**3. Mechanisms of renal aging**

It is essential to distinguish aging from age-related disease. Aging itself is not a disease but seems to be the greatest risk factor for age-related pathology [12]. The altered molecules with aging involve many different pathways, including cell integrity, cellular proliferation, cell transport and energy metabolism. Many of these molecules and processes are not unique to aging and are likely general pathways involved in tissue damage and repair. Aging is a programmed biological process that is associated with small transcriptional differences in many genes, rather than large expression changes in a small number of genes [13-16].

The aging phenotype is the consequence of cellular senescence, of increased susceptibility to apoptosis with older age, of impaired regeneration and repair, of decreased functional capacity of stem cells and progenitor cells, of changes in the expression of growth factors with increasing age, of mitochondrial changes, of dysregulation of autoregulatory pathways and of immune system alterations and different immunogenicity of older tissue.

greater than 1.5 mg/dL and cerebrovascular cause of death. The risk of graft failure after an

Also Ojo *et al*. have reported on the survival of recipients of marginal kidneys, defined as kidneys with one or more of the following pretransplant factors: donor age >55 years, nonheartbeating donor, cold ischemia time >36 h, and donor hypertension or diabetes mellitus of >10 years duration. Also in this study, marginal kidney transplants had a lower allograft

Inanotherstudy,Woo*etal.*comparedtwogroupsonlydividedbyage.Therewasalargerincrease in graft failure rates of kidneys from donors >55 years of age. Also the mean estimated glomeru‐ lar filtration rate 6 months post-transplant and the stability of the glomerular filtration rate in the

Recent data on 1063 kidney grafts from living donors confirm the association between older donor age and graft outcome even after living donation, where living donors are screened prior to transplantation and comorbidities are avoided. Increasing living donor age was associated with lower kidney function after transplantation, loss of glomerular filtration rate

With the increasing use of older and extended criteria donor kidneys, the intrinsic quality of the kidneys at transplantation is nowadays much more important for the post-transplant histological evolution and long-term graft survival than acute T-cell mediated rejection [1, 8, 9]. The causes by which older kidneys lose function after transplantation remain however incompletely understood. This may involve both early and late-onset processes and is likely to be found mainly in a significant effect of donor age on the subclinical progression of chronic histological damage [10]. In a large study using protocol biopsies, it was not only demonstrated that higher donor age is the major determinant of this non-specific chronic allograft damage, but also that the association between donor age and post-transplant histological damage is independent of the histological quality of the graft at implantation [11]. This suggests that donor age and the aging process in itself are playing an independent role on renal allograft histological progression and long-term outcome. From these studies, it can even be hypothe‐ sized that the aging process in itself is accelerated after transplantation, and contributes to

It is essential to distinguish aging from age-related disease. Aging itself is not a disease but seems to be the greatest risk factor for age-related pathology [12]. The altered molecules with aging involve many different pathways, including cell integrity, cellular proliferation, cell transport and energy metabolism. Many of these molecules and processes are not unique to aging and are likely general pathways involved in tissue damage and repair. Aging is a programmed biological process that is associated with small transcriptional differences in

many genes, rather than large expression changes in a small number of genes [13-16].

first transplant year were significantly higher in the recipients of donors <55 years [6].

ECD kidney transplant is 70% higher than after a non- ECDtransplant [4].

outcomes compared with organs from ideal donors [5].

186 Current Issues and Future Direction in Kidney Transplantation

beyond 1 year and reduced graft survival [7].

transplant outcome [10].

**3. Mechanisms of renal aging**

Of the previously mentioned mechanisms of aging, cellular senescence is classically seen as one of the most important drivers of the aging process. Cellular senescence leads to permanent and irreversible growth arrest and was detected in seminal *in vitro* studies by Hayflick and Moorhead [17, 18]. Senescent cells remain viable but show a changed morphology, greater heterogeneity, expression of SA-β-gal, accumulation of lipofuscin granules and lack of response to mitogenic stimuli.

Cellular senescence is a specific response of mitotically active cells to various stressors. It is determined by multiple factors, including the genetic regulation of metabolism, time, the number cell cycles of replication, and most importantly the answer to injury and stress [11, 19]. Examples of these different factors are telomere shortening and telomere dysfunction, nontelomere DNA damage (e.g. due to X-rays, oxidative stress and UV irradiation), mitogenic signals including those produces by oncogens (wich also cause DNA damage) and nongenotoxic stress like chromatin perturbation (epigenetic changes) and other stress factors [20, 21] (. Cellular senescence thus not only comprises exhaustion of a predetermined proliferative capacity (intrinsic senescence or replicative senescence), but can also be induced by extrinsic factors (stress-induced premature senescence).

In this light, the impact of cellular senescence goes beyond the importance for aging. Cellular senescence pathways play essential roles in tumor suppression, tumor promotion and tissue repair.

There is increasing evidence that cellular senescence is a tumor suppressive system (by inducing growth arrest) and a tumor-promoting phenomenon (by secretion of inflammatory cytokines) [22]. To reconcile the apparently conflicting impact of cellular senescence on cancer, Campisi *et al.* suggest that cellular senescence is a biological process that was selected to promote fitness in young organisms (beneficial: tumor suppression, tissue regeneration), but is deleterious in old organisms (harming: aging, tumor promotion) [23]. In the evolution, senescence pathways evolved in an environment where organism lifespan was short. There‐ fore tumor-suppressor mechanisms needed to be effective for only a relatively short (repro‐ ductive) period [21]. Even if this mechanism was harmful later on, this would not affect selective pressure. This concept is the essence of the "antagonistic pleiotropy hypothesis" and makes us understand the senescence concept much better [23].
