Aging can be seen as process characterized by accumulation of oxidative stress induced damage. Oxidative stress derives from different endogenous and exogenous processes, all of which ultimately lead to progressive loss in tissue and organ structure and functions. The oxidative stress theory of aging expresses itself in age-related diseases. Aging is in fact a primary risk factor for many diseases and in particular for cardiovascular diseases and its derived morbidity and mortality. Here we highlight the role of oxidative stress in age-related cardiovascular aging and diseases. We take into consideration the molecular mechanisms, the structural and functional alterations, and the diseases accompanied to the cardiovascular aging process.
In addition to being a common denominator to many chronic disease manifestations, oxidative stress-induced endothelial dysfunction is the key mechanism linking aging to increased risk of clinical cardiovascular disease and death . As we age, the continuous imbalance between the generation of ROS—which increases progressively—and the ability of endogenous anti-oxidant defense mechanisms—which becomes increasingly reduced—results in reduced NO bioavailability and impaired vasodilatory function . Longitudinal studies conducted in long-lived and very long-lived cohorts, including “centenarians” have demonstrated the undeniable role of genetic variations in the regulation of the oxidative stress response in aging , referred to as the capacity of triggering various regulatory processes in response to oxidative stress. Among the antioxidant enzymes, Soerensen and colleagues  showed that a major role in longevity seems to be attributed to manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPX1), indicating that variation in these genes may affect human life span.
In age-related cardiovascular diseases, a prominent role of sirtuins has also been thoroughly explored. Sirtuins (Sirt) belong to class III histone deacetylases that have been associated with aging for their nicotinamide adenine dinucleotide (NAD+)-dependent enzymatic activity. Seven sirtuin family members have been identified so far, denoted as Sirt1-Sirt7, each of which displays differential subcellular localizations: Sirt1, 6, and 7 are localized in the nucleus, Sirt2 is cytosolic, Sirt3 to Sirt5 are found in the mitochondrial compartment, the major source of intracellular ROS . Many existing studies have demonstrated a protective role of the sirtuins against both accelerated vascular aging and atherosclerosis . For instance, Sirt1 deficiency increases oxidative stress, inflammation, and foam cell formation and induced the senescence of endothelial as well as vascular smooth muscle cells. In support of this notion, using human vascular smooth muscle cells (VSMC) isolated from donors (from 12 to 88-year-old subjects), Thompson and colleagues  demonstrated an inverse correlation between the endogenous Sirt1 protein expression and the donor age. In an independent study conducted in 3763 subjects, the authors showed that homozygous minor allele genotypes within rs2841505 (Sirt5) and rs107251 (Sirt6) negatively influenced survival, whereas homozygous minor allele genotypes within rs511744 (Sirt3) were associated with an increased lifespan . Furthermore, while partial Sirt1 deletion in atherosclerotic mice enhanced atherogenesis , Sirt1 overexpression reduced atherosclerotic plaque formation in ApoE−/− mice following 10 weeks of high-fat diet feeding . In an attempt to investigate the molecular mechanisms behind the role of Sirt1 in inducing lifespan expansion, deletion of Beclin 1/Autophagy protein (Atg) 6 was found to abrogate longevity in C. Elegans . In fact, besides being implicated in a variety of cellular processes, including energy metabolism cell stress response and cell/tissue survival, recent studies have also identified a role for sirtuins in the regulation of autophagy, a cellular housekeeping process, which is critical for the maintenance of tissue homeostasis during aging, particularly cardiac and vascular health . For example, in response to cellular stress, including caloric restriction, Sirt1 upregulated the expression and directly deacetylated several Atg proteins, including Atg7 and Atg8, thereby inducing autophagy . Likewise, Sirt1-null mice have increased basal acetylation of autophagic proteins and a reduced autophagy function . In addition, knockdown of Sirt1 prevented the induction of autophagy by its indirect activator resveratrol and by nutrient deprivation in human cells . Acting in a distinct manner from that of Sirt1, Sirt3 also regulated autophagy both positively and negatively. In particular, it has been reported that Sirt3 overexpression activated the mammalian target of rapamycin complex 1 (mTORC1), a consistent inhibitor of autophagy. In addition, Sirt3 gene silencing promoted autophagy and protected human hepatocytes from lipotoxicity . In contrast, by inducing autophagy, Sirt3 prevented ischemia-induced neuronal apoptosis in cortical neurons cells . Recent findings have also reported the beneficial role for Sirt6-mediated autophagy against cardiovascular diseases . Indeed, using an in vitro model, Sirt6 reduced the formation of foam cells through an autophagy-dependent pathway, thus suggesting the protective role of Sirt6 in preventing atherosclerosis .
