J Clin Invest. 2009 Mar;119(3):524-30. doi: 10.1172/JCI36703. Epub
2009 Feb 9.
Disruption of the Ang II type 1 receptor promotes longevity in mice.
Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S,
Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G.
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11,
Bergamo, Italy. aben...@marionegri.it
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 (AT1 and AT2).
Here, we show that targeted disruption of the Agtr1a gene that encodes
AT1A 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 AT1 antagonist. These results
demonstrate that disruption of AT1 promotes longevity in mice,
possibly through the attenuation of oxidative stress and
overexpression of prosurvival genes, and suggests that the Ang II/AT1
pathway may be targeted to influence life span in mammals. PMID:
19197138
Pflugers Arch. 2010 Jan;459(2):325-32. Epub 2009 Sep 11.
Angiotensin receptors as determinants of life span.
Cassis P, Conti S, Remuzzi G, Benigni A. Mario Negri Institute for
Pharmacological Research, Via Gavazzeni, 11, 24125 Bergamo, Italy.
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. PMID:19763608
]).