2007-KIDNEY AGEING-ARA

Ageing Research Reviews 6 (2007) 211–222 www.elsevier.com/locate/arr

Review

Does renal ageing affect survival?

M. Shawkat Razzaque * Department of Developmental Biology, Research and Education Building, Room # 304, Harvard School of Dental Medicine, 190 Longwood Avenue, Boston, MA 02115, USA Received 14 May 2007; received in revised form 25 June 2007; accepted 26 June 2007

Abstract The effects of ageing on progressive deterioration of renal function, both in human and experimental animals, are described elsewhere, but the effect of renal damage on overall survival and longevity is not yet clearly established. The wild-type animals of various genetic backgrounds, fed with regular diet, overtime develop severe age-associated nephropathy, that include but not limited to inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis. Such renal damage significantly reduces their survival. Reducing renal damage, either by caloric restriction or by suppressing growth hormone (GH)/insulin-like growth factor-1 (IGF-1) activity could significantly enhance the longevity of these animals. Available survival studies using experimental animals clearly suggest that kidney pathology is one of the important non-neoplastic lesions that could affect overall survival, and that restoration of renal function by preventing kidney damage could significantly extend longevity. Careful long-term studies are needed to determine the human relevance of these experimental studies. # 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Ageing; Growth hormone; Caloric restriction; Insulin-like growth factor-1; Nephropathy

1. Ageing and kidney Ageing is a universal process that affects nearly all organisms. This process brings a major risk for developing diseases in elderly individuals. Despite the universality of ageing, a precise definition of ageing and biological mechanisms of its progression is not clear. The biological process of ageing is believed to be delicately regulated by complex genetic interactions that can also be influenced by environmental factors. Due to the slow progressive nature, it is difficult to study the molecular events of the mammalian ageing. In general, an overall decline in the functionality of the vital systems, decreased reproductive capacity and increased mortality are the direct affects of ageing. In other words, ageing results in an increased vulnerability of the tissues and organs due to decreased cellular viability. Such age-associated disrupted cellular homeostasis is thought to be partly caused by the oxidative injury through generating free radicals in the mitochondria. Moreover, shortening of telomeres may also contribute to the cellular ageing by preventing DNA replication and cell division. It is generally accepted that oxidative stress, DNA damage, mitochondrial dysfunction and various genetic and environmental factors affect mammalian ageing, possibly by altering the normal cellular and subcellular activities of various organ systems (Marciniak and Guarente, 2001; Rudolph et al., 1999). Age-related changes result in decline of organ functions, and their responsiveness to the physiologic stimuli. The kidney is one of the organs that is functionally affected by advanced ageing.

* Tel.: +1 617 432 5768.

E-mail addresses: mrazzaque@hms.harvard.edu, razzaquems@yahoo.com.

1568-1637/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.arr.2007.06.001

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The significance of kidney pathology on survival is generally underestimated. A recent National Health and Nutrition Examination Survey (NHANES) found that 11% of people over the age of 65, without any obvious renal diseases, had 60% less renal function when compared to normal younger individuals (Coresh et al., 2003). In addition to hypertension and diabetes, ageing is one of the important predictors of progressive renal diseases. Half of the patients undergoing dialysis therapy for end-stage kidney failure are 65 years or older (Eggers et al., 2002; Port, 2000).

Since the renal ageing process is usually superimposed with elderly diseases, it is difficult to estimate what extent of deteriorated renal function is caused by intrinsic renal ageing. It is, however, commonly accepted that age-associated decline of overall physiological functions can directly or indirectly affect the kidney structure and function; circulatory disturbances and gradual decrease in the numbers of functioning nephrons are the two most important pathologies of the ageing kidney. Despite documentation of functional and structural aspects of the ageing kidney in human and experimental models, whether renal ageing can affect overall survival and longevity, and if so, to what extent are not yet studied in enough depth and detail. To understand the impact of renal ageing on survival, it is necessary to understand the structural alterations and functional changes of the ageing kidneys.

2. Morphological and functional changes of the ageing kidney Kidney weight starts to gradually decrease beyond 50 years of age (Tauchi et al., 1971) and loss of renal tissues are associated with thinning of the cortical region (Gourtsoyiannis et al., 1990; McLachlan and Wasserman, 1981).

Morphometric analysis of the ageing kidney show less numbers of intact glomeruli (Kasiske, 1987), and higher numbers of globally sclerotic glomeruli. Moreover, glomerular basement membrane becomes wrinkled and thickened, and often associated with variable degree of mesangial matrix expansion in the ageing kidney (Baylis and Schmidt, 1996; Wagner, 1987; Yumura et al., 1989). Of importance, any underlying systemic (hypertension) or metabolic (diabetes) disorders can also induce similar structural changes in the kidney and perhaps with greater intensity. In addition to glomeruli, ageing can also affect tubulointerstitial components by reducing the number of functioning tubules, facilitating development of non-functioning atrophic tubules and inducing expansion of interstitial volume.

Again, circulatory disturbances, including reduced renal blood flow can precipitate some of the above-mentioned tubulointerstitial changes, and such hemodynamic alterations are closely linked to the age-associated vascular changes in the kidneys (Kasiske, 1987).

It thus appears that advanced ageing can affect all the components of the kidney, including glomeruli, tubulointerstitium and vessels, even without obvious association of the systemic, metabolic immunologic, or other diseases (Fig. 1). Despite morphological and functional disturbances of the ageing kidney, the clinical significance of such alteration is an unsettled issue. It is, however, beyond any doubt that ageing kidneys are more susceptible to various diseases affecting elderly individuals. For instance, more than two-third of elderly people, who do not have existing hypertension, have a 90% chance of developing hypertension in their life time, and declined renal function of the ageing kidney can be an important precipitating factor (Hajjar and Kotchen, 2003).

Mechanisms and dynamics of age-associated kidney lesions are difficult to study, but animal models have provided some molecular insights. For instance, age-associated reduction of endothelium derived factors such as nitric oxide (NO) bioactivity is related to the increased expression of inducible nitric oxide synthase (iNOS) II, an isoform that can be involved with inflammatory events of the ageing kidney (Csiszar et al., 2002; Goettsch et al., 2001). Moreover, increased expression of profibrogenic molecules, including transforming growth factor b1 (TGF-b1) (Bedossa and Paradis, 1995; Castilla and Prieto, 1993) and heat shock protein 47 (HSP47) (Razzaque et al., 2005; Razzaque and Taguchi, 1997, 1999a,b) are closely associated with increased renal accumulation of extracellular matrix proteins to induce structural damage of the ageing kidney (Razzaque et al., 1998b, 2005; Ruiz-Torres et al., 1998; Taguchi and Razzaque, 2007).

