A Review of Vascular Aging, with Thoughts on Reversing It

It seems to be a requirement that any review of what is known of the mechanisms of vascular aging must include a quote from Thomas Sydenham. You might compare the open access here with another noted earlier in the month, both of which feature that same quoted remark. Vascular aging is indeed an important component of age-related mortality, but we should expect two near future rejuvenation therapies to greatly improve matters, more so than has been possible through the medical advances of past decades, such as the introduction of statins.

Senescent cells and cross-links both contribute to vascular stiffness and chronic inflammation. Those two items drive much of the consequent dysfunction and progressive failure of the cardiovascular system. Fortunately, senolytic therapies are currently under development, involving numerous drug candidates and other approaches to clearance of senescent cells. In humans almost all of the persistent cross-links relevant to aging involve a single compound, glucosepane. Researchers are working on ways to break those links, with glucosepane as the target. Much of the research community continues to focus on aspects of vascular aging other than the root causes, however, focused on downstream changes. Progress will remain slower than it might be until that changes.

More than three centuries ago, a famous English physician and author, Thomas Sydenham, said "A man is as old as his arteries". This popular quote signifies a correlation between aging and the cardiovascular system including the susceptibility of this system to age-associated changes. Indeed, cardiovascular diseases such as atherosclerosis, hypertension, diabetes and heart attack are the leading causes of morbidity and mortality in the elderly population. In line with this, premature or normal aging is a major cardiovascular risk factor. About 40% of all deaths in the elderly (age 65 and older) are related to cardiovascular disease. The risk for cardiovascular morbidity between the ages of 50 and 80 increases by about 10-fold. Therefore, understanding the molecular and cell biological processes underlying age-associated structural and functional changes to the cardiovascular system including the heart and blood vessels is of significant importance.

The effect of aging on cardiovascular health is in part because aging perturbs a number of metabolic and hemodynamic mechanisms in the cardiovascular system in general and the vascular endothelium in particular. Some of these perturbations include increased oxidative stress and reduced telomere length resulting in DNA damage, impaired replicative capacity of cells and upregulated cardiovascular tissue senescence. These changes expose the heart and its vascular network to a series of risk factors that impair physiological repair mechanisms, and accelerate vascular dysfunction and cardiovascular disease.

Vascular endothelium, a diaphanous film of tissue, is the inner-most structure that coats the interior walls (tunica intima) of the cardiovascular and lymphatic systems. Endothelial dysfunction is one of the earliest indicators of cardiovascular disease. In line with this, the endothelium has emerged as one of the most important targets for the prevention and treatment of cardiovascular disease. Endothelial cells (ECs), mature or progenitor, are the building blocks of the vascular endothelium and are involved in active secretion of paracrine factors to modulate vascular homeostasis.

Unfortunately, aging exerts several pathological changes in the vascular system. The dysfunctional or aged endothelium is characterized by several phenotypic changes and molecular patterns that include impaired replicative capacity of cells, increased cellular senescence, reduced generation of anti-inflammatory molecules, antioxidants and other salutary mechanisms that are involved in vascular homeostasis. As a result, ECs lose their ability to proliferate and secrete vasoactive molecules. Several of the existing strategies attempt to restore key EC functions including production of nitric oxide (NO) - through exogenous supplementation or reactivation of cosubstrates and cofactors - and other vasodilators while decreasing inflammation, oxidative and nitrosative stress through antiinflammatory, antioxidants and restoration of eNOS coupling. However, these strategies have not been able to rejuvenate denuded or senescent endothelium in a meaningfully way.

In order to effectively overcome the exhausted number and function of mature ECs, endothelial lineage progenitors such as EPCs and endothelial colony-forming cells (ECFCs) may be isolated from circulation or from niches within the vascular wall and rejuvenated through ectopic expression of factors that halt senescence and other age-associated phenotypes. In this regard, transient extension of telomere length through non-viral and non-integrating approaches ex vivo is particularly appealing. This cell-based strategy may be combined with other mechanisms involved in the regulation of cellular senescence such as microRNA, senolytic drugs and/or new chemical entities that modulate DNA damage repair for preventative or therapeutic vascular rejuvenation.

Link: https://doi.org/10.4172/2161-1025.1000183


Has anyone tried to separate glucosepane effects from associated inflammation or plaque? Do crosslinks by themselves make arteries more brittle, weaker or prone to breaking? I would wonder if one bad effect could be dealt with apart from the other.

Posted by: chriszell at September 26th, 2017 8:39 AM

My understanding is the glucosepane is independent of plaque. Plaque can be prevented at least in some people while crosslinking will eventually get to you. Crosslinks make the arteries stiffer which increases blood pressure and probably other negative effects.

Posted by: gabor at September 26th, 2017 12:49 PM

Its pretty much all about the numbers. First, your good HDL should be above 60 (mine is 85). HDL carries bad oxidized LDL to the liver for disposal from the vascular system. Second, you should have a bilirubin level above 1.5 if possible (Mine is 2.3). Bilirubin is very strong antioxidant (10K stronger than glutathione, normally considered our best internal antioxidant) that coats the vascular endothelium, neutralizing oxidized particles like LDL and protecting against atherosclerosis and plaque. Third, you should have a lower than normal level of platelets (mine is 103K). How do I get these numbers? Well I have several genetic SNP's for high HDL. Then I also have Gilbert's Syndrome, a genetic condition that results in bilirubin levels 2 to 3 times higher than normal, and also results in platelet counts about 40% less than normal. What do you need all those damned platelets for? The more you have the more likely you are to get internal clots, more plaque, and more stenosis of arteries and veins which can result in increased risk of hear attacks and strokes. Perhaps in the future, CRISPR technology can transplant the good HDL and Gilbert's Syndrome SNP's to you.

Posted by: Biotechy at September 26th, 2017 2:39 PM

There is also elastin degradation, which is a programmed event, as elastin is produced mostly before and shortly after birth. When it is produced it adults it does not form elastic layers.
"The total elastin ranges from 58 to 75% of the weight of the dry defatted artery in normal canine arteries.[9] Comparison between fresh and digested tissues shows that, at 35% strain, a minimum of 48% of the arterial load is carried by elastin, and a minimum of 43% of the change in stiffness of arterial tissue is due to the change in elastin stiffness.[10]"
Elastin is replaced with collagen in the arteries, which is not nearly as good.
Additionally, elastic peptides which are formed from elastin degradation are toxic for the cells, so stoping elastin degradation should be the first line approach. However, we need a way to regenerate elastin as well

Posted by: Daria at October 2nd, 2017 5:41 AM
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