Tissues from aging animals have a reduced number of mitochondria (14) that show functional changes, including increased superoxide and H2O2 generation and decreased energy production (21)

Tissues from aging animals have a reduced number of mitochondria (14) that show functional changes, including increased superoxide and H2O2 generation and decreased energy production (21). blood pressure is highly prevalent in humans and is associated with complications, including heart disease, kidney disease, and stroke, which together represent the major (and neglected) health problems for high- and middle-income countries that are now impending on low-income countries (1). The renin-angiotensin system (RAS) has critical functions in regulation of blood pressure and cardiovascular physiology (2). Its role in the pathogenesis of a number of disease states has been well documented, and components of the RAS are important pharmacological targets in hypertension and cardiovascular disease. Responsiveness to Ang II is conferred by the expression of 2 classes of pharmacologically distinct rhodopsin-like G proteinCassociated receptors, the Ang II type 1 and 2 receptors (AT1 and AT2) (3). The effect of Ang II to increase blood pressure and to promote various pathologies Rabbit polyclonal to CD27 is mediated by AT1, which is expressed in various organ systems, including the heart, blood vessels, kidney, adrenal glands, and cardiovascular control centers in the brain (4). Targeted disruption of the gene encoding AT1A the major mouse AT1 isoform and mouse homolog to the single human gene (5) causes a reduction in blood pressure levels. Here, we investigated whether inactivation of gene in mice also confers protection from cardiovascular morbidity and mortality. The present study documented that inhibition of AT1 signaling promotes longevity. Results Inactivation of AT1A prolongs the life span of mice. A prospective observational study was performed in 20 homozygous mice deficient for AT1A the major mouse AT1 isoform and the closest murine homolog to the single human AT1 (5) and 10 wild-type controls. The animals lacking AT1A substantially outlived their wild-type littermates (Figure ?(Figure1).1). At 29 months, when all wild-type animals died, 17 AT1A-deficient mice (85%) were still alive. These remaining mice lived for an additional Preladenant 7 months. Comparison of survival curves showed a highly significant difference between groups ( 0.0001). The life span of the AT1A-deficient mice was approximately 26% longer than controls. Open in a separate window Preladenant Figure 1 Knocking-out AT1A prolongs life span in the mouse. A Kaplan-Meier analysis of survival in male animals and wild-type littermates is shown (log-rank test, 20.32; 0.0001 versus wild-type mice). The average life span of animals and wild-type littermates was 31.20 2.31 and 24.81 3.10 months, respectively. Caloric restriction is associated with increased longevity (6C8). To assess whether caloric intake was effected by the AT1A mutation, daily food intake was carefully monitored at 19 to 21 months of age. Food intake was virtually identical between and wild-type mice (Table ?(Table1).1). Small body size is also associated with extended life span in diet-restricted mice (9). Body weights were slightly but not significantly reduced in compared with wild-type littermates until month 18 when they became indistinguishable (Figure ?(Figure2A).2A). mice had normal physical activity as reflected by their ability to perform on a rotarod (Table ?(Table1).1). Adenocarcinoma of the lung was observed in 10%C15% of animals in both aging cohorts, an incidence of lung tumor not correlated with genotype and lower than previously reported (~30%) in C57BL/6 129 mice (10). Preladenant Open in a separate window Figure 2 Body weight and blood glucose levels in and wild-type mice. (A) Body weight in animals Preladenant and wild-type littermates. No significant difference in weight gain was observed. (B) Fasting blood glucose levels were comparable in Preladenant animals (= 9).