Multifaceted Mechanisms of Vascular Calcification in Aging

Abstract

Approximately 20% of the world’s population will be around or above 65 years of age by the next decade. Out of these, 40% are suspected to have cardiovascular diseases as a cause of mortality. Arteriosclerosis, characterized by increased vascular calcification, impairing Windkessel effect and tissue perfusion, and determining end-organ damage, is a hallmark of vascular pathology in the elderly population. Risk factors accumulated during aging affect the normal physiological and vascular aging process, which contributes to the progression of arteriosclerosis. Traditional risk factors, age-associated diseases, and respective regulating mechanisms influencing vascular calcification and vascular stiffness have been extensively studied for many years. Despite the well-known fact that aging alone can induce vascular damage, specific mechanisms that implicate physiological aging in vascular calcification, contributing to vascular stiffness, are poorly understood. This review focuses on mechanisms activated during normal aging, for example, cellular senescence, autophagy, extracellular vesicles secretion, and oxidative stress, along with the convergence of premature aging models’ pathophysiology, such as Hutchinson-Gilford Progeria (prelamin accumulation) and Klotho deficiency, to understand vascular calcification in aging. Understanding the mechanisms of vascular damage in aging that intersect with age-associated diseases and risk factors is crucial to foster innovative therapeutic targets to mitigate cardiovascular disease. Visual Overview— An online visual overview is available for this article.

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

“…In this way, atherosclerosis, as well as aging or age-related atherosclerosis, causes vascular wall senescence and, as a consequence, VC-the final step of the pathology process. Increased VC in atherosclerosis produces numerous marked vascular effects, such as a reduction of tissue perfusion, which eventually causes end-organ damage, particularly in the elderly population [125].…”

Intermedin1-53 attenuates aging-associated vascular calcification in rats by upregulating sirtuin 1

“…Numerous studies have shown that risk factors accumulating during aging contribute to VSMC osteogenic differentiation and vascular calcification, such as increased levels of the cyclin-dependent kinase inhibitors p16 and p21, extracellular matrix remodelingrelated collagen deposition and elastin degradation, impaired DNA and increased levels of prelamin A and reactive oxygen species, and matrix vesicles released by injured endothelium [2][3][4][5]. Recently, reduced levels of aging-related calcification inhibitors such as matrix γcarboxyglutamic acid (Gla) protein (MGP), anti-aging and anti-calcification factor α-klotho and sirtuin 1 (sirt1), were found to greatly promote vascular calcification [6][7][8][9][10].…”

“…Our previous research showed that exogenous IMD1-53 may attenuate CKD-associated vascular calcification by upregulating α-klotho and vitamin D3 plus nicotine (VDN)-induced vascular calcification by increasing MGP in young rats [6,7]. In addition, IMD1-53 treatment could improve vascular function by increasing endothelial nitric oxide synthase activity [25] and inhibiting reactive oxygen species production [26], which may affect vascular aging [4]. However, whether IMD inhibits aging-associated vascular calcification is unclear.…”

Aortic calcification in patients with rheumatoid arthritis and ankylosing spondylitis: a cross-sectional case-control study

“…Aging attributes to vascular calcification through multifaceted mechanisms [19]. Several researchers reported similar results that advanced age and FBG were independently related to aortic calcification in non-rheumatic population [20][21][22][23].…”