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• W2029971534 abstract "Excessive activation of the AT1A receptor (AT1AR) by angiotensin II (Ang II) is implicated in the age-related development of hypertension, diabetes, and kidney disease. AT1AR-deficient mice live longer and have lower levels of oxidative stress than wild-type mice (Benigni et al., 2009Benigni A. Corna D. Zoja C. Sonzogni A. Latini R. Salio M. Conti S. Rottoli D. Longaretti L. Cassis P. et al.J. Clin. Invest. 2009; 119: 524-530Crossref PubMed Scopus (357) Google Scholar), suggesting a role for AT1AR signaling in the aging process. Excessive activation of the AT1A receptor (AT1AR) by angiotensin II (Ang II) is implicated in the age-related development of hypertension, diabetes, and kidney disease. AT1AR-deficient mice live longer and have lower levels of oxidative stress than wild-type mice (Benigni et al., 2009Benigni A. Corna D. Zoja C. Sonzogni A. Latini R. Salio M. Conti S. Rottoli D. Longaretti L. Cassis P. et al.J. Clin. Invest. 2009; 119: 524-530Crossref PubMed Scopus (357) Google Scholar), suggesting a role for AT1AR signaling in the aging process. Persistent and poorly regulated hypertension is a major risk factor for many of the most prevalent age-related disorders that limit life span, including cardiovascular disease, stroke, kidney disease, and neurodegenerative diseases. Angiotensin II (Ang II), a peptide produced from renin via the proteolytic activity of angiotensin converting enzyme (ACE), is a key component of an endocrine/paracrine signaling system that increases vasoconstriction and blood pressure. Ang II functionally interacts with two forms of G protein-coupled receptor (GPCR), the AT1 or AT2 type receptors. The A subtype of the AT1 receptor (AT1AR) is located on the surface of vascular smooth muscle cells, and its activation by Ang II results in elevated levels of intracellular calcium, generation of reactive oxygen species (ROS), and contraction of the cells. Ang II therefore acts to increase vascular pressure, and accordingly ACE inhibitors and AT1AR antagonists have proven to be highly effective for the treatment of hypertension (Werner et al., 2008Werner C. Baumhäkel M. Teo K.K. Schmieder R. Mann J. Unger T. Yusuf S. Böhm M. Clin. Res. Cardiol. 2008; 97: 418-431Crossref PubMed Scopus (115) Google Scholar). As maintaining cardiovascular health can have a major impact on longevity in humans, Benigni et al., 2009Benigni A. Corna D. Zoja C. Sonzogni A. Latini R. Salio M. Conti S. Rottoli D. Longaretti L. Cassis P. et al.J. Clin. Invest. 2009; 119: 524-530Crossref PubMed Scopus (357) Google Scholar recently examined the consequences of disruption of the AT1AR gene on aging of the cardiovascular and renal organ systems in mice. Strikingly, both the average and maximum life spans of AT1AR-deficient mice were increased by approximately 20%. At a gross level the AT1AR-deficient mice demonstrated no significant alteration in body weight, fasting blood glucose, heart weight/body weight ratio, or activity levels demonstrating an ability of the animal to partly mitigate the loss of AT1AR with respect to overall energy metabolism. However, age-related pathologies in the cardiovascular system, including atherosclerotic lesions and cardiac fibrosis, were reduced in AT1AR-deficient mice compared to wild-type control mice (Benigni et al., 2009Benigni A. Corna D. Zoja C. Sonzogni A. Latini R. Salio M. Conti S. Rottoli D. Longaretti L. Cassis P. et al.J. Clin. Invest. 2009; 119: 524-530Crossref PubMed Scopus (357) Google Scholar). While the cellular structure and function of the kidneys and pancreas were unaffected by AT1AR deficiency, age-related changes in the liver (degeneration of hepatocytes, vesicular steatosis, and exudation) were reduced in the AT1AR-deficient mice. The aging process involves damage to cells by ROS, probably as the result of both increased free radical production and a reduced ability of cells to protect themselves against the ROS (Bokov et al., 2004Bokov A. Chaudhuri A. Richardson A. Mech. Ageing Dev. 2004; 125: 811-826Crossref PubMed Scopus (459) Google Scholar). To determine whether the increased longevity of AT1AR-deficient mice was associated with reduced levels of oxidative stress, levels of nitrotyrosine, a marker of oxidative attack on cellular proteins, were measured in the heart, artery, and kidney tissues from young and old wild-type mice and aged AT1AR-deficient mice. In all three tissues, levels of oxidative protein damage were increased by aging in wild-type mice, but not in the AT1AR-deficient mice. Benigni et al. used only 20 AT1A-deficient and 10 wild-type male mice of one mixed genetic background for their life span studies, an unusually small number of animals for such a study. It will therefore be important to repeat the experiments with larger numbers of mice of more than one genetic background; females should also be evaluated, as there may be sex differences in the effects of AT1AR signaling on aging. In addition, a comprehensive assessment of how other blood-borne metabolic factors and hormones also change in response to the loss of Ang II signaling may also provide insights into the longevity mechanism. The low-level oxidative damage in old AT1AR-deficient mice may not be due to reduced production of ROS because numbers of mitochondria, a major source of free radicals, were increased in cells from the AT1AR-deficient mice. Instead, the authors' data suggest that the lack of AT1AR-mediated signaling results in increased production of proteins that protect cells against free radical attack. Indeed, the expression of two cytoprotective mitochondrial proteins, Nampt and sirtuin 3, were increased in kidney cells of old AT1AR-deficient mice compared to old wild-type mice (Benigni et al., 2009Benigni A. Corna D. Zoja C. Sonzogni A. Latini R. Salio M. Conti S. Rottoli D. Longaretti L. Cassis P. et al.J. Clin. Invest. 