The mitochondrial adaptor protein p66Shc is another key determinant of aging since its genetic deletion induces stress resistance and prolongs lifespan by 30% . The mammalian SHC locus encodes for three different isoforms carrying a Src-homology 2 domain. Owing to its unique N-terminal region, p66Shc is the only protein playing a critical role in redox metabolism . Genetic deletion of p66Shc has been shown to reduce the production of free radicals in the brain, improve stroke outcome, and preserve neurological function in an ischemia-reperfusion injury model . In patients with acute ischemic stroke, p66Shc expression was transiently increased and correlated with short-term neurological outcome . Furthermore, p66Shc has also been involved in hyperglycemia-associated changes in endothelial function. In a mouse model of streptozotocin-induced diabetes, deletion of p66Shc protein protected mice against oxidative stress-induced endothelial dysfunction as well as lipid peroxidation in aortic tissue .
By modulating the expression of several antioxidant enzymes, the proto-oncogene JunD has been suggested as a potential target to prevent ROS-driven age-related cardiovascular diseases; indeed, JunD knockout mice exhibited impaired endothelium-dependent relaxation and reduced life span . Conversely, in vivo JunD overexpression rescued age-induced endothelial dysfunction . Moreover, low levels of JunD have been reported in monocytes of old healthy subjects when compared with young individuals, and the decrease was correlated with the expression of scavenging and oxidative enzymes .
Bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) has recently emerged as another molecule with important role in regulating aging and longevity. Recent studies have shown the role of a polymorphic variant in the gene encoding BPIFB4 in determining exceptional longevity in 3 independent populations . In addition, homozygous carriers of the so-called longevity-associated variant (LAV)-BPIFB4 exhibited higher circulating BPIFB4 levels and increased eNOS activity in circulating mononuclear cells . In line with these findings, circulating BPIFB4 levels were closely linked with the health status of long-living individuals . Interestingly, LAV-BPIFB4 gene transfer decelerated frailty progression in aged mice and homozygous LAV-BPIFB4 haplotype inversely correlated with frailty in elderly subjects .
Growing evidence suggests microRNAs (miRNA) as critical regulators of aging and cardiovascular disease . Acting at the post-transcriptional levels, these small non-coding RNA molecules are able to negatively regulate gene expression by inducing mRNA degradation or translational repression of their targets .
First discovered in Caenorhabditis elegans, several miRNAs have been found to both positive and negatively regulate longevity through canonical pathways during aging, including insulin signaling, heat-shock factors (HSFs), AMP-activated protein kinases (AMPKs), mitogen-activated protein kinases (MAPKs), sirtuins, target of rapamycin (TOR), and mitochondria. Because miRNAs and aging signaling pathways are conserved across species, from nematodes to humans, studies on C. Elegans have provided clues to understanding mechanisms of age-related processes. For example, it has been shown that adult-specific loss of argonaute-like gene-1 activity resulted in a shorter lifespan when compared with that of wild-type . Furthermore, a loss-of-function mutation in lin-4 and gain-of-function mutants of its target lin-14 displayed a reduced lifespan, which was rescued to a significant extent by knockdown of lin-14 only during adulthood . Van Almen et al. found decreased miR-18 and miR-19 levels in aged heart failure-prone mice when compared to age-matched controls . Importantly, these findings were also confirmed in cardiac biopsies of idiopathic cardiomyopathy patients at old age, where decreased miR-18a, miR-19a, and miR-19b expression was associated with severe heart failure . Together with increased ROS production, miR-21 was found to be upregulated in heart, liver, kidney, and aorta of spontaneous hypertensive rats (SHR). Interestingly, exposure to exogenous miR-21 was able to lower blood pressure levels in the SHR rats, indicating miRNAs as novel potential therapeutic target in hypertension . Among the most studied miRNAs, circulating levels of miR-126, miR-130a, miR-142, miR-21, and miR-93 have been found to be associated with human aging . For example, miR-21 level is increased with aging process and aging associated-diseases, but its expression level decreased in individuals aged over 80 and in centenarians, suggesting the beneficial effects of low levels of miR-21 for longevity . Menghini et al. found that miR-217 is widely expressed in aged but not young endothelial cells, and that its overexpression can induce endothelial cell senescence formation, thus suggesting the involvement of miR-217 in the pathogenesis of cardiovascular diseases . Finally, using PCR arrays, Smith-Vikos et al.  identified multiple differentially expressed microRNA in serum samples from individuals who had documented lifespans from 58 to 92. Interestingly, six of these circulating miRNAs significantly correlated with subsequent longevity, suggesting that these miRNAs may serve as useful biomarkers of human aging .
Along with findings from several clinical trials that have failed to show long-term improvement with antioxidants , the above studies suggest the importance of directly acting on upstream signaling rather than adopting strategies to scavenge formed ROS to delay age-related disease onset.