Employing a functional genomics approach using human kidneys obtained from 74 individuals (27–92 years), out of 33,000 known human genes on the microarrays, 985 genes show changes in expression with age; 49 of these genes encode extracellular matrix proteins, all but four of which are increased in the ageing kidney (Rodwell et al., 2004), reemphasizing the fact that altered regulation of the extracellular matrix is related to age-related structural alterations in the kidney (Fig. 2). In the same study, in addition to the extracellular matrix-related genes, an increase expression of genes known to be specifically expressed in immunoinfllamatory cells are detected, that led the investigators to speculate that immune surveillance or inflammation increase in the kidney with age (Rodwell et al., 2004).

Why ageing kidneys produce proinflammatory and profibrogenic molecules, as seen in most of the renal diseases (Azouz et al., 2004; Razzaque et al., 1994, 1998a; Razzaque and Taguchi, 2002, 2003), is not yet clear, but altered

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Fig. 1. Histological features of kidneys from 6-month-old (A and C) and 24-month-old (B and D) Fischer 344 rats that are fed with either standard diet (A and B) or calorie restricted diet (C and D). Severe glomerular and tubulointerstitial damages, with massive infiltration of inflammatory cells and interstitial fibrosis are consistently noted in 24-month-old Fischer 344 rats fed with standard diet (B). A life-long calorie restricted diet (about 30%) significantly reduces age-associated renal damage in Fischer 344 rats (D). There are no significant changes in the kidneys of 6-month-old standard diet fed (A) and calorie restricted (C) rats (A–D: PAM staining).

cellular homeostasis due to senescence and/or phenotypic transdifferentiation of the resident renal cells may play a role in altered production of certain factors that exert pathologic effects in ageing kidneys (Fig. 3). Needless to mention that there are scientists who believe that age-associated structural alterations of the kidney and subsequent functional deterioration are not a pathologic process, rather a natural progression. Despite differences in the opinion, there is a general consensus that ageing kidneys are more likely to be affected by systemic, metabolic and/or immunologic diseases.

Although reduced functional ability of the ageing kidney is documented elsewhere, it is difficult to estimate whether such a decline is caused by intrinsic renal ageing or an affect of systemic ageing. Decreased renal blood flow and progressive reduction of glomerular filtration rate are associated with renal ageing. The age-associated atherosclerotic changes of the vessel walls can not only affect the renal blood flow, but can also induce microinfraction in the ageing kidney; such pathological changes are molecularly evident from the induction of hypoxiainducible factor (HIF) and vascular endothelial growth factor (VEGF) (Tanaka et al., 2006). There are, however, reports that claim that impaired tissue repair is partly associated with reduced sprouting of new blood vessel formation due to less availability of VEGF in the ageing kidney (Rivard et al., 1999). Despite differences in experimental observations, effects of impaired hemodynamic changes in ageing kidney are an established fact.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NOS. A positive correlation with age, blood pressure and plasma levels of ADMA has been found in a cross-sectional study of a random population samples (Miyazaki et al., 2000). Furthermore, increased ADMA blood levels in the elderly, may reduce NO availability by inhibiting the NOS activities to induce endothelial dysfunction, which might lead to increased renovascular resistance and hypertension commonly encountered in elderly individuals (Cooke, 2000; Xiong et al., 2001). More importantly, significantly increased levels of plasma ADMA in the non-smoking healthy, normotensive elderly individuals

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Fig. 2. Calorie restriction modulates age-associated renal fibrosis. Expression of collagen-specific molecular chaperone HSP47 in kidneys obtained from 24-month-old Fischer 344 rats fed a standard diet (A) and 24-month-old Fischer 344 rats fed with about 30% calorie-restricted diet (B). Note increased expression of HSP47 in the kidney of the rat fed a standard diet (A), but in the calorie-restricted rat, the expression is minimum (B). Such reduced expression of HSP47 is associated less accumulation of matrix proteins in the kidneys of calorie-restricted rats, as shown through collagen staining (D and F). Increased renal accumulation of type I collagen (C) and type IV collagen (E) is noted in the interstitial fibrosis (C and E, arrows), sclerotic glomeruli (E), and thickened tubular basement membrane (E) of rats fed with a standard diet. In contrast, relatively less accumulation of type I collagen (D) and type IV collagen (F) is seen in the kidneys of calorie-restricted rats. g: glomerulus (A–F, immunoperoxidase staining).

inversely correlate with reduced renal perfusion (Kielstein et al., 2003a). In fact, systemic ADMA infusion in healthy subjects significantly decreased effective renal plasma flow, and increased renovascular resistance and mean arterial blood pressure (Kielstein et al., 2003b). Increased activity of ADMA appears to partly contribute to the age-related functional impairments of the kidneys. ADMA can be excreted by the kidneys, but is mostly degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyses ADMA to dimethylamine and L-citrulline (Cooke, 2000; Kielstein et al., 2002); studies have found that DDAH activity is reduced in the presence of such

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Fig. 3. Calorie restriction modulates age-associated phenotypic alteration of resident renal cells. Immunohistochemistry evaluations show desmin (A and B), and vimentin (C and D) in kidneys obtained from 24-month-old Fischer 344 rats fed a standard diet (A and C) and 24-month-old 30% calorie-restricted Fischer 344 rats (B and D). In contrast to the strong expression for desmin in glomerular epithelial cells (arrows) in a rat fed with standard diet (A), expression is weak or absent in the glomerular epithelial cells of a calorie-restricted rat (B), suggesting that calorie restriction can reduce phenotypic conversion of glomerular epithelial cells. Positive staining for vimentin is noted in the tubular epithelial cells (arrows) in a rat kidney fed with a standard diet (C); in comparison, most of the tubular epithelial cells are negative for vimentin staining in a kidney obtained from a calorie-restricted rat (D), suggesting that age-associated phenotypic differentiation of tubular epithelial cells is reduced in rats fed with calorierestricted diet. Collectively, reduce phenotypic differentiation of renal cells may partly explain how renal ageing is delayed in calorie-restricted animals. g: glomerulus; t: tubules; v: blood vessels (A–D, immunoperoxidase staining).

conditions as hypercholesterolaemia and insulin resistance (Cooke, 2000; Stuhlinger et al., 2002) that have a high prevalence among the elderly individuals. Collectively, the above-mentioned evidence suggests that dysregulation of components of NO system can significantly influence renal ageing by impairing renal blood flow.