2009; 119: 524-530Crossref PubMed Scopus (357) Google Scholar). Nampt is a NAD+ biosynthetic enzyme that protects cells against genotoxic stress (Yang et al., 2007Yang H. Yang T. Baur J.A. Perez E. Matsui T. Carmona J.J. Lamming D.W. Souza-Pinto N.C. Bohr V.A. Rosenzweig A. et al.Cell. 2007; 130: 1095-1107Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar), while sirtuin 3 is a histone deacetylase that protects cells against oxidative stress-induced apoptosis (Sundaresan et al., 2008Sundaresan N.R. Samant S.A. Pillai V.B. Rajamohan S.B. Gupta M.P. Mol. Cell. Biol. 2008; 28: 6384-6401Crossref PubMed Scopus (392) Google Scholar). Benigni et al., 2009Benigni A. Corna D. Zoja C. Sonzogni A. Latini R. Salio M. Conti S. Rottoli D. Longaretti L. Cassis P. et al.J. Clin. Invest. 2009; 119: 524-530Crossref PubMed Scopus (357) Google Scholar did not evaluate levels of Nampt and sirtuin 3 in the heart or blood vessels, so it is unclear whether these stress-resistance proteins contribute to the reduced cardiovascular pathology in aged AT1AR-deficient mice. Interestingly, the effects of AT1AR deficiency on cellular stress resistance are similar to the effects of dietary energy restriction and exercise, two conditions that can improve health and longevity (Martin et al., 2007Martin B. Golden E. Egan J.M. Mattson M.P. Maudsley S. IBS J. Sci. 2007; 2: 35-39PubMed Google Scholar). An impaired ability to efficiently adapt to stressors is a common feature of the aging process, and it will be of interest to determine the cellular signaling pathway(s) that mediate the apparent adverse effects of Ang II on stress responses. The AT1AR is a member of the rhodopsin-like GPCRs and is primarily associated with Gαq and Gαi type G proteins. Like many other receptors in this superfamily, its activation can impact a variety of signal transduction pathways (Higuchi et al., 2007Higuchi S. Ohtsu H. Suzuki H. Shirai H. Frank G.D. Eguchi S. Clin. Sci. 2007; 112: 417-428Crossref PubMed Scopus (318) Google Scholar) (Figure 1). One pathway involving the protein kinases (Rho kinase) ROCK and (c-jun N-terminal kinase) JNK promotes inflammation and cellular hypertrophy and migration, while another can activate NADPH oxidase, resulting in oxidative damage to DNA, proteins, and lipids. The insulin/insulin-like growth factor-1 (IGF-1) signaling pathway is strongly implicated in aging as mutations in the genes that encode components of this pathway extend life span in organisms ranging from worms and flies to mice (Tatar et al., 2003Tatar M. Bartke A. Antebi A. Science. 2003; 299: 1346-1351Crossref PubMed Scopus (991) Google Scholar). Ang II signaling through an epidermal growth factor receptor-mediated “transactivation” pathway activates components of the insulin signaling pathway including the Shc adaptor protein, phosphatidyl inositol-3 kinase (PI3K), and Akt kinases. Two substrates of Akt implicated in aging are forkhead transcription factors (FHTF) and the mammalian target of rapamycin (mTOR). FHTF are inhibited by Akt, resulting in reduced cellular production of antioxidant proteins, whereas mTOR is activated by Akt resulting in increased protein synthesis and cell hypertrophy. It will be important to establish which of the AT1AR signaling pathways enhances cardiovascular aging and whether AT1AR deficiency suppresses age-related changes in other tissues. In particular, the activation status of p66Shc and mTOR should be evaluated in tissues of the AT1AR-deficient mice in light of the increased longevity of mice lacking p66Shc (Purdom and Chen, 2003Purdom S. Chen Q.M. Biogerontology. 2003; 4: 181-191Crossref PubMed Scopus (40) Google Scholar). Is the increased longevity of AT1AR-deficient mice simply the result of reduced cardiovascular pathology as suggested by the authors (Benigni et al., 2009Benigni A. Corna D. Zoja C. Sonzogni A. Latini R. Salio M. Conti S. Rottoli D. Longaretti L. Cassis P. et al.J. Clin. Invest. 2009; 119: 524-530Crossref PubMed Scopus (357) Google Scholar)? Mice rarely die from cardiovascular disease—instead in laboratory settings they typically succumb to cancers, infections, or renal disease (Brayton, 2007Brayton, C. (2007). Charles Louis Davis, D.V.M. Foundation, http://www.cldavis.org/cgi-bin/download.cgi?pid=52.Google Scholar). The observation that AT1AR deficiency extended both average and maximum life span suggests that AT1AR signaling may accelerate the aging process in cells throughout the whole body rather than affecting only age-related cardiovascular disease. Although Ang II is best known for its effects on cardiovascular and renal cells, AT1AR are widely expressed in cells of the nervous system where they may influence neuroendocrine function, autonomic/stress responses, and possibly a range of behaviors, some of which may be preferentially preserved during aging in AT1AR-deficient mice. Moreover, AT1AR have been shown to play an important role in tumor angiogenesis and growth (Egami et al., 2003Egami K. Murohara T. Shimada T. Sasaki K. Shintani S. Sugaya T. Ishii M. Akagi T. Ikeda H. Matsuishi T. Imaizumi T. J. Clin. Invest. 2003; 112: 67-75Crossref PubMed Scopus (290) Google Scholar), which could contribute to the extended survival of the AT1AR-deficient mice. Finally, the findings of Benigni et al. open the possibility that ACE inhibitors and AT1AR antagonists could increase the longevity of healthy humans who may not present significant hypertensive symptomology." @default.
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