Two Recent Review Papers on the Aging of Blood Vessels

Today I'll point out a couple of recently published open access papers that discuss aspects of arterial aging. The age-related decline of blood vessel structure and function is one of the more important aspects of aging, given that it is at present a largely one-way road to cardiovascular disease and death. Despite the efforts of the research community over past decades, which have included the noteworthy success story of statins, and an ongoing reduction in cardiovascular mortality rates, this remains the principal cause of age-related death in humans. To a first approximation, old humans die when the heart or blood vessels fail. The many other age-related causes of death taken together make up a minority of overall late-life mortality.

Perhaps the most important aspect of blood vessel aging is loss of elasticity. The stiffening of major blood vessels is enough on its own to break the feedback mechanisms that control blood pressure, causing progressively worsening hypertension. Increased blood pressure causes the heart to become larger and weaker, and also increases the rate at which pressure-related damage and blood vessel rupture occurs in more delicate tissues. Stiffening of blood vessels is probably primarily caused by cross-linking in the extracellular matrix, but evidence suggests that senescent cell accumulation and the inflammation generated by these cells also plays a role. These errant cells promote calcification in blood vessel walls, which can also contribute to loss of elasticity. There are also other mechanisms to consider, such as disruption of the normal processes by which blood vessel smooth muscle controls dilation and constriction of blood vessels - separately from stiffening, that can produce similar problems in regulation of blood pressure.

Rising blood pressure on its own is bad, and will ultimately cause death via heart failure. This is made much worse, however, by the progression of atherosclerosis. This is the generation of fatty deposits that narrow and weaken blood vessel walls: high blood pressure plus weakened blood vessels is a recipe for a fatal rupture. Even without that, the fat deposits become unstable and can break off inside the blood vessel to produce a fatal blockage, a process that again is accelerated by higher blood pressure. Atherosclerosis is the result of an unfortunate inflammatory feedback loop. Lipids become oxidatively damaged in ever greater amounts with advancing age, enter the bloodstream, and then irritate the blood vessel walls. Cells respond with an inflammatory response that draws in macrophages to clean up the unwanted lipids, but the macrophages can become overwhelmed and die. That in turn creates debris that calls in more macrophages, generates a larger inflammatory response, and makes the problem worse. The atherosclerotic plaques in aged blood vessels are inflamed graveyards of countless cells, surrounded by ever more cells in the process of adding their corpses to the mass.

In the SENS rejuvenation research viewpoint, all of these problems can be addressed with suitable forms of repair, granting natural repair processes enough breathing room to fix the remainder. Cross-links can be removed via suitable cross-link breakers, pharmaceuticals current in the early stages of development in programs such as that running at the Spiegel Lab at Yale. Senescent cells can be cleared out via senolytic therapies, presently under development by a number of companies. The various forms of damaged lipid, such as 7-ketocholesterol, can be identified and small molecule drugs developed to safely break them down. Many of the errant macrophages crowding around plaques can be targeted and removed to stop them making matters worse, as they have become senescent and can be targeted with senolytics. All of these are plausible near future treatments.

The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis

Atherosclerosis is the most significant human health problem globally. We know today that the disease does not follow a simple, unidirectional progression, and is determined by a myriad of pathways, control mechanisms, and repair processes; these encompass multiple inflammatory molecules, bone marrow (BM)-derived progenitor cells, a range of immune cells such as specific monocyte subpopulations, genetic mutations, and epigenetic modifications among numerous other participants both known and those yet to be discovered. Ultimately, however, the clinical result for an immensely large number of individuals is the formation and growth of vascular lesions with the potential to rupture, leading to life-threatening conditions. It is imperative to continue to evolve technological strategies to both predict and detect the formation, progression, and clinical status of these atherosclerotic plaques, while additional details are elucidated regarding the process of disease progression.

One example of important progress has been made in the control of inflammation when inflammation is no longer promoting repair, but instead has taken a damaging role for the artery. It was recently reported that a monoclonal antibody against IL1-beta, when injected systemically to patient with cardiovascular disease and high inflammatory index, is capable of reducing risk for coronary events, even with already reduced lipids and had no further effect on lipid levels. The role of inflammation is increasingly established in the progression of arterial lesions, and it is useful to consider inflammation in the context of arterial homeostasis.

Arterial repair is triggered and controlled by molecules that belong to inflammatory pathways. However, as was hypothesized and subsequently demonstrated in an animal model, the progression of atherosclerotic inflammation is modulated by the presence or the absence of an efficient repair process. In the presence of BM vascular progenitor cells capable of arterial repair, the artery heals and inflammatory signals subside and vanish. However, reductions in the availability of BM-derived vascular progenitor cells occurring as a consequence of aging or genetic susceptibility (exhaustion or dysfunction) result in a lack of arterial healing.

