I find this paper fascinating. Yes, it seems like we want is to rejuvenate eNOS (while over expressed iNOS might be a culprit in aging?).
" In aged endothelial cells, up-regulated iNOS, which may be associated with NF-κB-induced vascular inflammation, produces high levels of NO. NO reacts with cysteine residues of proteins (arginase in this example), forming S-nitrosothiol (-SNO)–arginase, which increases arginase activity and L-arginine consumption. NO directly reacts with ∙O−2 produced by uncoupled eNOS, and other vascular sources, generating the harmful reactive nitrogen specie peroxynitrite (ONOO−), which contributes to vascular dysfunction."
"Reduced NO bioavailability in aging is a consistent feature in experimental and clinical studies. Vascular aging is accompanied by reduced eNOS expression/activity or augmented breakdown of NO by ROS. In addition, senescent endothelial cells phenotype shifts toward an inflammatory state, with up-regulation of adhesion molecules, cytokines, and chemokines. This phenotype favors platelet aggregation and inflammatory cell adhesion, which may progress to thrombotic and atherosclerotic events. "
““The main vascular sources of ROS have been identified in aging: detaching mitochondria (Ungvari et al., 2010) and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase)””
" NO seems to be a key molecule to longevity and cardiovascular health. This concept was partially derived from studies addressing the cardiovascular function in mice that do not express at least one, a combination of two, or all NOS isozymes genes (nNOS−/−; iNOS−/−; eNOS−/−; n/iNOSs−/−; n/eNOSs−/−; i/eNOSs−/−; n/i/eNOSs−/−; Tsutsui et al., 2009). Accordingly, the survival rate of 10 month-old triple NOS knockout mice is reduced by ∼80%, mainly as a consequence of spontaneous myocardial infarction, coronary arteriosclerosis and mast cell infiltration in the coronary artery adventitia (Tsutsui et al., 2009). The role of each NOS is well established in some CVD. For instance, studies in mice models of atherogenesis demonstrated that eNOS and nNOS play protective roles, whereas iNOS is pro-atherosclerotic (Tsutsui et al., 2009). On the other hand, in particular conditions such as myocardial ischemia, iNOS up-regulation represents a compensatory molecular mechanism that protects myocardial cells from damage (Bolli, 2001). However, few studies have addressed whether chronic ablation of a specific NOS isoform affects lifespan. A role for eNOS in lifespan and spatial memory was suggested by a report showing that the survival rate of eNOS knockout mice was reduced by 50%. Those mice also exhibit decreased exploratory behavior at 18–22 weeks of age when compared to age-matched controls (Dere et al., 2002). In addition, it has been reported that caloric restriction extends lifespan. However, this effect was strongly attenuated in eNOS knockout mice (Nisoli et al., 2005). This implicates eNOS-derived NO as one of the mechanisms by which caloric restriction extends lifespan."!!
