body insulin clearance in older individuals is generally compromised when compared with younger individuals, older patients are at a higher risk of glucose intolerance. In addition, this lower insulin clearance rate may be a serious problem and present a higher risk of sustained hypoglycemia in older diabetic patients who are treated with hypoglycemic agents.

The sympathetic nervous system is also affected by the aging kidneys and exhibits enhanced activity in patients with chronic kidney disease,45 which can persist even after transplantation.46 Chronic activation of the sympathetic nervous system may also contribute to arterial stiffening with advanced arterial disease. Older individuals may also exhibit arterial stiffening, which is probably associated with the deterioration in their renal function. It is therefore reasonable to assume that the enhanced sympathetic tone associated with declining glomerular filtration rates and other factors may contribute to the vascular pathologies in elderly patients.

Pathological changes in aged kidneys

The weight of the kidneys progressively declines after the fifth decade of life.47 Renal cortical lesions become thinner, whereas the medulla remains relatively unaltered by aging.47 Although kidney weight declines with age, there is no evidence of an age-dependent decline in kidney volume when analyzed by computed tomography; imaging analyses demonstrate that the kidney parenchymal volume remains unaltered.48, 49, 50 The reason for the unaltered kidney volume in the elderly despite age-related glomerulosclerosis51 may be the compensatory hypertrophy of unaffected nephrons in response to the significant nephron loss caused by glomerulosclerosis and tubular atrophy.4 Studies have reported both increased volume in the functional glomeruli and decreased glomerular density in aging kidneys.52, 53, 54, 55

The pathological characteristics of aging kidneys include glomerular sclerosis, tubular atrophy and tubulointerstitial fibrosis.51

In aging kidney glomerulus, hyaline mesangial matrix expansion results in the obliteration of the glomerular capillary loops56, 57 and is associated with capillary tuft collapse and intra-capsular fibrosis. Different cell types within the glomeruli are also affected by aging. Aging-related glomerular enlargement is associated with significant mesangial expansion.58 Glomerular mesangial cells and endothelial cells increase in number till age 50,59 thereby maintaining the ratio of the number of glomerular mesangial cells to the enlarged glomerular volume, suggesting a physiologically appropriate increase. After age 50, both mesangial cells and endothelial cell exhibited decreased trend and it become significant after age 70.59 On the other hand, podocytes do not increase despite the significant enlargement of the glomeruli, resulting in a relative depletion of podocytes.59 Podocytes exhibit hypertrophy in association with glomerular hypertrophy.60 Electron microscopy analysis reveals that podocyte injury with features such as hypertrophy, intracellular uptake of protein/absorptive droplets, foot process fusion and detachment of the podocytes from the glomerular basement membranes.57, 61

It is thought that age-related fibrointimal hyperplasia in the small arteries leads to glomerulosclerosis and the subsequent initiation of associated local tubular atrophy and interstitial fibrosis.62 The presence of underlying diseases, such as hypertension and diabetes, may accelerate the pathological alterations observed in aging kidneys.2 The intimal hyperplasia in the interlobular arteries may allow for the transmission of abnormal arterial pulse waves into the smaller distal branches.63, 64 These arterial pulse waves can lead to hyaline changes in the arterioles, resulting in an acceleration of the intimal fibrosis.63, 64 Aging kidneys exhibit an elevated number of aglomerular arteries, which are characterized by directly connected arteries that bypass the afferent and efferent arterioles due to the loss of the glomeruli.62 In aging kidneys, tubular diverticula are often observed and are a probable source of renal cysts.65, 66 These aging-related pathological alterations in the glomeruli and tubulointerstitium are not specific to aging kidneys but are also common pathways of kidney fibrosis in a number of renal diseases.

