**3. Oxidative stress in aging-associated cardiovascular disease and cancer**

#### **3.1 Oxidative stress and aging-associated cardiovascular disease**

Decreasing in absolute number of cardiomyocytes due to increased apoptosis and necrosis and decreasing in repopulation of cardiomyocytes from cardiac stem cell reserves were occurred in aging heart [49, 50]. The increase in oxidative stress due to the increase in ROS production with age results in an overall enhancement in the rate of cardiomyocyte death with age. With advancing age, we accumulate mutations in our somatic cells. The expression of such factors as p53, p21, p16, senescenceassociated β-galactosidase activity and phosphorylation status of γ-H2Ax are widely used to detect the DNA damage. These biomarkers of aging can be used in cardiac tissue to assess how modulation of longevity genes influences the rate and degree of cardiovascular aging at the cellular level [51, 52].

Many aging-associated CVDs including ischemia/reperfusion, hypertensive heart disease and diabetes are related to oxidative stress and that will exhibit cytokines. In addition, increased ROS-responsive signaling pathways are objective by inflammatory oxidative stress and ROS generative system like unfolded protein response of the endoplasmic reticulum or NADPH oxidase activation [53].

The Apoptosis signal-regulating kinase 1(ASK1)-signalosome regulates p38 MAPK and SAPK/JNK and NFκB signaling networks promote senescence (in vitro) and aging (in vivo, animal models and human cohorts) in response to oxidative stress and inflammation leading to age-associated CVDs. Furthermore, their inhibition delays the onset of these CVDs as well as senescence and aging [53, 54].

The Energy generation from mitochondria is through oxidative phosphorylation and will also increase in ROS production which leads to free radical–imposed damage to macromolecules and cellular component. p66Shc, a mitochondrial adaptor, plays an important role in the generation of ROS and as a molecular effector which may explain how aging is connected with CVD and metabolic disease [55]. Several studies show that increased p66Shc expression with time may promote ROS accumulation with subsequent deregulation of pathways implicated in mitochondrial dysfunction, fat accumulation, insulin resistance and diabetes [56–58].

The AMPK-SIRT1 pathway is involved in energy metabolism in cell. The functional AMP-activated protein kinase (AMPK) is a heterotrimer consisting of a catalytic alpha (α), a regulatory gamma (γ) and a scaffolding beta (β) subunit and is activated by low cellular energy status [59]. AMPK activates eNOS, and facilitates autophagy and mitophagy, thus preventing mitochondrial insufficiency, inflammation and cellular death [60]. Sirtuin 1 (SIRT1) is a NAD+ -dependent class III histone deacetylase (HDAC) that mediates the effects of caloric restriction on lifespan and metabolic pathways in various organisms. SIRT1 prevents cardiovascular aging by activating of eNOS [61].