Furthermore, tubulointerstitial changes of the ageing kidney can alter the tubular ion transport system to affect normal concentrating abilities of the urine (Bengele et al., 1983; Rowe et al., 1976). The ability of the medulla to concentrate urine declines progressively with age. Electrolyte imbalances due to reduced functional ability of the ageing kidney usually lead to other systemic complications and can modify drug potency (McLean and Le Couteur, 2004). Such age-related electrolyte imbalance might be associated with altered salt sensitivity of the elderly individuals, and may facilitate development of hypertension. It is, however, necessary to mention that the progression of renal ageing does not always take a uniform pattern, may vary from individual to individual, and can be influenced by race, gender, diet, and surrounding environment.

3. Factors influencing renal ageing As commonly seen in various acquired and inherited diseases, the progression of ageing can be influenced by gender and genetic backgrounds of both human and experimental animals. For instance, using 500 male and 500 female Sprague–Dawley rats that were observed as long as 108 weeks of age showed that male rats have almost double

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the rate of chronic nephropathy, compared to the female rats (male 81% versus female 44%) (Owen and Heywood, 1986). Moreover, compared to the female rats, the total capillary lumen area of the aged male rats was reduced by 20% in superficial glomeruli and by 36% in deep glomeruli. Such structural changes might partly explain why glomerular filtration rate in old female rats are better preserved than their male counterparts (Francois et al., 1996). In a separate study, age-associated reduction of glomerular filtration rate in Munich–Wistar male rats has been shown to be prevented by castration (Baylis, 1994).

In addition to gender, genetic background appears to have profound affect on renal injury, and subsequent renal ageing. Remnant kidney models induced in mice of different genetic backgrounds, including male C57BL/6, 129/Sv and Swiss-Webster mice show variable degree of glomerulosclerosis, hypertension, and mortality in response to 5/6 nephrectomy injury (Ma and Fogo, 2003). Genetically altered transgenic rats with reduced growth hormone (GH)/ insulin-like growth factor-1 (IGF-1) activity could reduce age-associated renal damage, compared to that in wildtype rats. Genetic inactivation of SMP-30 (senescence-marker protein 30) from the mice could facilitate renal ageing by inducing senescence in the proximal tubular epithelial cells (Yumura et al., 2006). Of relevance, the expression of SMP-30 protein was reduced in the proximal tubular epithelial cells with the age. Another genetically altered animal, heterozygous glial cell-derived neurotrophic factor ablated mice have 30% less numbers of glomeruli than the wild-type mice by 14 months of age (Cullen-McEwen et al., 2003); hyperfiltration and glomerular hypertrophy of these aged mutant mice are associated with the development of hypertension (Cullen-McEwen et al., 2003).

Moreover, genetic inactivation of klotho, a mainly kidney-derived circulating factor, has shown to have profound systemic accelerated ageing-like effects (Kuro-o et al., 1997). Angiotensin II has been found to suppress klotho expression and in vivo transfer of klotho gene can ameliorate angiotensin II-induced renal damage in experimental rats (Mitani et al., 2002). Similarly, genetic ablation of fibroblast growth factor 23, a potent renal phosphaturic factor, can induce similar systemic premature ageing-like features as found in the klotho hypomorphs (Lanske and Razzaque, 2007a,b; Razzaque and Lanske, 2006, 2007; Razzaque et al., 2006). Furthermore, loss of genomic stability has an impact on cellular viability and eventual survival (Kujoth et al., 2005; Zhang et al., 1998).

Collectively, all the above-mentioned evidence suggests the influence of genetic background on systemic and renal ageing in experimental animals.

Similar to the animal studies, in humans, genetic backgrounds have an important role in the development of certain renal diseases. For instance, the African-American population are more susceptible to the development of hypertensive renal damage, which significantly influence their eventual morbidity and mortality (Nzerue et al., 1998; Obialo and Hewan-Lowe, 1998). What precisely accelerates thickening of the medial and intimal layers that eventually narrow the vascular lumen in certain race is an intense area of research. Genetic variation that affects the functionality of the renin-angiotensin system is thought to play a crucial role in the development of hypertension in African-American individuals (Hsu et al., 2006). Although genetic background has an important determining effect on renal ageing (Martin and Sheaff, 2007), genetic variations on progression of ageing, even within similar strains, make it harder to pinpoint or narrow down the factors involved in the process. It is, however, clear that systemic abnormalities could affect and enhance renal ageing process, while functional abnormalities of the kidney can affect systemic ageing.

4. Renal diseases associated with advanced age The incidence of primary renal diseases is significantly increased in the elderly individuals. For instance, studies have found that the occurrence of membranous glomerulonephritis is almost three times more common in elderly than young individuals. Similarly, crescentic glomerulonephritis is likely to involve elderly individuals, four times higher than the young individuals (Kingswood et al., 1984; Moorthy and Zimmerman, 1980). Of relevance, de novo occurrence of IgA nephropathy and minimal change nephrotic syndrome are relatively less common in the elderly. In addition to the primary renal diseases, systemic and metabolic disorders, including hypertension, diabetes, and amyloidosis can accelerate renal impairments in elderly patients. In addition, the incidence of drug associated renal toxicity is higher in elderly individuals (McLean and Le Couteur, 2004; Roxe, 1989). Ageing kidneys are more vulnerable to acute tubular necrosis following hypovolemic or septic shock (Silva, 2005b). Similarly, obstructive nephropathy due to benign prostatic hyperplasia is a serious complication, mostly observed in elderly patients, which can be accompanied with urinary tract infection and pyelonephritis. The likelihood of renal stone formation increases with the advancement of age, and almost one out of five patients first possess renal stones at the age of 60 years or more

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(Sutherland et al., 1985). Similar to other systems, the probabilities of renal tumor are higher in elderly individuals. As apparent from the above-mentioned observations of various human studies, ageing kidneys are at risk to be affected by various primary and secondary renal diseases. Such pathologic renal involvements are likely to affect overall survival and longevity of the elderly.

