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The renin–angiotensin system (RAS)—a classical blood pressure regulator—largely contributes to healthy organ development and function. Besides, RAS activation promotes age‐related changes and age‐associated diseases, which are attenuated/abolished by RAS‐blockade in several mammalian species. RAS‐blockers also increase rodent lifespan. In previous work, we discussed how RAS‐blockade downregulates mTOR and growth hormone/IGF‐1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D‐receptor upregulation), and proposed that at least some of RAS‐blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS‐blockade's impact on other aging regulatory pathways, that is, TGF‐ß, NF‐kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS‐blockade‐aging regulatory pathway–mitochondria interactions. However, existing results allow to conjecture that RAS‐blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)—even at subclinical doses—offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well‐tolerated anti‐hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement. [ABSTRACT FROM AUTHOR]

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Malfunctioning mitochondria strongly participate in the pathogenesis of cardiovascular damage associated with hypertension and other disease conditions. Eukaryotic cells move, assume their shape, resist mechanical stress, accommodate their internal constituents, and transmit signals by relying on the constant remodeling of cytoskeleton filaments. Mitochondrial ATP is needed to support cytoskeletal dynamics. Conversely, mitochondria need to interact with cytoskeletal elements to achieve normal motility, morphology, localization, and function. Extracellular matrix (ECM) quantity and quality influence cellular growth, differentiation, morphology, survival, and mobility. Mitochondria can sense ECM composition changes, and changes in mitochondrial functioning modify the ECM. Maladaptive ECM and cytoskeletal alterations occur in a number of cardiac conditions and in most types of glomerulosclerosis, leading to cardiovascular and renal fibrosis, respectively. Angiotensin II (ANG II), a vasoactive peptide and growth factor, stimulates cytosolic and mitochondrial oxidant production, eventually leading to mitochondrial dysfunction. Also, by inducing integrin/focal adhesion changes, ANG II regulates ECM and cytoskeletal composition and organization and, accordingly, contributes to the pathogenesis of cardiovascular remodeling. ANG II-initiated integrin signaling results in the release of transforming growth factor-[[beta].sub.1] (TGF-[[beta].sub.1]), a cytokine that modifies ECM composition and structure, induces reorganization of the cytoskeleton, and modifies mitochondrial function. Therefore, it is possible to hypothesize that the depression of mitochondrial energy metabolism brought about by ANG II is preceded by ANG II-induced integrin signaling and the consequent derangement of the cytoskeletal filament network and/or ECM organization. ANG II-dependent TGF-[[beta].sub.1] release is a potential link between ANG II, ECM, and cytoskeleton derangements and mitochondrial dysfunction. It is necessary to emphasize that the present hypothesis is among many other plausible explanations for ANG II-mediated mitochondrial dysfunction. A potential limitation of this proposal is that the results compiled here were obtained in different cells, tissues, and/or experimental models. cytoskeleton; transforming growth factor-[beta]; integrin; renin-angiotensin system

Intrauterine and postnatal zinc restriction may result in an adverse environment for the development of cardiovascular and renal systems. This study evaluated the effects of moderate zinc deficiency during fetal life, lactation, and/or postweaning growth on systolic blood pressure, renal function, and morphology in adult life. Female Wistar rats received low (8 ppm) or control (30 ppm) zinc diets from the beginning of pregnancy up to weaning. After weaning, male offspring of each group of mothers were fed low or control zinc diet. Systolic blood pressure, creatinine clearance, proteinuria, renal morphology, renal apoptosis, and renal oxidative stress state were evaluated after 60 days. Zinc deficiency during pre-and postweaning growth induced an increase in systolic blood pressure and a decrease in the glomerular filtration rate associated with a reduction in the number and size of nephrons. Activation of renal apoptosis, reduction in catalase activity, glutathione peroxidase activity, and glutathione levels and increase in lipid peroxidation end products could explain these morphometric changes. Zinc deficiency through pre-and postweaning growth induced more pronounced renal alteration than postweaning zinc deficiency. These animals showed signs of renal fibrosis, proteinuria, increased renal apoptosis, and higher lipid peroxidation end products. A control diet during postweaning growth did not totally overcome renal oxidative stress damage, apoptosis, and fibrosis induced by zinc deficiency before weaning. In conclusion, zinc deficiency during a critical period of renal development and maturation could induce functional and morphological alterations that result in elevated blood pressure and renal dysfunction in adult life. renal function and morphology; renal apoptosis; renal oxidative stress; early renal fibrosis

