Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria?

Abstract

Protein and lipid oxidation-mainly by mitochondrial reactive oxygen species (mtROS)-was proposed as a crucial determinant of health and lifespan. Angiotensin II (Ang II) enhances ROS production by activating NAD(P)H oxidase and uncoupling endothelial nitric oxide synthase (NOS). Ang II also stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS blockade) increases survival and prevents age-associated changes. RAS blockade reduces mtROS and enhances mitochondrial content and function. This suggests that Ang II contributes to the ageing process by prompting mitochondrial dysfunction. Since Ang II is a pleiotropic peptide, the age-protecting effects of RAS blockade are expected to involve a variety of other mechanisms. Caloric restriction (CR)-an age-retarding intervention in humans and animals-and RAS blockade display a number of converging effects, i.e. they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease, and cancer; increase body temperature; reduce body weight, plasma glucose, insulin, and insulin-like growth factor-1; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H(2)O(2) production; and increase uncoupling protein-2 and sirtuin expression. A number of these overlapping effects involve changes in mitochondrial function. In CR, peroxisome proliferator-activated receptors (PPARs) seem to contribute to age-retardation partly by regulating mitochondrial function. RAS inhibition up-regulates PPARs; therefore, it is feasible that PPAR modulation is pivotal for mitochondrial protection by RAS blockade during rodent ageing. Other potential mechanisms that may underlie RAS blockade's mitochondrial benefits are TGF-β down-regulation and up-regulation of Klotho and sirtuins. In conclusion, the available data suggest that RAS blockade deserves further research efforts to establish its role as a potential tool to mitigate the growing problem of age-associated chronic disease.

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…In a previous review (101) we summarized data showing that, apart from retarding age-related alterations, CR and RAS-bl display a number of converging effects in rodents, primates, and humans, i.e., they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease, and cancer; increase body temperature; reduce body weight, plasma glucose, insulin, and IGF-I; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochon- Fig. 6.…”

Effects of exercise training on mitochondrial function in patients with type 2 diabetes

“…In addition, studies have investigated the effect of ACE inhibitors on insulin sensitivity and found divergent results, with either no effect [66] or an improvement [67] . It has previously been reported that Angiotensin Ⅱ receptor blockers (ARBs) have a positive effect on reactive oxygen species production and mitochondrial function in animals (for review see [68] ). It has been reported that ARBs have different effects on glucose homeostasis in hypertensive patients with the metabolic syndrome [69] .…”

The AGT M235T (RS699, 4072T>C) polymorphism is not associated with elite weightlifting performance

“…The RAS controls cardiovascular and renal functions, inflammatory cytokine and free radical production [4] as well as cell growth and proliferation [7]. M235T (rs699, 4072T>C) is a missense polymorphism that leads to T to C transition at position 4072 in exon 2 and results in a replacement of the amino acid methionine (M) by threonine (T) at residue 235 of the mature AGT.…”