**8. Telomere length in other organ transplants**

or a severe damage because of telomere shortening. We initially hypothesized that idiopathic post-transplant hepatitis may show more progressive telomere shortening due to higher cell turnover [3-4]. Cellular senescence in the explanted livers of young children was reported to be associated with hepatocyte damage rather than to a corresponding age-dependent phe‐ nomenon [80]. However, we observed no significant telomere reduction in hepatocytes taken from patients with idiopathic post-transplant hepatitis at late biopsy. Telomere shortening does not necessarily reflect the long-term graft status in idiopathic post-transplant hepatitis, which differs clinically and histologically. Telomere length in hepatocytes already shortened during the early post-transplant period. Increasing number of senescent cells associated with telomere shortening confirmed in a mouse model of ischemia–reperfusion injury [81]. Therefore, hepatocyte damage related to ischemia–reperfusion injury is likely to be a major factor in the accelerated telomere decline observed in the early post-transplant period. On the other hand, from the standpoint of telomere shortening in the early post-transplantation phase, telomere decline is considered a risk factor for late dysfunction of the graft. This finding is

Tolerance is a condition in which an allograft functions normally and lacks histological evidence of rejection in the absence of immunosuppression [82]. Tolerated grafts are suitable study materials for evaluating the biological organ age of grafts unaffected by inflammation and immunosuppression. We have previously reported a significant reduction in hepatocyte telomere signal intensity compared to the predicted age-dependent decline in the tolerated liver allograft, using quantitative fluorescence in situ hybridization [80,21]. Recently it has been demonstrated that measurement of relative average telomere lengths can be accomplished by real-time polymerase chain reaction (PCR) using a carefully designed pair of oligonucleotide primers [83]. In a larger number of cases, we performed quantitative real-time PCR, and confirmed accelerated telomere shortening relative to the chronological graft age in tolerated grafts. It is possible that a significant proportion of liver transplantation recipients are tolerant [84-86]. Accelerated telomere intensity decline occurred in hepatocytes in tolerated graft within a year of transplantation. The results of the previous study have suggested that even tolerated grafts might undergo a lowering of renewal capacity and a decrease in function as the recipients become older [2]. According to our previous study, the allograft could be older than the predicted age of the allograft even in tolerated grafts, and the telomere length shortened

clinically significant in follow-up examinations of high-risk allografts.

**7. Oxidative stress after living-donor liver transplantation**

Ischemia and reperfusion during transplantation produce a transient increase of reactive oxygen species in the organ, which are potent inducers of DNA breaks. In a rat model, both allogeneic and syngeneic transplants were characterized by shortened telomeres during

**6. Tolerance**

6 Telomere - A Complex End of a Chromosome

based on the graft age.

Telomere length is associated with kidney function [95]. Ischemia–reperfusion during kidney transplantation is associated with rapid telomere shortening [96]. Cellular senescence in zero hour biopsies predicts outcome in renal transplantation [97]. Telomere length assessed in biopsy specimens collected in the peri-transplant period predicts long-term kidney allograft function. Complications of kidney transplantation, like delayed graft function, acute rejection, and chronic allograft dysfunction are linked with the telomere length and thus, graft ageing [98]. Moreover, telomere length is a predictive marker of transplant outcome [99]. Rapid telomere reduction in the first year after hematopoietic stem cell transplantation were identi‐ fied in recipients of bone marrow grafts [100-101]. Short telomeres are associated with the presence of chronic graft versus host disease and receiving graft from a female donor [102].
