The largest cause of human mortality is cardiovascular disease. Further, looking beyond all of the deaths clearly defined as a failure of the cardiovascular system - such as stroke, heart attack, heart failure, and so forth - it is the case that vascular aging contributes to the progressive dysfunction of organs throughout the body, and thus to death by many other causes. Narrowing of blood vessels due to atherosclerosis deprives energy-hungry tissues of the nutrients and oxygen that they need. Stiffness of blood vessel walls disrupts the finely balanced feedback mechanisms that govern blood pressure, giving rise to the chronically raised blood pressure of hypertension. Hypertension in turn causes pressure damage to delicate tissues throughout the body, accelerating the dysfunctions of aging. That "a man is as old as his arteries" is as true in spirit now as it was in the 1600s when Thomas Sydenham first said as much.
What can be done about vascular stiffening? Clearing senescent cells and reducing inflammatory signaling should help with some of the dynamic dysfunction in the smooth muscle responsible for contraction and relaxation of blood vessels. Finding ways to break persistent cross-links in the vascular extracellular matrix will also hopefully prove to be useful. The real challenge will be restoration of elastin and its relationship with collagen in the extracellular matrix, as elastin is largely only deposited during the developmental period of life. The structure of elastin is complex and the details of that complexity matter when it comes to the structural properties of tissue, such as elasticity. This likely means that sophisticated control over the cell populations capable of depositing elastin will be needed in order to rejuvenate the extracellular matrix in this way, and all too little work in that direction has been undertaken to date.
The mechanisms of increased stiffness in aging are both extracellular and cellular. The three main aortic wall components, elastin, collagen, and smooth muscle cells, vary along the length of the aortic tree. With aging, these components of the aortic wall are altered. The number of elastic fibers and smooth muscle cells in the tunica media decrease, while collagen fibers increase with advancing age. The number of smooth muscle cells in the tunica media decreases with age and vascular smooth muscle cell migration from the tunica media thickens the intima.
The most important mechanism studied as a cause of age-related increases in vascular stiffness is alteration in the extracellular matrix (ECM), resulting from an increase in collagen and decrease in elastin. The ECM is composed of a complex network of different matrix proteins, metalloproteases, and glycosaminoglycans, which are also responsible for the structural integrity of the vasculature, and therefore contribute to its stiffness. Collagen is a very stiff protein with the function of limiting vessel elasticity and distension, and is therefore fundamental to defining the stiffness of the arterial wall. Collagen deposition throughout the vasculature increases with age, which alters the normal ECM network. This has been shown to occur in the intima, media, and adventitia of the vessel wall leading to substantial changes in its morphology and function. In addition to increased collagen deposition, there is also increased non-enzymatic glycation. This is also responsible for age-related increases in arterial stiffness, as it induces collagen cross-linking, which increases stiffness.
Unlike collagen, elastin, the other major ECM protein, provides flexibility and extensibility of the vessel wall. Elastin fibers are mainly found in the medial layer of large elastic arteries and are oriented around smooth muscle cells and collagen. Degradation of elastin fibers with aging is mediated by the increases of proteolytic enzymes, e.g., matrix metalloproteases (MMP), which degrade elastin fibers, resulting in an increase in collagen/elastin ratio, which in turn increase vessel wall stiffness. Nevertheless, the extent to which increases in collagen and decreases in elastin contribute to increased vascular stiffness with aging remains controversial.
Calcification of the vessel wall occurs with normal aging, reducing the vessel wall's distensibility. In humans there is a direct correlation between aortic calcification and arterial stiffness. Calcinosis of arterial walls with aging has been associated with increased cholesterol content in the elderly, suggesting a relationship between these processes. However, it is unknown which process occurs first, although some have speculated that calcinosis increases interaction with cholesterol molecules in the arterial wall. Increases in oxidative stress that occur with aging, mainly due to decreases in mitophagy and autophagy, stimulate vascular calcification by activating several signaling cascades. One of the best studied signaling pathways involves the upregulation of bone morphogenetic proteins due to increases in oxidative stress, which results in increased vascular calcification.
The vascular endothelium is the innermost, monolayer of cells in blood vessels. When the endothelium is healthy, vascular tone is regulated by a balance of vasoconstriction and vasodilation; the latter controlled by nitric oxide (NO) release. Reduced bioavailability of nitric oxide leads to endothelial dysfunction, resulting in impaired vasodilation, which increases arterial stiffness. Endothelium impairment and decreased NO bioavailability occur with normal aging, ultimately leading to a proinflammatory, vasoconstrictive state, resulting in increased vascular fibrosis and arterial stiffness. Furthermore, endothelial dysfunction leads to an increase in oxidative stress through an increase in the production of superoxide causing damage to the vessels leading to changes in hemodynamics. Recently, it has also been proposed that autophagy, the cellular housekeeping mechanism that maintains cellular homeostasis, decreases in the aging endothelium, further leading to increases in oxidative stress. This was further confirmed with the use of a pro-autophagy treatment, which reduced arterial stiffness and oxidative stress in aged mice.
Vascular smooth muscle cells (VSMCs) have recently been discovered as important contributors to age-related increases in arterial stiffness. This increased VSMC stiffness is due to the direct relationship between VSMCs and endothelial cells. Endothelial cells regulate vascular tone mainly through the release of nitric oxide. This reduces active tone of VSMCs, which counteracts the increase in wall shear stress that occurs with both aging and high blood pressure. However, aging also leads to a decrease in the number of cells within the vascular wall due to a decrease in cell proliferation with age. Multiple mechanisms mediate the decrease of VSMCs with age, but most notably inflammation and calcification, which increase VSMC apoptosis. In humans, the VSMCs lost with aging are replaced by collagen fibers in the media of the arterial wall, resulting in increased vascular stiffness.