Abstract
The cellular mechanisms underlying impaired function of aged liver grafts have not been fully elucidated, but mitochondrial dysfunction appears to be contributory. Sirtuin1 has been identified as a key mediator of mitochondrial recovery following ischemia–reperfusion injury. The purpose of this study was to determine whether differences exist in sirtuin-1 expression/activity in old vs. young liver grafts and to determine correlations with mitochondrial function, graft metabolic function, and graft injury. Old and young rat liver grafts (N = 7 per group) were exposed to 12 h of static cold storage (SCS), followed by a 2 h period of graft reperfusion ex vivo. Sirtuin1 expression and activity, mitochondrial function, graft metabolic function, and graft injury were compared. Sirtuin1 expression is upregulated in young, but not old, liver grafts in response to cold storage and reperfusion. This is associated with diminished tissue ATP, antioxidant defense, and graft metabolic function in old liver grafts. There was no evidence of increased inflammation or histologic injury in old grafts. Sirtuin1 expression is diminished in old liver grafts and correlates with mitochondrial and metabolic function. The sirtuin pathway may represent a target for intervention to enhance the function of aged liver grafts.
Highlights
The cellular mechanisms underlying impaired function of aged liver grafts have not been fully elucidated, but mitochondrial dysfunction appears to be contributory
Sirtuin[1] mRNA expression was significantly upregulated in young liver grafts in response to ischemia–reperfusion, while this was not observed for old grafts (Fig. 2a)
The underlying cellular mechanisms contributing to increased susceptibility of old liver grafts to I–R injury have not been fully elucidated
Summary
The cellular mechanisms underlying impaired function of aged liver grafts have not been fully elucidated, but mitochondrial dysfunction appears to be contributory. Sirtuin[1] expression is upregulated in young, but not old, liver grafts in response to cold storage and reperfusion This is associated with diminished tissue ATP, antioxidant defense, and graft metabolic function in old liver grafts. Sirtuin-1 in the clearance of damaged mitochondria (mitophagy), production of new mitochondria (biogenesis), and antioxidant d efense[14,17,18,19,20] These mitochondrial recovery pathways appear to be diminished in old hepatocytes subjected to I–R injury. A recent study by Chun et al demonstrated that in contrast to young hepatocytes, aged hepatocytes exhibited a near complete loss of sirtuin-1 following I–R, which corresponded with significantly increased injury[16]. These studies highlight the importance of sirtuin-1 activity in the mitochondrial response to I–R injury, and indicate that differences in sirtuin-1 activity between young and old hepatocytes may contribute to differences in the severity of I–R injury
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