5. Effects of renal ageing on survival The adverse effects of renal damage on ageing and survival have been documented in various experimental models (Shimokawa et al., 1993; Zha et al., 2006). For instance, male Fischer 344 rats fed ad libitum develop chronic nephropathy with age, and such renal disease severely compromised their overall survival (Masoro et al., 1989; Yu et al., 1982). Restricting food intake by around 40% not only prevented the progression of these renal lesions, but significantly enhanced their survival (Masoro et al., 1989; Shimokawa et al., 1993; Yu et al., 1982). What induces such severe renal injury in the aged experimental animals is not clear, but the GH/IGF-1 system seems to play a major role in both systemic and renal ageing. Reduced insulin/IGF-1 activity has been found to be associated with a prolonged lifespan in various species (Shimokawa et al., 2003; Sonntag et al., 2005b; Zha et al., 2006).

A role for GH in developing renal lesions was elegantly demonstrated in transgenic mice overexpressing human and bovine GH genes; these mice exhibited a giant phenotype and developed diffuse progressive glomerulosclerosis (Chen et al., 1995). In contrast, transgenic mice expressing GH antagonists (bGH-G119R and hGH-G120R) had a dwarf phenotype and did not produce renal lesions, perhaps due to a block in endogenous GH activity (Chen et al., 1994a,b, 1995). Using a transgenic strain of rats in which GH synthesis and release are suppressed by the induction of an antisense GH transgene (Shimokawa et al., 2003), Zha et al. have recently shown that chronic suppression of GH/ IGF-1 activity for the entire lifespan of rats (about 3 years) prevented the development of naturally occurring ageassociated renal damage to enhance their survival (Zha et al., 2006). It is presumed that most of the effects of GH are mediated through IGF-1, as effects of suppressing IGF-1 activities, often produce a similar phenotype as GH suppression. Of relevance, heterozygous IGF-1 receptor-knockout mice lived 26% longer than the wild-type cohorts (mice homozygous for this mutation die at birth). As discussed above, there was a gender variation in survival, with female IGF-1 receptor mutants living 33% longer than wild-type females, while male mutant mice lived approximately 16% longer compared to wild-type males (Holzenberger et al., 2003).

It is however necessary to mention that evidences also exist for GH-independent effects of IGF-1 in the kidney. For instance, both IGF-1 transgenic and GH transgenic mice developed glomerular hypertrophy, but the IGF-1 transgenic mutants did not develop glomerular sclerosis, even though circulating IGF-I levels in the IGF-I transgenic mice were higher than in the GH transgenic mice (Doi et al., 1990). Furthermore, in mice transgenically expressing human IGFbinding protein-1, a progressive glomerular sclerosis developed, despite having low plasma levels of bioactive IGF-1 (Doublier et al., 2000; Gay et al., 1997). Another issue that is becoming more evident form recent studies is that the beneficial effects of suppression of GH/IGF-1 activities could mostly be achieved through controlled suppression (Sonntag et al., 2005a). Extremely reduced GH/IGF-1 activity can not only affect overall growth and development, but may also exert harmful effects on survival by facilitating tumorigenesis and by compromising immune functions (Shimokawa et al., 2002). Genetically altered transgenic rats with reduced GH/IGF-1 activity showed that the lifespan of hemizygote rats was greater than that of homozygote rats, despite significant reduction of age-associated renal damages in the homozygotes (Shimokawa et al., 2002), suggesting that extremely reduced GH/IGF-1 activity does not necessarily have life prolonging effect. On the other hand, the life span of hemizygote rats was longer than the wildtype rats of similar genetic background, possibly due to reduced renal injury in the mutant rats (Shimokawa et al., 2002, 2003; Zha et al., 2006).

6. Can renal ageing be delayed?

Now that we know that renal ageing can influence overall survival, can renal ageing be delayed? Several ageingrelated pathways are identified, and manipulation of certain components of these pathways can alter longevity of various species. One important issue that needs further study is to determine the effects of ageing-related pathways on the kidney. The role of insulin/IGF-1 signaling in ageing is one of the most extensively studied pathways. For instance, mutations in the gene encoding IGF-1 receptor can alter lifespan in worms, flies, and mice, suggesting the importance of endocrine signaling pathways in ageing (Hekimi and Guarente, 2003). Despite, the positive effects of controlled

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suppression of GH/IGF-1 signaling in ageing, the effects of such suppression on preventing renal ageing is not yet studied in similar depth and detail, possibly because the importance of kidney pathology on overall survival is generally underestimated.

In a survival study, wild-type Wistar rats fed with a standard diet develop age-associated nephropathy; about 87% of the spontaneously died wild-type rats showed features of nephropathy (maximum survival 158 weeks). In contrast, rats that were fed with 30% calorie-restricted diet for entire lifespan had a markedly reduced rate of age-associated nephropathy (6.8%), more importantly, such reduction in chronic nephropathy was associated with about 22% longer survival rate (maximum survival 194 weeks) (Shimokawa et al., 2003). Furthermore, a complete prevention of ageassociated nephropathy in calorie-restricted Wistar rats with genetic suppression of GH/IGF-1 activities resulted in about 30% increased survival (maximum survival 204 weeks) over the wild-type rats. Needless to mention that the incidence of tumors or non-neoplastic lesions other than kidney diseases in all the above-mentioned groups of spontaneously dead rats were quite similar, suggesting that delaying or preventing development of renal ageing can increase survival (Shimokawa et al., 2003). Similar increases in the longevity of Fischer 344 rats has been documented by reducing age-related renal damage by providing calorie-restricted diet (Masoro et al., 1989; Shimokawa et al., 1993). Results showed that life-long caloric restriction suppresses age-associated renal inflammation, decrease renal expression of apoptosis-inducing molecules such as Fas, and reduce renal production of such profibrogenic molecules as HSP47 and collagens (Razzaque et al., 1999a,b). More importantly, calorie-restricted diets can suppress oxidative renal damage (Abid et al., 2005; Adler et al., 2004; Sohal and Weindruch, 1996).