These reductions can occur either because repair-capable cells are no longer produced effectively by the BM, because the produced cells have become dysfunctional, or a combination thereof. Consequently, inflammatory signals do not subside and vanish, and indeed are heightened to the point where they attract and support monocytes/macrophages and other immune competent cells that further enhance arterial injury. Hence, the maintenance of arterial homeostasis is a complex process that must balance injuries to the arterial wall, inflammatory processes required for triggering and supporting arterial repair, and the renewal of BM-derived vascular progenitor cells that are necessary for such repair.

The Role of MicroRNAs in Arterial Stiffness and Arterial Calcification

Arterial stiffness is a characteristic feature of normal arterial aging, but is also associated with accelerated cardiovascular disorders. Another age-related process is arterial calcification, which in turn is a known risk predictor that increases morbidity and mortality in cardiovascular diseases. MicroRNAs (miRNAs) are small non-coding RNAs that downregulate their target gene expression post-transcriptionally. They are widely studied in recent years and their role in cardiovascular dysfunction is to some extent revealed. Identification of over- or underproduction of miRNAs could be therapeutic targets for prevention and treatment of vascular diseases.

Arterial stiffness results from complicated interactions between multiple components of the vessel wall, including extracellular matrix (ECM) composition, vascular smooth muscle cell (VSMC), and endothelial dysfunction. Collagen and elastin are the most important structural proteins of ECM and key regulators of arterial stiffness as they are responsible for blood vessels' strength and elasticity. Reconstruction of ECM, notably increased levels of aberrant types of collagen and reduction of elastin, appears to be the most important mechanism contributing to arterial stiffness. Matrix metalloproteases (MMPs) are endopeptidases which degrade all kinds of ECM proteins. Thus they play a significant role in arterial stiffness via regulating collagen and elastin levels in ECM.

Moreover, advanced glycation end products (AGEs) contribute to arterial stiffness through cross-linking with ECM proteins, including collagen, which reduces vessel's flexibility. Furthermore, many hormones and cytokines are involved in aortic stiffness, such as angiotensin II (Ang II) which promotes arterial stiffness through regulating signaling pathways that result in altered ECM accumulation and increased vascular tone. Apart from structural abnormalities, VSMC proliferation, migration and calcification, as well as impaired endothelium-dependent dilation through paracrine molecules such as nitric oxide (NO) and endothelin are, also, implicated in the development of arterial stiffness.

Extensive research during the last decade confirmed the association of miRNAs with cardiovascular diseases. MiRNAs seem to play a significant role in arterial stiffness and calcification through modulating critical pathways and molecules such as TGF-β and BMP signaling, Ang II, MMP activity, Runx, and phenotypic switch of VSMC. Thus, they may be used as therapeutic targets or diagnostic markers in the future to decrease arterial stiffness and prevent the development of cardiovascular diseases. However, it is more than obvious that the molecular biology and pathophysiology is very complex. Many miRNAs might have the same target gene (e.g., Runx2 is suppressed by miR-30b-c but enhanced by miR-32), while a single miRNA might exert multiple functions by targeting more than one genes and affecting different pathways with opposing results (e.g., miR-29, miR-19b and their role in fibrosis). Futhermore, miR-145, one of the most important miRNAs in cardiovascular pathophysiology, decreases arterial stiffness by inhibiting TGF-β signaling while, on the contrary, TGF-β activates miR-145 to promote the contractile phenotype of VSMCs and reduce arterial stiffness as well. Targeting TGF-b through miR-145 might have controversial results. To conclude, additional clinical and laboratory research should be continued for the establishment of miRNAs as treatment targets and biomarkers of cardiovascular diseases.


In addition to this complex mixture of genetic interrelationships in the causes of cardiovascular diseases, we should also look for lifestyle causes such as sleep deprivation and stress. Various studies have shown that getting less than 6 hours of sleep greatly increases your cardiovascular and atherosclerotic disease risks, and consequent heart attacks, strokes and dementia risks. So don't take all this genetic mumbo-jumbo too seriously because you can't figure out all the interrelationships anyway. Getting less than 6 hours of sleep decreases your growth hormone level which is vitally needed to repair and restore your blood vessel endothelium. Without that, atherosclerosis and cardiovascular disease increase as you age, and beneficial genes are turned off, and inflammation genes begin to run rampant.

Posted by: Biotechy at February 3rd, 2018 8:55 AM

PS: It must be added that you need a strong redox system to protect your blood vessel endothelium too. That is why centenarians have higher levels of such antioxidants as catalase and superoxide dismutase. Certain genetic conditions may give you a strong redox system to protect the blood vessel endothelium too, namely moderately high bilirubin levels as occurs with Gilbert's Syndrome (GS). Bilirubin is a very strong lipophilic antioxidant that protects the blood vessel endothelium of those with GS that has a 0.5 all cause mortality risk compared to normal people. Too slow atherosclerosis, it helps to have a high HDL level above 70. My HDL level is about 85, and I have no calcium plaques in my arteries as I have had my arteries scanned with no evidence of these plaques.

Posted by: Biotechy at February 3rd, 2018 10:38 AM
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