Vascular defects in aging kidneys are associated with renal parenchymal hypoxia and altered responses to hypoxia. The degree of hypoxia is positively associated with age-related tubulointerstitial injury.67 Tissue hypoxia induces the accumulation of hypoxia-inducible factors (HIFs),68 master regulators of oxygen tension in tissues by the regulation of hypoxia-responsive genes such as vascular endothelial growth factor and EPO.68 Some reports indicate that the activation of HIFs may protect aging kidneys from kidney hypoxia.69 However, this relationship is undoubtedly complex, as renal tubule-specific knockout of von Hippel-Lindau tumor suppressor protein (VHL), which acts as an ubiquitin ligase to promote proteolysis of HIF-1α,70 induces severe fibrosis when compared with control littermates.71 VHL is not specific for HIF, and it is possible that HIF-independent effects stimulate renal fibrosis, whereas mice with HIF-1α deletion in the kidney tubules also exhibit amelioration of kidney fibrosis in a unilateral ureteral obstruction model.72 Knockout mice studies71, 72 are not performed in an aging-associated kidney disease model, but the altered regulation of HIFs in the aging kidney could be considered for potential interventions.

Combating renal aging

Numerous metabolic, physiological and pathological factors contribute to the pathogenesis of kidney aging. Repeated tissue inflammation is one such factor involved in the kidney aging process.73 Underlying disease conditions are important therapeutic targets for the prevention of kidney aging.73 In addition to these established risk factors and interventions targeting them, such as renin–angiotensin system blockade, we will discuss kidney aging-associated molecules and potential methods for combating kidney aging (Figure 1).

Figure 1
figure 1

Working hypothesis of combating aging kidney. The kidney continuously suffers from various physiological/pathological stresses/toxins, and several such factors could accelerate kidney aging. In addition to the appropriate treatments for underlying diseases and the inhibition of aging accelerating factors, recent advances in geriatrics and the discovery of novel molecular targets revealed potential interventional clues for the aging kidney. In addition, anti-fibrosis therapies could be beneficial interventions for the aging kidney.

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Calorie restriction and activation of sirtuins

Calorie restriction consists of established dietary interventions that have been shown to increase both the median and maximum lifespan of a variety of species, including yeast, fish and mammals.9, 74 The health benefits of calorie restriction have also been demonstrated in primates; calorie restriction in rhesus monkeys blunts aging and significantly delays the onset of age-related disorders, including cancer, diabetes, cardiovascular disease and brain atrophy.75

Numerous molecules may mediate the beneficial effects of calorie restriction. Among these calorie restriction-mediated molecules, sirtuin 1 (SIRT1) has a well-established importance in calorie restriction-mediated signaling.76 Calorie restriction likely enhances SIRT1 activity in most tissues, including the kidneys.77, 78 In support of this finding, in SIRT1 knockout mice, the beneficial effects of calorie restriction are diminished.78 SIRT1 transgenic mice display a similar phenotype in response to calorie restriction.79 The potential SIRT1 activator, resveratrol, may induce a similar transcriptional profile to that of calorie restriction and provide protection against glomerulosclerosis.80, 81, 82 The significance of resveratrol dependence on SIRT1 activation in the renoprotection is, however, controversial.83 Calorie restriction-induced SIRT1 enhances forkhead box protein O 3 (FoxO3) deacetylation and the subsequent upregulation of Bnip3. FoxO3 and Bnip3 activation induces autophagy in the renal proximal tubular cells and mitochondria biogenesis.78 SIRT1 also deacetylates HIF-2α and has an important role in EPO production, which suggests that SIRT1 may act as a critical modulator of systemic oxygen levels and local oxygen tension.84 SIRT1 stimulates the activity of the liver-X receptor (LXR)85 and the farnesoid X receptor (FXR),86 both of which regulate lipid metabolism.85, 86 SIRT1 activated-LXR and -FXR play preventative roles in the onset and progression of proteinuria and glomerulosclerosis in type 2 diabetes and diet-induced obesity in animal models.87, 88, 89, 90 Although the beneficial effects of calorie restriction and SIRT1 activation on halting kidney aging and expanding longevity has not yet been reported in humans, the above evidence indicates that calorie restriction and/or SIRT1 activation may provide a potential clue to combat kidney aging.