Experimental studies indicate that angiotensin II (ANG II) through its type 1 receptor (A[T.sub.1]) promotes cardiovascular hypertrophy and fibrosis. Therefore, the aim of this study was to analyze whether chronic long-term inhibition of the renin-angiotensin system (RAS) can prevent most of the deleterious effects due to aging in the cardiovascular system of the normal rat. The main objective was to compare two strategies of ANG II blockade: a converting enzyme inhibitor (CEI) and an A[T.sub.1] receptor blocker (A[T.sub.1]RB). A control group remained untreated; treatment was initiated 2 wk after weaning. A CEI, enalapril (10 mg*[kg.sup.-1]*[day.sup.-1]), or an A[T.sub.1]RB, losartan (30 mg*[kg.sup.-1]*[day.sup.-1]), was used to inhibit the RAS. Systolic blood pressure, body weight, and water and food intake were recorded over the whole experimental period. Heart, aorta, and mesenteric artery weight as well as histological analysis of cardiovascular structure were performed at 6 and 18 too. Twenty animals in each of the three experimental groups were allowed to die spontaneously. The results demonstrated a significant protective effect on the function and structure of the cardiovascular system in all treated animals. Changes observed at 18 mo of age in the hearts and aortas were quite significant, but each treatment completely abolished this deterioration. The similarity between the results detected with either enalapril or losartan treatment clearly indicates that most of the effects are exerted through A[T.sub.1] receptors. An outstanding finding was the significant and similar prolongation of life span in both groups of treated animals compared with untreated control animals. losartan; enalapril; heart; aorta; life span

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with [Ca.sup.2+] channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg*[kg.sup.-1]*[day.sup.-1], SHR + Los), amlodipine (3 mg*[kg.sup.-]*[day.sup.-1], SHR + Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR + Los and WKY. In SHR + Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR + Los. In kidney mitochondria from SHR and SHR + Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR + Los and WKY. In SHR and SHR + Amlo, mitochondrial [H.sub.2][O.sub.2] production was higher than in SHR + Los and WKY. Renal glutathione content was lower in SHR + Amlo relative to SHR, SHR + Los, and WKY. In SHR and SHR + Amlo, glutathione was relatively more oxidized than in SHR + Los and WKY. Tubulointerstitial [alpha]-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of [AT.sub.1]-receptor antagonists. kidney disease; nitric oxide; mitochondria; oxidative stress; hypertension

The brain, heart, kidney and erythrocytes of mice treated with angiotensin converting enzyme inhibitors (ACEi) were analyzed to determine the effects of ACEi on tissue antioxidant defenses. Analysis of mucine kidney medulla, heart and erythrocytes after pretreatment with enalapril or captopril indicated the presence of elevated CuZn-superoxide dismutase (SOD) activity. The mucine tissues also exhibited enhanced nonenzymatic antioxidant capacity due to ACEi-induced synthesis of antioxidants.

The mitochondrial DNA undergoes certain modifications during the process of aging, altering the amount of the DNA present in the cell. These effects are a counter response to the influence of angiotensin-converting enzyme (ACE) inhibitors on the cellular structure and function in the physiology of CF1 experimental mice. It is postulated that modifications in mitochondrial calcium pathways activate angiotensin II, causing it to modulate the activity of mitochondrial steroidogenic enzymes. ACE inhibition in some animals leads to an enhancement in the number of mitochondria. It alters their natural aging mechanism by rendering them less susceptible to sclerosis and increases their life span, thus elucidating the role of renin-angiotensin.