The free radical theory of ageing was first proposed in the mid-1950s (Harman, 1956), and since then substantial evidence supports that free radical damage by various endogenous reactive oxygen species (ROS) significantly contribute to systemic and organ-specific ageing (Harman, 2001). The role of ROS in ageing is further supported from the observations that animals with higher metabolic rates have shorter lifespans (Finkel and Holbrook, 2000). Caloric restriction has convincingly been shown to extend lifespan in yeast, drosophila, worms, and rodents (Masoro, 1985, 1991, 1992; Sohal and Weindruch, 1996), possibly by reducing the production of ROS. A marker of DNA oxidation, 8oxo-2-deoxyguanosine, increases with age in the rat kidney, and can be reduced by caloric restriction (Hamilton et al., 2001). It is believed that caloric restriction suppresses overall metabolism and thereby reduces the production of ROS to delay age-associated organ damage, including kidneys (Cho et al., 2003; Kim et al., 2002; Sohal et al., 1994). In a recent study, adult-onset calorie restriction in Fischer 344 and Brown Norway hybrid rats could significantly reduce age-associated renal damage, possibly by delaying the mitochondrial enzyme alterations in the tubular epithelial cells (McKiernan et al., 2007).

Furthermore, accumulation of advanced glycation end products has shown to be related to cardiovascular and renal ageing in experimental animals (Li et al., 1996). Caloric restriction delays accumulation of advanced glycation end

Fig. 4. Schematic outline of effects of calorie restriction on reno-protection and eventual survival. Calorie restriction can suppress GH/IGF-1, ROS (Chung et al., 1999; Sohal et al., 1994) and Fas (Razzaque et al., 1999a) activities to reduce renal inflammatory and fibrogenic events (Razzaque et al., 1998b, 1999b) to delay age-associated kidney damage (Zha et al., 2006). Such delay has positive impact on overall survival (Shimokawa et al., 2003).

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products to reduce renal ageing (Teillet et al., 2000). Although, further studies are needed to study how GH/IGF-1 activities or oxidative systems are molecularly regulated by a calorie-restricted diet (Cho et al., 2003; Kim et al., 2002), it is obvious from the experimental studies that reno-protection can increase survival (Fig. 4).

7. Conclusion Normal human ageing is associated with structural alterations and functional deterioration of almost all organ systems, including the renal system. The interrelationships among various organ systems often accelerate the ageing process. Renal ageing is mostly affected by hemodynamic changes and by co-morbid conditions such as hypertension, atherosclerosis and heart failure (Silva, 2005a,b). The high prevalence of diseases in elderly individuals results in an increased consumption of drugs that can either cause additional strain to the ageing kidney, or can induce adverse drug reactions partly due to impaired renal clearance. Such adverse drug reactions are related to as high as 18% of deaths among the elderly hospitalized patients in a Norwegian study (Ebbesen et al., 2001). It is, however, needed to mention that elderly people must not be excluded from receiving the benefits of novel pharmacotherapy where there are either no adverse effects or unfavorable effects have yet to be determined (Editorial, 1993). Whether hepatic drug metabolism is affected by ageing is an ongoing issue of research, and is required to be categorized for individual drugs.

Despite limitations and restrictions, carefully designed studies focused on understanding the biology of ageing have significantly increased our knowledge of the delicate interrelationship among the organ systems and age-related diseases. Such understanding has laid the foundation to minimize the risk of age-associated diseases, and extend survival. It is likely that tumors and kidney lesions have differential effects on survival. Tumors are usually associated with premature death and thereby suppressing tumorigenesis would result in prevention of premature death, but that might not essentially extend survival beyond normal expectancy of life. On the other hand, once survival is beyond normal expectancy, certain additional non-neoplastic factors might determine the extent of longevity, and from the available information, kidney pathology appears to be one of the single most important non-neoplastic lesions that affects overall survival. Of particular importance is the observation that survival can be enhanced as much as 20–30% in the experimental animals by reducing age-associated renal damages. Future studies will determine whether such animal studies have human relevance.

Acknowledgements The author acknowledges the institutional supports of the Nagasaki University Graduate School of Biomedical Sciences, Nagasaki Japan, and Harvard School of Dental Medicine, Boston, MA, USA. The author is grateful to Dr. I. Shimokawa (Nagasaki University, Nagasaki, Japan) for kindly providing Fischer 344 rat kidneys, and to D. Medici (Harvard University, Boston, USA) for useful suggestions. Special thanks go to Dr. T. Taguchi (Nagasaki University, Nagasaki, Japan) for technical supports and continued encouragements.

References Abid, M.R., Razzaque, M.S., Taguchi, T., 2005. Oxidant stress in renal pathophysiology. Contrib. Nephrol. 148, 135–153.

Adler, S., Huang, H., Wolin, M.S., Kaminski, P.M., 2004. Oxidant stress leads to impaired regulation of renal cortical oxygen consumption by nitric oxide in the aging kidney. J. Am. Soc. Nephrol. 15, 52–60.

Azouz, A., Razzaque, M.S., El-Hallak, M., Taguchi, T., 2004. Immunoinflammatory responses and fibrogenesis. Med. Electron. Microsc. 37, 141– 148.

Baylis, C., 1994. Age-dependent glomerular damage in the rat. Dissociation between glomerular injury and both glomerular hypertension and hypertrophy. Male gender as a primary risk factor. J. Clin. Invest. 94, 1823–1829.

Baylis, C., Schmidt, R., 1996. The aging glomerulus. Semin. Nephrol. 16, 265–276.

Bedossa, P., Paradis, V., 1995. Transforming growth factor-beta (TGF-beta): a key-role in liver fibrogenesis. J. Hepatol. 22, 37–42.

Bengele, H.H., Mathias, R., Perkins, J.H., McNamara, E.R., Alexander, E.A., 1983. Impaired renal and extrarenal potassium adaptation in old rats.

Kidney Int. 23, 684–690.

Castilla, A., Prieto, J., 1993. Human fibrogenesis and transforming growth factor beta-1. J. Hepatol. 18, 378–379.

Chen, N.Y., Chen, W.Y., Bellush, L., Yang, C.W., Striker, L.J., Striker, G.E., Kopchick, J.J., 1995. Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. Endocrinology 136, 660–667.

Chen, W.Y., Chen, N., Yun, J., Wagner, T.E., Kopchick, J.J., 1994a. In vitro and in vivo studies of the antagonistic effects of human growth hormone analogs. J. Biol. Chem. 269, 20806.

220

M.S. Razzaque / Ageing Research Reviews 6 (2007) 211–222

Chen, W.Y., Chen, N.Y., Yun, J., Wagner, T.E., Kopchick, J.J., 1994b. In vitro and in vivo studies of antagonistic effects of human growth hormone analogs. J. Biol. Chem. 269, 15892–15897.

Cho, C.G., Kim, H.J., Chung, S.W., Jung, K.J., Shim, K.H., Yu, B.P., Yodoi, J., Chung, H.Y., 2003. Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process. Exp. Gerontol. 38, 539–548.

