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.