Klotho

The Klotho gene encodes a transmembrane protein and is expressed primarily in the kidney.10 In 1997, Kuro-o et al.10 reported that mutations in the Klotho gene in mice resulted in multiple phenotypes of human aging, such as the calcification of soft tissue and vascular walls, hyperphosphatemia, muscle and skin atrophy, and early death. Furthermore, Klotho gene overexpression in mice has been shown to extend life span when compared with control mice.10, 91 The Klotho gene has vital roles in the regulation of both phosphorus and calcium phosphate transport.92 Membrane-bound Klotho functions as the obligate coreceptor for fibroblast growth factor (FGF) 23, and any defects in the function of either Klotho or FGF23 in mice lead to phosphate accumulation and premature aging.93 Patients with CKD eventually suffer premature death not from renal failure but as a result of the early onset of common aging-related diseases, such as cardiovascular disease and diabetes.94 CKD patients exhibit remarkable declines in the kidney expression of Klotho,95 which is associated with resistance to FGF23,96 hyperphosphatemia and vascular calcification, symptoms similar to those of Klotho-deficient mice.10, 91 These data suggest a significant link between phosphate metabolism and kidney aging. Thus, Klotho deficiency may be a candidate therapeutic target for kidney aging.95

Perspective: anti-fibrosis therapy

Similar to the advanced features in all progressive kidney diseases, the pathological hallmarks of aging kidneys include fibroproliferative changes, such as glomerulosclerosis and tubulointerstitial fibrosis. Therefore, if an anti-fibrosis therapy were available, it could be an effective therapy for aging kidneys and their associated health problems.

The role of transforming growth factor (TGF)-β in kidney fibrosis is well established.97 TGF-β induces the intracellular signaling molecules specific to the TGF-β family, smads.98, 99, 100 Smads are subclassified into three types: (1) receptor-regulated smads or R-smads (smad2 and 3); (2) common smads or co-smad (smad4); and (3) inhibitory smads or I-smads (smad6 and 7). During TGF-β binding, the phosphorylated type I receptor recruits R-smads for phosphorylation, and phosphorylated R-smads interact with the co-smad in the cell cytoplasm. The smad heterodimer binds to smad-binding elements in the DNA promoter regions. Unlike the other smads, I-smad competitively inhibits R-smad phosphorylation by the type I receptor.101 Therefore, when examining the biology of the profibrotic cytokine TGF-β, the anti-fibrotic strategy may be (1) to antagonize TGF-β and its signaling pathway, (2) to counteract TGF-β or (3) to enhance the function of I-smads.

(1) Block TGF-β signaling

Several studies have reported the remarkable effects of TGF-β-neutralizing antibodies on diabetic glomerulosclerosis.102, 103 The overexpression of TGF-β-binding peptide, which keeps TGF-β in its latent form, has also been shown to inhibit tissue fibrosis.104, 105 This evidence indicates that blocking the TGF-β signaling pathway may be an essential therapy for tissue fibrosis.

The profibrotic TGF-β signaling pathway transduces primarily through R-smads, smad2 or smad3. Recently, smad2 and smad3 have been shown to have distinct roles in kidney fibrosis. Smad3 appears to mediate renal fibrosis, whereas smad2 antagonizes the profibrotic action of smad3.106 Therefore, targeting R-smads and, in particular, smad3 could be another potential strategy for treating kidney fibrosis by manipulating the TGF-β signaling pathway.97 Pirfenidone has been shown to exhibit anti-R-smad effects,107 as well as beneficial effects on experimental renal disease108, 109 diabetic kidney disease110 and focal segmental glomerulosclerosis.111

(2) Counteract the TGF-β signaling pathway

Counteracting the profibrotic TGF-β-smad signaling pathway by targeting other pathways is another anti-fibrosis strategy. The bone morphogenetic protein-7 (BMP7) and its associated molecules are well-established anti-fibrotic molecules. Several BMP7 antagonists have demonstrated physiological significance, and several extracellular molecules have been identified that bind to BMP7, acting as agonists or antagonists in the kidney.112, 113 BMP antagonists function by direct interaction with BMPs, thereby preventing BMPs from binding to their receptors. Such extracellular BMP signaling inhibitors include noggin,114 gremlin,115 CRIM1,116 DAN/cerberus,117 vertebrate chordin118 and uterine sensitization-associated gene-1 (USAG-1).119 In contrast, Kielin/chordin-like protein (KCP) protein is an extracellular protein that enhances the activity of BMP7 by amplifying the physical interaction of BMP7 with its receptor.120