Chung, H.Y., Song, S.H., Kim, H.J., Ikeno, Y., Yu, B.P., 1999. Modulation of renal xanthine oxidoreductase in aging: gene expression and reactive oxygen species generation. J. Nutr. Health Aging 3, 19–23.

Cooke, J.P., 2000. Does ADMA cause endothelial dysfunction? Arterioscler. Thromb. Vasc. Biol. 20, 2032–2037.

Coresh, J., Astor, B.C., Greene, T., Eknoyan, G., Levey, A.S., 2003. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am. J. Kidney Dis. 41, 1–12.

Csiszar, A., Ungvari, Z., Edwards, J.G., Kaminski, P., Wolin, M.S., Koller, A., Kaley, G., 2002. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ. Res. 90, 1159–1166.

Cullen-McEwen, L.A., Kett, M.M., Dowling, J., Anderson, W.P., Bertram, J.F., 2003. Nephron number, renal function, and arterial pressure in aged GDNF heterozygous mice. Hypertension 41, 335–340.

Doi, T., Striker, L.J., Gibson, C.C., Agodoa, L.Y., Brinster, R.L., Striker, G.E., 1990. Glomerular lesions in mice transgenic for growth hormone and insulinlike growth factor-I I. Relationship between increased glomerular size and mesangial sclerosis. Am. J. Pathol. 137, 541–552.

Doublier, S., Seurin, D., Fouqueray, B., Verpont, M.C., Callard, P., Striker, L.J., Striker, G.E., Binoux, M., Baud, L., 2000. Glomerulosclerosis in mice transgenic for human insulin-like growth factor-binding protein-1. Kidney Int. 57, 2299–2307.

Ebbesen, J., Buajordet, I., Erikssen, J., Brors, O., Hilberg, T., Svaar, H., Sandvik, L., 2001. Drug-related deaths in a department of internal medicine.

Arch. Intern. Med. 161, 2317–2323.

Editorial, 1993. Do doctors short-change old people? Lancet 342, 1–2.

Eggers, P.W., Frankenfield, D.L., Greer, J.W., McClellan, W., Owen Jr., W.F., Rocco, M.V., 2002. Comparison of mortality and intermediate outcomes between medicare dialysis patients in HMO and fee for service. Am. J. Kidney Dis. 39, 796–804.

Finkel, T., Holbrook, N.J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247.

Francois, V., Heudes, D., Bariety, J., Bruneval, P., Corman, B., 1996. Glomerular capillary network of cortical nephrons is reduced in male but not in female aging rats. Mech. Ageing Dev. 91, 11–22.

Gay, E., Seurin, D., Babajko, S., Doublier, S., Cazillis, M., Binoux, M., 1997. Liver-specific expression of human insulin-like growth factor binding protein-1 in transgenic mice: repercussions on reproduction, ante- and perinatal mortality and postnatal growth. Endocrinology 138, 2937–2947.

Goettsch, W., Lattmann, T., Amann, K., Szibor, M., Morawietz, H., Munter, K., Muller, S.P., Shaw, S., Barton, M., 2001. Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis. Biochem. Biophys. Res. Commun. 280, 908–913.

Gourtsoyiannis, N., Prassopoulos, P., Cavouras, D., Pantelidis, N., 1990. The thickness of the renal parenchyma decreases with age: a CT study of 360 patients. Am. J. Roentgenol. 155, 541–544.

Hajjar, I., Kotchen, T.A., 2003. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA 290, 199–206.

Hamilton, M.L., Van Remmen, H., Drake, J.A., Yang, H., Guo, Z.M., Kewitt, K., Walter, C.A., Richardson, A., 2001. Does oxidative damage to DNA increase with age? Proc. Natl. Acad. Sci. U.S.A. 98, 10469–10474.

Harman, D., 1956. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300.

Harman, D., 2001. Aging: overview. Ann. NY Acad. Sci. 928, 1–21.

Hekimi, S., Guarente, L., 2003. Genetics and the specificity of the aging process. Science 299, 1351–1354.

Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Even, P.C., Cervera, P., Le Bouc, Y., 2003. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187.

Hsu, C.C., Bray, M.S., Kao, W.H., Pankow, J.S., Boerwinkle, E., Coresh, J., 2006. Genetic variation of the renin-angiotensin system and chronic kidney disease progression in black individuals in the atherosclerosis risk in communities study. J. Am. Soc. Nephrol. 17, 504–512.

Kasiske, B.L., 1987. Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int. 31, 1153–1159.

Kielstein, J.T., Bode-Boger, S.M., Frolich, J.C., Ritz, E., Haller, H., Fliser, D., 2003a. Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation 107, 1891–1895.

Kielstein, J.T., Bode-Boger, S.M., Haller, H., Fliser, D., 2003b. Functional changes in the ageing kidney: is there a role for asymmetric dimethylarginine? Nephrol. Dial. Transplant. 18, 1245–1248.

Kielstein, J.T., Boger, R.H., Bode-Boger, S.M., Frolich, J.C., Haller, H., Ritz, E., Fliser, D., 2002. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J. Am. Soc. Nephrol. 13, 170–176.

Kim, H.J., Yu, B.P., Chung, H.Y., 2002. Molecular exploration of age-related NF-kappaB/IKK downregulation by calorie restriction in rat kidney.

Free Radic. Biol. Med. 32, 991–1005.

Kingswood, J.C., Banks, R.A., Tribe, C.R., Owen-Jones, J., Mackenzie, J.C., 1984. Renal biopsy in the elderly: clinicopathological correlations in 143 patients. Clin. Nephrol. 22, 183–187.

Kujoth, G.C., Hiona, A., Pugh, T.D., Someya, S., Panzer, K., Wohlgemuth, S.E., Hofer, T., Seo, A.Y., Sullivan, R., Jobling, W.A., Morrow, J.D., Van Remmen, H., Sedivy, J.M., Yamasoba, T., Tanokura, M., Weindruch, R., Leeuwenburgh, C., Prolla, T.A., 2005. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484.

Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., Iwasaki, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y.I., 1997. Mutation of the mouse klotho gene leads to a syndrome resembling ageing.

Nature 390, 45–51.

Lanske, B., Razzaque, M.S., 2007a. Mineral metabolism and aging: the FGF-23 enigma. Curr. Opin. Nephrol. Hypertens. 16, 311–318.

Lanske, B., Razzaque, M.S., 2007b. Premature aging in klotho mutant mice: cause or consequence? Ageing Res. Rev. 6, 73–79.

