Angiotensin receptors as determinants of life span

Paola Cassis, Sara Conti, Giuseppe Remuzzi, Ariela Benigni

Angiotensin II (Ang II), the central product of renin-angiotensin system, has a role in the etiology of hypertension and in pathophysiology of cardiac and renal diseases in humans. Other functions of Ang II include effects on immune response, inflammation, cell growth and proliferation, which are largely mediated by Ang II type 1 receptor (AT(1)). Several experimental studies have demonstrated that Ang II acts through AT(1) as a mediator of normal aging processes by increasing oxidant damage to mitochondria and in consequences by affecting mitochondrial function. Recently, our group has demonstrated that the inhibition of Ang II activity by targeted disruption of the Agtr1a gene encoding Ang II type 1A receptor (AT(1A)) in mice translates into marked prolongation of life span. The absence of AT(1A) protected multiple organs from oxidative damage and the alleviation of aging-like phenotype was associated with increased number of mitochondria and upregulation of the prosurvival gene sirtuin 3. AT(1) receptor antagonists have been proven safe and well-tolerated for chronic use and are used as a key component of the modern therapy for hypertension and cardiac failure, therefore Ang II/AT(1) pathway represents a feasible therapeutic strategy to prolong life span in humans.