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Increased Elastin Production as a Therapy for Age-Related Arterial Stiffening

Elastin, as the name might suggest, is an important structural molecule in the extracellular matrix of elastic tissues, such as blood vessels. Elastin content in blood vessel walls falls with age, alongside the stiffening of those blood vessels, though it is an open question as to the degree to which that is secondary to various mechanisms such as chronic inflammation, presence of senescent cells, and so forth. A very interesting study in mice from a few years ago demonstrated improved elasticity in the lung tissue of mice resulting from clearance of senescent cells, for example.

It is also an open question as to whether the reduction in elastin is as important as the cross-linking of molecules in the extracellular matrix when it comes to stiffening of blood vessels - absent the ability to selectively fix just one of these problems, firm answers will remain elusive. And that is before we consider other mechanisms such as calcification, probably also due in large part to the presence of senescent cells, or disrupted signaling that hampers the ability of smooth muscle cells in blood vessels to coordinate vasoconstriction and vasodilation.

The line of evidence constructed in the research results noted here is somewhat tenuous, since it was carried out in animal models of a genetic condition in which elastin levels are abnormally low, and with a focus on young patients rather than older individuals. It doesn't necessarily follow that because a boost in elastin production helped to restore blood vessel elasticity in this situation, then the same result will occur in old patients. Old blood vessels may have reduced elastin to some degree, but also have the range of other problems mentioned above. If there is a suitable drug candidate or other means of increased elastin production ready to go, as appears to be the case, then it would seem cost-effective to try it and see - but I'd wager on better results from cross-link breaking if this turns out to be a matter of significant investment in further research first.

Arteries in young, healthy humans and other mammals stretch easily because they contain a protein called elastin. Elastin is produced only during development, however, and is slowly lost with aging. Stiff arteries contribute to development of high blood pressure and significantly increase the risk of sudden death, stroke, myocardial infarction, and cognitive decline. "We know that genetic conditions, such as Williams-Beuren Syndrome (WS) and supravalvar aortic stenosis (SVAS), lead to abnormally low levels of elastin in developing arteries. As a result, children with WS or SVAS have stiff, narrow arteries and high blood pressure. Like older adults, they are also at increased risk of sudden death and stroke. We therefore tested whether a medicine called minoxidil would not only reduce blood pressure but also would help relax arteries and increase their diameter, thus improving organ perfusion."

Minoxidil is perhaps best known for its potential to improve hair growth when applied to the skin. In a different formulation, minoxidil is sometimes prescribed orally for high blood pressure that has not responded to other medications. Earlier studies have suggested that minoxidil may increase elastin deposition even in mature tissues. The research team conducted the work in experimental models of hypertension and chronic vascular stiffness associated with WS and SVAS. They used ultrasound imaging and magnetic resonance imaging-based arterial spin labeling to gauge minoxidil's impact on vessel mechanics, carotid and cerebral blood flow, and gene expression.

"Minoxidil not only lowered blood pressure, but also increased arterial diameter and restored carotid and cerebral blood flow. Minoxidil also reduced functional arterial stiffness and increased arterial elastin content. Equally important, these beneficial changes persisted weeks after the drug was no longer in the bloodstream. The sustained improvements and the increased elastin gene expression suggest that minoxidil treatment may help remodel stiff arteries. Such remodeling may benefit humans whose elastin insufficiency is due to either advanced age or genetic conditions."

Link: https://childrensnational.org/news-and-events/childrens-newsroom/2018/medicine-that-slows-balding-may-turn-stiff-vessels-supple-helping-vital-organs

Comments

ECM damage and dysfunction is literally the first sign of aging we see as people enter their 30's and 40's. Surely there is more to it than senescent cells or AGEs since there are so few at this age. What else is causing the ECM to lose its collagen, elastin, loss of subcutaneous fat and bone density? Even the best of those who stay out of the sun and have a great diet barely stave off this inevitable damage. Shouldn't this be a bigger focus?

Posted by: Nathan at March 21st, 2018 1:23 PM

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