Disruption of the Ang II type 1 receptor promotes longevity in mice

Abstract

The renin-angiotensin system plays a role in the etiology of hypertension and the pathophysiology of cardiac and renal diseases in humans. Ang II is the central product of this system and is involved in regulating immune responses, inflammation, cell growth, and proliferation by acting through Ang II type 1 receptors (AT 1 and AT 2 ). Here, we show that targeted disruption of the Agtr1a gene that encodes AT 1A results in marked prolongation of life span in mice. Agtr1a -/-mice developed less cardiac and vascular injury, and multiple organs from these mice displayed less oxidative damage than wild-type mice. The longevity phenotype was associated with an increased number of mitochondria and upregulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney. In cultured tubular epithelial cells, Ang II downregulated Sirt3 mRNA, and this effect was inhibited by an AT 1 antagonist. These results demonstrate that disruption of AT 1 promotes longevity in mice, possibly through the attenuation of oxidative stress and overexpression of prosurvival genes, and suggests that the Ang II/AT 1 pathway may be targeted to influence life span in mammals.

Mitochondrial ATP-sensitive potassium channels enhance angiotensin-induced oxidative damage and dopaminergic neuron degeneration. Relevance for aging-associated susceptibility to Parkinson’s disease

“…Normal aging has been associated with a pro-inflammatory, pro-oxidant state that may favor an exaggerated response to injury and degenerative diseases (Choi et al 2010;Csiszar et al 2003;Ungvari et al 2004). In accordance with this, several recent studies have suggested the potential of inhibition of angiotensin for treatment of age-associated diseases and longevity (Benigni et al 2009(Benigni et al , 2010Mattson and Maudsley 2009;Nishiyama et al 2009). …”

“…In accordance with this, recent studies with angiotensin II type 1 receptor deficient mice indicate that disruption of this receptor promotes longevity through attenuation of oxidative stress and additional mechanisms (Benigni et al 2009(Benigni et al , 2010Mattson and Maudsley 2009), and completely protects against the age-related progression of atherosclerosis (Umemoto 2008). It is known that angiotensin II, acting via type 1 receptors, is one of the most important known inducers of inflammation and oxidative stress in several tissues (Mattson and Maudsley 2009;Min et al 2009;Ruiz-Ortega et al 2001).…”

Identification and characterization of a functional mitochondrial angiotensin system

“…In addition, AT 1 R blockers have been reported to reduce agerelated mitochondrial dysfunction, attenuate hypertension-induced renal mitochondrial dysfunction, and protect against cardiac mitochondrial dysfunction in the setting of acute ischemia (39,40). Interestingly, disruption of AT 1 Rs was associated with an increased number of mitochondria and up-regulation of the prosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in the kidney, leading to marked prolongation of life span in mice (41).…”

Ameliorative Effects of Telmisartan on the Inflammatory Response and Impaired Spatial Memory in a Rat Model of Alzheimer’s Disease Incorporating Additional Cerebrovascular Disease Factors

“…The expression levels of nicotinamide phosphoribosyl transferase (Nampt), sirtuin 3 (Sirt3) and other prosurvival genes are increased by AT1 suppression. 30) While PPARγ is expressed in the fetal brain as a factor involved in cellular development, its expression is quite limited in the healthy mature brain. 31) However, it has been suggested that while the PPARγ pathway is necessary for the growth of undifferentiated neural stem cells, it also plays an important role in maintaining the undifferentiated state.…”