M.S. Razzaque / Ageing Research Reviews 6 (2007) 211–222

221

Li, Y.M., Steffes, M., Donnelly, T., Liu, C., Fuh, H., Basgen, J., Bucala, R., Vlassara, H., 1996. Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine. Proc. Natl. Acad. Sci. U.S.A. 93, 3902–3907.

Ma, L.J., Fogo, A.B., 2003. Model of robust induction of glomerulosclerosis in mice: importance of genetic background. Kidney Int. 64, 350– 355.

Marciniak, R., Guarente, L., 2001. Human genetics. Testing telomerase. Nature 413 370-1, 373.

Martin, J.E., Sheaff, M.T., 2007. Renal ageing. J. Pathol. 211, 198–205.

Masoro, E.J., 1985. Aging and nutrition—can diet affect life span? Trans. Assoc. Life Insur. Med. Dir. Am. 67, 30–44.

Masoro, E.J., 1991. How does dietary restriction alter aging and survival in rodents? Aging (Milano) 3, 384–386.

Masoro, E.J., 1992. Retardation of aging processes by food restriction: an experimental tool. Am. J. Clin. Nutr. 55, 1250S–1252S. Masoro, E.J., Iwasaki, K., Gleiser, C.A., McMahan, C.A., Seo, E.J., Yu, B.P., 1989. Dietary modulation of the progression of nephropathy in aging rats: an evaluation of the importance of protein. Am. J. Clin. Nutr. 49, 1217–1227.

McKiernan, S.H., Tuen, V.C., Baldwin, K., Wanagat, J., Djamali, A., Aiken, J.M., 2007. Adult-onset calorie restriction delays the accumulation of mitochondrial enzyme abnormalities in aging rat kidney tubular epithelial cells. Am. J. Physiol. Renal. Physiol. 292, F1751–F1760.

McLachlan, M., Wasserman, P., 1981. Changes in sizes and distensibility of the aging kidney. Br. J. Radiol. 54, 488–491.

McLean, A.J., Le Couteur, D.G., 2004. Aging biology and geriatric clinical pharmacology. Pharmacol. Rev. 56, 163–184.

Mitani, H., Ishizaka, N., Aizawa, T., Ohno, M., Usui, S., Suzuki, T., Amaki, T., Mori, I., Nakamura, Y., Sato, M., Nangaku, M., Hirata, Y., Nagai, R., 2002. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 39, 838–843.

Miyazaki, H., Matsuoka, H., Itabe, H., Usui, M., Ueda, S., Okuda, S., Imaizumi, T., 2000. Hemodialysis impairs endothelial function via oxidative stress: effects of vitamin E-coated dialyzer. Circulation 101, 1002–1006.

Moorthy, A.V., Zimmerman, S.W., 1980. Renal disease in the elderly: clinicopathologic analysis of renal disease in 115 elderly patients. Clin.

Nephrol. 14, 223–229.

Nzerue, C.M., Hewan-Lowe, K., Nwawka, C., 1998. Acute renal failure in pregnancy: a review of clinical outcomes at an inner-city hospital from 1986 to 1996. J. Natl. Med. Assoc. 90, 486–490.

Obialo, C.I., Hewan-Lowe, K., 1998. Rapid progression to end-stage renal disease in young hypertensive African Americans with proteinuria. J. Natl. Med. Assoc. 90, 649–655.

Owen, R.A., Heywood, R., 1986. Age-related variations in renal structure and function in Sprague-Dawley rats. Toxicol. Pathol. 14, 158–167.

Port, F.K., 2000. Description and clinical outcomes of peritoneal dialysis: analyses from the United States Renal Data System. Perit. Dial. Int. 20 (Suppl. 2), S114–S117.

Razzaque, M.S., Koji, T., Taguchi, T., Harada, T., Nakane, P.K., 1994. In situ localization of type III and type IV collagen-expressing cells in human diabetic nephropathy. J. Pathol. 174, 131–138.

Razzaque, M.S., Kumatori, A., Harada, T., Taguchi, T., 1998a. Coexpression of collagens and collagen-binding heat shock protein 47 in human diabetic nephropathy and IgA nephropathy. Nephron 80, 434–443.

Razzaque, M.S., Lanske, B., 2006. Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice. Trends Mol. Med. 12, 298–305.

Razzaque, M.S., Lanske, B., 2007. The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J. Endocrinol. 194, 1–10.

Razzaque, M.S., Le, V.T., Taguchi, T., 2005. Heat shock protein 47 and renal fibrogenesis. Contrib. Nephrol. 148, 57–69.

Razzaque, M.S., Shimokawa, I., Koji, T., Higami, Y., Taguchi, T., 1999a. Life-long caloric restriction suppresses age-associated Fas expression in the Fischer 344 rat kidney. Mol. Cell Biol. Res. Commun. 1, 82–85.

Razzaque, M.S., Shimokawa, I., Nazneen, A., Higami, Y., Taguchi, T., 1998b. Age-related nephropathy in the Fischer 344 rat is associated with overexpression of collagens and collagen-binding heat shock protein 47. Cell Tissue Res. 293, 471–478.

Razzaque, M.S., Shimokawa, I., Nazneen, A., Liu, D., Naito, T., Higami, Y., Taguchi, T., 1999b. Life-long dietary restriction modulates the expression of collagens and collagen-binding heat shock protein 47 in aged Fischer 344 rat kidney. Histochem. J. 31, 123–132.

Razzaque, M.S., Sitara, D., Taguchi, T., St-Arnaud, R., Lanske, B., 2006. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J. 20, 720–722.

Razzaque, M.S., Taguchi, T., 1997. Collagen-binding heat shock protein (HSP) 47 expression in anti-thymocyte serum (ATS)-induced glomerulonephritis. J. Pathol. 183, 24–29.

Razzaque, M.S., Taguchi, T., 1999a. The possible role of colligin/HSP47, a collagen-binding protein, in the pathogenesis of human and experimental fibrotic diseases. Histol. Histopathol. 14, 1199–1212.

Razzaque, M.S., Taguchi, T., 1999b. Role of glomerular epithelial cell-derived heat shock protein 47 in experimental lipid nephropathy. Kidney Int. Suppl. 71, S256–S259.

Razzaque, M.S., Taguchi, T., 2002. Cellular and molecular events leading to renal tubulointerstitial fibrosis. Med. Electron. Microsc. 35, 68–80.

