Mechanisms of vascular aging: new perspectives

Abstract

This review focuses on molecular, cellular, and functional changes that occur in the vasculature during aging; explores the links between mitochondrial oxidative stress, inflammation, and development of vascular disease in the elderly patients; and provides a landscape of molecular mechanisms involved in cellular oxidative stress resistance, which could be targeted for the prevention or amelioration of unsuccessful vascular aging. Practical interventions for prevention of age-associated vascular dysfunction and disease in old age are considered here based on emerging knowledge of the effects of anti-inflammatory treatments, regular exercise, dietary interventions, and caloric restriction mimetics.

Figures

Figure 1.

Proposed scheme for pathways contributing to cellular oxidative stress and NF-κB activation in aged endothelial cells. In aged endothelial cells, increased levels of O2·− generated by the electron transport chain are dismutated to H2O2, which can penetrate the mitochondrial membrane increasing cytoplasmic H2O2 levels. H2O2 contributes to the activation of NF-κB, resulting in a proinflammatory shift in endothelial gene expression profile. Aging is also associated with upregulated expression of membrane-bound tumor necrosis factor-alpha (TNFα), which increases soluble TNFα levels in the vascular wall due to the action of TNFα-converting enzyme (TACE). In aged endothelial cells, increased levels of O2·− generated by NAD(P)H oxidases (stimulated by elevated TNFα levels and/or by the activated local renin–angiotensin system [RAS] in the vascular wall) decrease the bioavailability of NO by forming ONOO −. Lack of NO leads to vasodilator dysfunction and promotes endothelial apoptosis, whereas nitrative stress and increased H2O2 levels lead to poly(ADP-ribose) polymerase (PARP)-1 activation, which contributes to NF-κB-dependent gene transcription. Increased oxidative stress and chronic low-grade vascular inflammation increase the risk for the development of vascular diseases in the elderly patients.

Figure 2.

Proposed scheme for the mechanisms by which insulin-like growth factor-1 (IGF-1) confers antioxidative and anti-inflammatory vasoprotective effects in aging. During aging, increased mitochondria-derived reactive oxygen species (ROS) production enhances NF-κB activation, which promotes inflammatory cytokine and chemokine expression, microvascular endothelial activation, leukocyte adhesion, and extravasation. The ensuing inflammatory response contributes to the age-related decline of organ function (eg, heart failure and cognitive decline). The model predicts that IGF-1, via upregulating antioxidant enzymes and exerting mitochondrial protective effects, significantly attenuates mitochondrial oxidative stress in aging, resulting in inhibition of endothelial activation and vascular inflammation. IGF-1 also promotes progenitor cell function, improves NO bioavailability, and limits apoptotic cell death, which contributes to its microvascular protective effects. GH = growth hormone.

Figure 3.

Proposed scheme for the mechanisms by which caloric restriction and the caloric restriction mimetic resveratrol confers vasoprotection. In aging, calorie restriction and resveratrol induce/activate SIRT1 and upregulate eNOS in the endothelial cells promoting mitochondrial biogenesis, restoring cellular energetics, attenuating mitochondrial oxidative stress, improving endothelial function, attenuating apoptotic cell death, and inhibiting NF-κB. Caloric restriction and/or resveratrol may also activate Nrf2 (NF-E2-related factor 2). Nrf2 is translocated to the nucleus and binds to the antioxidant response element, which upregulates antioxidant enzymes, increases glutathione synthesis (upregulating γ-glutamylcysteine synthetase), and induces the NQO1-dependent transplasma membrane–associated redox system. The model predicts that there is an interaction between SIRT1 and activation of Nrf2-dependent ROS detoxification pathways.