BMP7 is a member of the TGF-β superfamily.121, 122, 123 BMP7 binds to three type I receptors, activin-like kinases (Alk) -2, -3 and -6, and a type II receptor (BMPR-II) and exhibits distinct activities in various cell types,124 as well as anti-inflammatory and anti-apoptotic functions.125, 126 The ligand-induced activation of BMP receptors exhibits intrinsic serine/threonine kinase activity that triggers the phosphorylation of R-smads. Smad2 and smad3 are phosphorylated by type I receptors of TGF-β and activin, whereas smad 1, smad5 and smad8 act downstream of the BMP type I receptors.124

Although the anti-fibrotic action of BMP-7 has been considered useful in the treatment of progressive kidney diseases, the multiple functions of BMP-7 limit its use due to the potential adverse non-anti-fibrogenic effects, such as bone formation. Recently, Sugimoto et al.127 reported that the BMP-7 receptor Alk-3 is essential for kidney tubular homeostasis, including anti-fibrosis, anti-inflammation and anti-apoptosis activity. The small molecular BMP-7 mimetic (known as THR-123), which is designed to bind directly to the Alk-3 receptor, exhibited anti-fibrotic effects and anti-apoptotic and anti-inflammatory actions in five mouse models of acute and chronic kidney injury.127 Combining the THR-123 with ACE-I captopril had an additive therapeutic benefit in controlling renal fibrosis,127 which suggests that THR-123 may be an additional anti-fibrotic therapy in the conventional ACE-I-based intervention of fibrotic kidney diseases.

(3) Induction of I-smads

A final strategy for anti-TGF-β signaling and anti-fibrosis therapy is to enhance the activity of I-smads. Gene transfer to induce smad7, an I-smad, can prevent diabetic glomerulosclerosis by inhibition of the renal TGF-β/smad signaling pathway.128 There is as yet no such molecule with which to target I-smads, but this potential therapy may lie in the function of the ACE inhibition-associated rise in the anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP).100

AcSDKP, a natural inhibitor of hematopoietic stem cell proliferation, is a tetrapeptide originally isolated from fetal calf bone marrow129 and has emerged as an anti-fibrotic molecule. Although the details of the endogenous AcSDKP production pathway are not yet clear, the available evidence suggests that thymosin β4 (Tβ4) is the most likely candidate precursor of AcSDKP.130, 131 AcSDKP is the N-terminal sequence of Tβ4. Prolyl oligopeptidase may be responsible for the formation of AcSDKP, and prolyl oligopeptidase inhibitors may block the formation of AcSDKP from Tβ4.100, 132 Tβ4 also exhibits extracellular organ-protective functions that are associated with anti-fibrosis and enhanced angiogenesis, which are partially mediated by the accumulation of AcSDKP.133

AcSDKP is a substrate of the ACE N-terminal catalytic domain and is hydrolyzed in the presence of ACE. The plasma levels of AcSDKP are minimal under normal conditions, whereas ACE-I leads to a fivefold increase in the concentration of AcSDKP.134 AcSDKP suppresses the proliferation of human mesangial cells135 and renal fibroblasts,136 and the collagen deposition in mouse cardiac fibroblasts.137 AcSDKP restored glomerular sclerosis and renal fibrosis in hypertensive rat models and diabetic and non-diabetic kidney disease models without altering blood pressure.138, 139 The incubation of human mesangial cells in the presence of AcSDKP leads to the cytoplasmic mobilization of smad7 in the absence of TGFβ stimulation.140 The smad7 level increases in vivo following AcSDKP administration, supporting the smad7 mediated anti-TGF-β effects of AcSDKP.141, 142 Given that AcSDKP is increased by the inhibition of ACE, AcSDKP might have an important role in the renoprotective effects of ACE-I.100 This evidence also suggests that the potential anti-TGF-β effects of AcSDKP by I-smad may provide a new therapeutic candidate for progressive kidney fibrosis.100

Conclusion

In almost every country, the proportion of people over 60 years of age is increasing much faster than any other age group as a result of both longer life expectancy and declining fertility rates. Functional deficiencies in the kidney may be associated with health problems in multiple organs, and therefore, the prevention of kidney aging may be an appropriate approach for combating age-related diseases (Figure 1). Aging kidneys are good candidates for such an intervention, and the aging process in kidneys could be preventable (Figure 1).