**1.** Replicative senescence pathways ARF-p53-p21 (associated with telomere shortening).

evidence for an increased cell turnover at the time of transplantation and a phase of increased cell regeneration directly after transplantation that correlates with cold ischemia time [37, 38]. Also a small study showed that shorter telomere length in biopsies obtained at implantation was associated with lower graft function at 12 months after transplantation, but no correlation with p21 or p53 was found [39]. These studies need further validation to confirm the role of

Renal Aging and Kidney Transplantation http://dx.doi.org/10.5772/55469 189

DNA damage by environmental stress is the main stressor for activation of the p16-pRB pathway although dysfunctional telomeres can also induce p16 [21]. This telomere-independ‐ ent senescence pathway is currently often referred to as 'STATIS' (Stress and Aberrant Signaling-Induced Senescence. P16 (encoded by *CDKN2A*) is an important tumor suppressor in the p53 pathway. P16 keeps pRB in an active hypophosphorylated form, which inhibits cell proliferation and induces growth arrest [12]. The p53 and p16-pRB pathways interact witch

In native kidneys increased p16 expression is found in human kidneys with glomerular disease [16], interstitial fibrosis, diabetic nefropathy [40] and animal kidneys with hypertension [41]. Furthermore p16 is induced by cyclosporine, catch up growth in low birth weight and is attenuated by calorie restriction [12]. Finally, p16 expression correlates significantly with

Like the p53 pathway p16 expression relates to ischemia-reperfusion, at least in mice [43]. Furthermore, a rapid increase in p16 expression after transplantation has been described in murine kidney grafts, which was most pronounced in older animals. Whether these findings

In summary, there is extensive data that the outcome of kidney transplantation is heavily influenced by the age of the transplanted kidneys. There is some scant evidence that trans‐ plantation in itself increases cell turnover and leads to accelerate replicative senescence. Whether the association between older kidneys and impaired graft outcome relates to this accelerate replicative senescence after transplantation is however not clear, and the few

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven,

suggestions in the literature need to be validated in large-enough patient cohorts.

telomere shortening on transplant outcome.

each other and there is a reciprocal regulation.

are also valid in humans, remains unknown.

Katrien De Vusser and Maarten Naesens

kidney age [42].

**5. Summary**

**Author details**

Belgium

**2.** p16-pRB pathways (independent of telomere dysfunction).

Telomeres comprise tandem TTAGGG repeats of 5000 to 15000 base pairs that normally reside at the ends of chromosome ends as protection and prevent end-to-end fusion of chromosomes. Telomeric DNA is synthesized and its length is regulated by telomerase. Most somatic cells don't express telomerase and mature telomeres tend to progressively shorten with every cell division. The crucial role of telomerase absence in the telomere shortening is proven *in vitro* as telomere shortening can be bypassed by transfection with telomerase [25].

Telomere length reflects several important factors such as heredity, telomerase activity, the efficiency of telomere-binding proteins, the rate of cellular proliferation and oxidative stress in the milieu. Although telomere length is partly heritable, there are major differences in telomere length even among monozygotic twins, which suggests that environmental factors (e.g. hyperglycemie, oxidative stress [26, 27]) play a major role in telomere attrition and aging.

When the telomeres become critically short (reach the "Hayflick limit") a classical DNAdamage response is triggered with participation of several protein kinases (e.g. ATM and CHK2), adaptor proteins (e.g. 53BP1 and MDC1) and chromatin modifiers (e.g. gammaH2AX). Telomere shortening also leads to activation of the p53 pathway (trough p53 phosphorylation) and herewith associated p21 (also termed CDKN1a, p21Cip1, Waf1 or SD11) expression. Also other DNA damage responses (DDRs) and ARF (alternate reading frame, p14) can lead to activation of the p53 pathway. SIRT1 (sirtuin 1) can negatively regulate p53 localization to the nucleus and its function as a transcription factor.

The clinical importance of telomere shortening has been suggested in a very interesting study, where leukocyte telomere length was used as a biomarker of aging. In this study, the associ‐ ation between telomere length and various disease processes was independent of chronolog‐ ical age, which suggests the value of telomere length measurement as a biomarker of biological or cellular age [28].

In contrast to, e.g. blood cells, the association between age and telomere shortening in renal tissue was only studied scarcely. The supposed association with reduced regenerative capacity during aging and chronic diseases, and after acute injury, seems valid but has never been proven in humans. Only Westhoff 's study in telomerase deficient mice suggests that critical telomere shortening in kidneys leads to increased senescence and apoptosis, thereby limiting regenerative capacity [29].

In adult kidneys, telomerase activity is very low, which results in telomere shortening by every cell division, as was demonstrated by Melk *et al* [25]*.* . Also ischemia can induce telomere shortening as has been shown in different animal models [30-32] Finally, glomerular diseases like IgA nephropathy, lupus nephritis and focal glomerulosclerosis are associated with increased p53 expression compared to kidneys without lesions, both in animals [33] and in humans [34, 35] Whether this relates to telomere length has not been studied to date.

After bone marrow transplantation telomere shortening occurs significantly more rapidly than would be expected in graft-derived leukocytes. Probably due to the replicative stress on the blood cell caused the kinetics of haemopoietic engraftment [36]. After solid organ transplan‐ tation there are arguments to state that transplantation is associated with accelerated short‐ ening of telomere length in the transplanted cells [12]. In transplanted renal cells, there is evidence for an increased cell turnover at the time of transplantation and a phase of increased cell regeneration directly after transplantation that correlates with cold ischemia time [37, 38]. Also a small study showed that shorter telomere length in biopsies obtained at implantation was associated with lower graft function at 12 months after transplantation, but no correlation with p21 or p53 was found [39]. These studies need further validation to confirm the role of telomere shortening on transplant outcome.

**2.** p16-pRB pathways (independent of telomere dysfunction).

DNA damage by environmental stress is the main stressor for activation of the p16-pRB pathway although dysfunctional telomeres can also induce p16 [21]. This telomere-independ‐ ent senescence pathway is currently often referred to as 'STATIS' (Stress and Aberrant Signaling-Induced Senescence. P16 (encoded by *CDKN2A*) is an important tumor suppressor in the p53 pathway. P16 keeps pRB in an active hypophosphorylated form, which inhibits cell proliferation and induces growth arrest [12]. The p53 and p16-pRB pathways interact witch each other and there is a reciprocal regulation.

In native kidneys increased p16 expression is found in human kidneys with glomerular disease [16], interstitial fibrosis, diabetic nefropathy [40] and animal kidneys with hypertension [41]. Furthermore p16 is induced by cyclosporine, catch up growth in low birth weight and is attenuated by calorie restriction [12]. Finally, p16 expression correlates significantly with kidney age [42].

Like the p53 pathway p16 expression relates to ischemia-reperfusion, at least in mice [43]. Furthermore, a rapid increase in p16 expression after transplantation has been described in murine kidney grafts, which was most pronounced in older animals. Whether these findings are also valid in humans, remains unknown.