Razzaque, M.S., Taguchi, T., 2003. Factors that influence and contribute to the regulation of fibrosis. Contrib. Nephrol. 139, 1–11.

Rivard, A., Fabre, J.E., Silver, M., Chen, D., Murohara, T., Kearney, M., Magner, M., Asahara, T., Isner, J.M., 1999. Age-dependent impairment of angiogenesis. Circulation 99, 111–120.

Rodwell, G.E., Sonu, R., Zahn, J.M., Lund, J., Wilhelmy, J., Wang, L., Xiao, W., Mindrinos, M., Crane, E., Segal, E., Myers, B.D., Brooks, J.D., Davis, R.W., Higgins, J., Owen, A.B., Kim, S.K., 2004. A transcriptional profile of aging in the human kidney. PLoS Biol. 2, e427.

Rowe, J.W., Andres, R., Tobin, J.D., Norris, A.H., Shock, N.W., 1976. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J. Gerontol. 31, 155–163.

Roxe, D.M., 1989. Renal function, aging, and drug therapy. Compr. Ther. 15, 13–18.

Rudolph, K.L., Chang, S., Lee, H.W., Blasco, M., Gottlieb, G.J., Greider, C., DePinho, R.A., 1999. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712.

222

M.S. Razzaque / Ageing Research Reviews 6 (2007) 211–222

Ruiz-Torres, M.P., Bosch, R.J., O’Valle, F., Del Moral, R.G., Ramirez, C., Masseroli, M., Perez-Caballero, C., Iglesias, M.C., Rodriguez-Puyol, M., Rodriguez-Puyol, D., 1998. Age-related increase in expression of TGF-beta1 in the rat kidney: relationship to morphologic changes. J. Am. Soc. Nephrol. 9, 782–791.

Shimokawa, I., Higami, Y., Hubbard, G.B., McMahan, C.A., Masoro, E.J., Yu, B.P., 1993. Diet and the suitability of the male Fischer 344 rat as a model for aging research. J. Gerontol. 48, B27–B32.

Shimokawa, I., Higami, Y., Tsuchiya, T., Otani, H., Komatsu, T., Chiba, T., Yamaza, H., 2003. Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction. FASEB J. 17, 1108–1109.

Shimokawa, I., Higami, Y., Utsuyama, M., Tuchiya, T., Komatsu, T., Chiba, T., Yamaza, H., 2002. Life span extension by reduction in growth hormone-insulin-like growth factor-1 axis in a transgenic rat model. Am. J. Pathol. 160, 2259–2265.

Silva, F.G., 2005a. The aging kidney: a review, Part I. Int. Urol. Nephrol. 37, 185–205.

Silva, F.G., 2005b. The aging kidney: a review, Part II. Int. Urol. Nephrol. 37, 419–432.

Sohal, R.S., Agarwal, S., Candas, M., Forster, M.J., Lal, H., 1994. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech. Ageing Dev. 76, 215–224.

Sohal, R.S., Weindruch, R., 1996. Oxidative stress, caloric restriction, and aging. Science 273, 59–63.

Sonntag, W.E., Carter, C.S., Ikeno, Y., Ekenstedt, K., Carlson, C.S., Loeser, R.F., Chakrabarty, S., Lee, S., Bennett, C., Ingram, R., Moore, T., Ramsey, M., 2005a. Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Endocrinology 146, 2920–2932.

Sonntag, W.E., Ramsey, M., Carter, C.S., 2005b. Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging.

Ageing Res. Rev. 4, 195–212.

Stuhlinger, M.C., Abbasi, F., Chu, J.W., Lamendola, C., McLaughlin, T.L., Cooke, J.P., Reaven, G.M., Tsao, P.S., 2002. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287, 1420–1426.

Sutherland, J.W., Parks, J.H., Coe, F.L., 1985. Recurrence after a single renal stone in a community practice. Miner. Electrolyte Metab. 11, 267–269.

Taguchi, T., Razzaque, M.S., 2007. The collagen-specific molecular chaperone HSP47: is there a role in fibrosis? Trends Mol. Med. 13, 45–53.

Tanaka, T., Kato, H., Kojima, I., Ohse, T., Son, D., Tawakami, T., Yatagawa, T., Inagi, R., Fujita, T., Nangaku, M., 2006. Hypoxia and expression of hypoxia-inducible factor in the aging kidney. J. Gerontol. A: Biol. Sci. Med. Sci. 61, 795–805.

Tauchi, H., Tsuboi, K., Okutomi, J., 1971. Age changes in the human kidney of the different races. Gerontologia 17, 87–97.

Teillet, L., Verbeke, P., Gouraud, S., Bakala, H., Borot-Laloi, C., Heudes, D., Bruneval, P., Corman, B., 2000. Food restriction prevents advanced glycation end product accumulation and retards kidney aging in lean rats. J. Am. Soc. Nephrol. 11, 1488–1497.

Wagner, B.M., 1987. Renal pathology and aging. Hum. Pathol. 18, 659–660.

Xiong, Y., Yuan, L.W., Deng, H.W., Li, Y.J., Chen, B.M., 2001. Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats. Clin. Exp. Pharmacol. Physiol. 28, 842–847.

Yu, B.P., Masoro, E.J., Murata, I., Bertrand, H.A., Lynd, F.T., 1982. Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: longevity, growth, lean body mass and disease. J. Gerontol. 37, 130–141.

Yumura, W., Imasawa, T., Suganuma, S., Ishigami, A., Handa, S., Kubo, S., Joh, K., Maruyama, N., 2006. Accelerated tubular cell senescence in SMP30 knockout mice. Histol. Histopathol. 21, 1151–1156.

Yumura, W., Sugino, N., Nagasawa, R., Kubo, S., Hirokawa, K., Maruyama, N., 1989. Age-associated changes in renal glomeruli of mice. Exp. Gerontol. 24, 237–249.

Zha, Y., Le, V.T., Higami, Y., Shimokawa, I., Taguchi, T., Razzaque, M.S., 2006. Life-long suppression of growth hormone-insulin-like growth factor I activity in genetically altered rats could prevent age-related renal damage. Endocrinology 147, 5690–5698.

Zhang, C., Liu, V.W., Addessi, C.L., Sheffield, D.A., Linnane, A.W., Nagley, P., 1998. Differential occurrence of mutations in mitochondrial DNA of human skeletal muscle during aging. Hum. Mutat. 11, 360–371.