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Objective: Senescent patients exhibit an elevated perioperative risk for cardiac dysfunction, hemodynamic depression and subsequent cardiac death compared to young patients. Despite the fact that a growing proportion of cardiac surgery patients are octogenarians, cardioplegic regimes remain comparable across patients of all ages. We compared the hemodynamic performance, metabolic parameters and ultrastructural changes in adult and senescent rat hearts after application of Buckberg's blood cardioplegia (BCP) to evaluate differences between the age groups regarding postischemic myocardial function and cellular ultrastructure., Methods: Hearts of adult (young adult group, 3-4 months) and senescent (old group, 24 months) male Wistar rats were excised and inserted into a blood perfused isolated heart apparatus (Langendorff perfusion). After a stabilization period of 30 min, in 16 adult and 16 senescent hearts, Buckberg BCP was administered antegradely and repeated every 20 min. Six young adult and 3 senescent hearts served as ischemia control. After an aortic clamping time of 90 min an antegrade hot shot was administered. During reperfusion ex vivo cardiac functional parameters were recorded, including coronary blood flow, left ventricular developed pressure (LVDP) and velocity of myocardial contraction or relaxation (+/-dp/dt). Oxygen consumption and lactate production of the hearts were calculated. After perfusion fixation, the hearts of five rats in each BCP group and 3 rats in each ischemia group were investigated for cellular edema and mitochondrial damage by morphometry using transmission electron microscopy., Results: While recovery of cardiac function after 90 min of unprotected ischemia was significantly impaired in senescent hearts, functional recovery after ischemia protected by BCP was similar in adult and senescent hearts. Mitochondrial ultrastructure was severely damaged in both age groups after 90 min ischemia, but well preserved in both BCP groups. The qualitative analysis was confirmed by the morphometric cellular edema index and the volume-to-surface ratio of the mitochondria. Myocardial oxygen consumption was highest and lactate production was lowest in senescent hearts., Conclusion: Senescent rat hearts were more susceptible to unprotected ischemia/reperfusion injury than young adult hearts. When protected by BCP, we found no difference in hemodynamic performance between adult and senescent hearts indicating preserved myocardial protection even in senescent individuals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Obesity is associated with an increased incidence of left ventricular hypertrophy, diastolic dysfunction, heart failure, and premature cardiac aging. In the heart, intrinsic activation of the AMP-dependent protein kinase (AMPK) plays a pivotal role in the stress response to ischemia and hypertrophy. Furthermore, AMPK is an important regulator of cardiac mitochondrial biogenesis. The purpose of the present study was to investigate the influence of obesity and aging on the AMPK signaling pathway in human cardiac tissue., Methods: 60 male cardiac surgery patients were included in the study and divided into 4 groups (old normal weight: ON; old obese: OO; young normal weight: YN, young obese: YO) according to their body mass index (18.5-25: normal weight or 30-35: obese) and age (<55 years: young or >70: old) with 15 patients each. Right atrial tissue (RA) was analyzed for the expression of the AMPK upstream kinases CAMKK and LKB1, activation of AMPK as well as phosphorylation of the AMPK downstream targets ACC, eEF2, mTOR and eNOS. Epicardial adipose tissue was analyzed for the expression of the endogenous AMPK activator adiponectin. The metabolic state of all patients was further characterized in fasting blood samples., Results: Old patients (ON, OO) and young obese (YO) subjects displayed higher fasting glucose, insulin and leptin serum levels compared to the young, normal weight group, although HbA1c was below the threshold required for the diagnosis of type 2 diabetes. Serum adiponectin as well as total adiponectin protein expression in epicardial adipose tissue was decreased in these three groups. Analyses of adiponectin isoforms by native gel electrophoresis revealed significant differences in the high molecular weight (HMW) isoforms between the groups. Despite the low total serum adiponectin and HMW adiponectin, AMPK activation was high in the RA of obese patients (YO, OO). Among the AMPK upstream kinases, LKB1 expression showed a strong positive correlation with AMPK activation. While the phosphorylation of the AMPK downstream targets mTOR, eEF-2 and ACC was not altered, phospho-eNOS was significantly lower in old patients (ON, OO). Despite strong AMPK activation, mitochondrial biogenesis and respiration were impaired in old (ON, OO) and young obese (YO) subjects., Conclusion: These data indicate that obesity and aging result in significant changes although many direct parameters in the AMPK signaling pathway are not changed in the same direction. LKB1 may represent a stronger activator of the AMPK pathway than adiponectin or the CAMKKs in human right atrial tissue., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hormonal signals from adipose tissue regulate energy homeostasis and may be involved in anti-aging effects of caloric restriction (CR). The adipokine adiponectin is abundantly expressed in adipose tissue and directly sensitizes the body to insulin. The purpose of the current study was to investigate age-dependent effects of different levels of CR (16%, 2 months or 40%, 6 months) on adiponectin and on its receptors AdipoR1 and AdipoR2 in the left ventricle (LV). In young and senescent rats, 2 months of moderate CR reduced serum leptin. The same diet was sufficient to enhance serum adiponectin, adiponectin expression (visceral fat) and left ventricular AdipoR1 expression in young but not in senescent rats. The higher degree of CR, however, resulted in a mild induction of adiponectin expression in adipose tissue and release into plasma together with increased LV AdipoR1 also in old rats, while these effects were more pronounced in young rats. These changes in adiponectin activation were associated with reduced LV triglyceride content, suggesting an adiponectin-mediated reduced ectopic lipid deposition in nonadipose tissues. Thus, aging is associated with a loss of adiponectin inducibility by moderate CR. This reduction can only partially be overcome by increasing the degree and duration of CR.

Extension of life span by caloric restriction is assumed to result from retardation of a genetically determined program of ageing, but the new concept of hormesis regards caloric restriction as mild stress, which triggers active, protective reactions with reparative capacities. Here, we discuss two potential hormetic reactions with protective efficacy against dysfunctional mitochondria: restoration of neuregulin signalling by upregulation of erbB receptors and enhanced biogenesis of functionally active mitochondria by an eNOS-dependent mechanism. Mitochondrial ageing is considered to result from a vicious cycle of mitochondrial ROS-formation, ROS-mediated damage of mitochondrial DNA, disproportional respiratory chain composition and thereby additionally enhanced ROS production leading to apoptotic cell loss. Proof-of- principle for such a cycle was obtained from transgenic mice with impaired mitochondrial DNA repair capacity. Indirect arguments suggest this cycle operating also in ageing wild-type mammals, accelerated by downregulation of mitochondrial gene expression in insulin resistance, by inflammatory excess NO formation, and by downregulation of erbB receptors in cardiac ageing and failure. Attenuated neuregulin signalling induces a shift in the splice products of the Bcl-x gene from the antiapoptotic Bcl-xL protein towards the proapoptotic Bcl-xS protein, resulting in mitochondrial dysfunction and apoptosis in cardiomyocytes. Transient caloric restriction upregulates erbB receptors and restores mitochondrial Bcl-x-isoform patterns and mitochondrial dysfunction in the ageing heart.