Atherosclerosis and Age

Have a minute? Good because that might be all it takes to save your life. There are many biological processes that contribute to aging that includes changes at the cellular level that occurs as we mature. Some are inevitable as we age and there are many others that do not have to be a definitive part of our aging plan. There are wide varieties of conditions such as Atherosclerosis that contributes to excessive inflammatory and fibro-proliferative processes that will affect the arteries. Atherosclerosis kills about a half a million people every year.

Yet such deaths can be avoided through developing effective therapies to prevent the transition from largely benign age-related vascular changes to pathological atherosclerotic degeneration. Efficient removal of DNA damage can prevent the initiation and progression of atherosclerosis by avoiding the development of vascular cell senescence and/or apoptosis. Atherosclerosis is defined as being a degenerative disease of the arteries characterized by patchy thickening of the inner lining of the arterial walls, caused by deposits of fatty material (Collins English Dictionary, 2009).

Aging and atherosclerosis have something in common and that is, they share several biochemical pathways and similar vascular alterations. Cellular senescence (process by which cells lose their ability to replicate after a finite number of cell divisions) is linked to the pathogenesis of atherosclerosis. Endothelial cells and vascular smooth muscle cells, both derived from human atherosclerotic plaques, show a lower rate of cell proliferation in vitro and undergo senescence earlier than cells from normal vessels (Maria Andreassi, 2008). Page 2

Consequently, every single person with atherosclerosis has endothelial dysfunction. A normal artery wall consists of three layers a thin smooth layer (tunica intima) that lines the inside of the artery that helps blood flow, a muscular elastic layer (tunica media) that helps the pulse circulates blood, and a tough outer layer (tunic adventitia) that protects the artery. Endothelial cells prevent toxic, blood-borne substances from penetrating the smooth muscle of the blood vessel. As we age many atherogenic factors, if left unchecked damages the delicate endothelial cells.

Endothelial dysfunction allows lipids and toxins to penetrate the endothelial layer and enter smooth muscle cells. This results in the initiation of an oxidative and inflammatory process that starts the development of plaque deposits. The body tries to prevent the invasion of LDL-C from entering the artery walls by activating Macrophages to consume the LDL-C. The Macrophages become enlarged cholesterol enriched cells called Foam Cells that are embedded in the cell walls. The artery walls become saturated with Foam Cells known as Fatty Streaks in the vessel walls.

As the Fatty Streaks grow, the body tries to protect the artery from them by surrounding them in the fibrous capsule and it is at this stage that the growth is called plaque. Undoubtedly, DNA plays a pivot role in Atherosclerosis. DNA strands break and chromosomal damage presents itself in the circulating cells in individuals with Atherosclerosis. DNA damage is present in the human atherosclerotic plaque ranging from “macro” damage, including deletions or additions of whole chromosomes or parts of chromosomes, to “micro” damage, which includes loss of heterozygosity and micro-satellite instability (mutations in DNA regions that may

Page 3 affect gene expression), DNA strands breaks and modifications of DNA (including oxidation) or DNA adducts, DNA adducts are covalent adducts between chemical mutagens, and DNA. Such couplings activate DNA repair processes, and unless repaired prior to DNA replication, may lead to nucleotide substitutions, deletions, and chromosome rearrangements, (Andreassi, 2008). The accumulation of DNA damage may be a critical mechanism, able to accelerate senescence of vascular cells in atherosclerosis.

One example is Werner Syndrome (WS), caused by a heritable mutation in the WRN gene, encoding both a helicase and an exonuclease and playing a role in suppressing genomic instability. WRN protein appears to be involved in DNA recombination, replication, repair and transcription, as well as in maintaining telomere integrity (telomeres are special DNA regions located at the ends of eukaryotic chromosomes that prevent chromosomal fusion by cellular DNA repair processes, offering genomic integrity and stability, (Andreassi, 2008).

Cultured somatic cells from patients with WS display an elevated somatic mutation rate and a variety of cytogenetic abnormalities, such as deletions and translocations. Furthermore, other progeroid syndromes, such as Cockayne syndrome and Hutchinson-Gilford Progeria syndrome, prematurely develop atherosclerosis, (Andreassi, 2008). There’s no doubt that, progressive telomere shortening during ageing is a characteristic of most adult somatic cells, which exhibit very weak or undetectable telomerase activity.

In contrast to adult somatic cells, germ, stem and tumor cells maintain high telomerase activity, long telomeres and high proliferative potential. Telomeres are thought to cap chromosome ends by virtue of their ability to form a protected end structure. It is believed that telomere shortening destabilizes telomeric loops and as a consequence, increases the probability of telomere uncapping leading to a great risk for degradation, recombination and/or fusion by cellular DNA repair systems. Telomeric fusions create dicentric chromosomes, chromosome bridges, breakage and complex genomic rearrangements in the cells (Andreassi, 2008).

There is evidence that shows that telomere shortening occurs in patients with coronary heart disease. Atherosclerosis tends to happen through out the body. Reactive Oxygen Species (ROS) seem to be the most likely trigger of DNA damage and telomere dysfunction in atherosclerosis. Reactive Oxygen Species (ROS) serve as signaling molecules or could cause oxidative damage to the tissues. If and when ROS is increased it produces vascular dysfunction by causing endothelium-dependent vasodilatation and cell growth, migration, inflammation, secretion, extra cellular matrix protein production and apoptosis.

Importantly, several studies have shown that both oxidative mitochondrial DNA (mtDNA) mutations and progressive respiratory chain dysfunction are associated with atherosclerosis or cardiomypathy in human investigations and animal models of oxidative stress. This accumulation evidence suggests that mitochondria play a significant role in the regulation of cardiovascular cell function. In particular, vascular dysfunction may be linked to an increased mitochondrial ROS production affecting the integrity of mtDNA that, in turn lead to cellular senescence and death, causing atherosclerosis (Andreassi, 2008).

Atherosclerosis is very sneaky because the process of developing the disease begins early in life. The disease starts silently and by the time the symptoms occur, atherosclerosis is advanced and represents a serious problem. There are three serious diseases caused by atherosclerosis and each has its own warning signs. If a person develops Coronary artery disease, they might experience chest pain on exertion or angina. Individuals have complained about shortness of breath and fatigue. Another serious disease caused by atherosclerosis is cerebrovascular disease.

Individuals may have difficulty speaking or weakness on one side and are said to be symptoms of strokes or transient ischemic attack. Lastly, Peripheral arterial disease, the legs usually shows symptoms of poor circulation first. Pain in the calf muscles when walking is the most common symptom. Poor wound healing or decreased pulses in the feet are other symptoms, (WebMD, 2005-2013). The American Heart Association recommends seeing your doctor beginning at age 20 to routinely assess your risk for heart disease.

The rate of developing atherosclerosis accelerates in middle age, and so should your approach to reducing the risk. Risk factors (high blood pressure or cholesterol, diabetes, obesity, and smoking) become extremely important through these years. Everyone should see a doctor sometime soon after turning 40. He or she can assess your risk factors and provide a treatment plan. Exercise: If you’ve been sedentary most of your life, you don’t need to run marathons to get a benefit. Any activity is better than none. * Start slow and work up to 30 minutes of walking daily. * Take the stairs.

Walk up one flight, or down two. * At the grocery store, park the car at the far end of the lot and walk. * Take an extra lap around the mall before heading home. Diet: Ask each member of your family to choose a favorite (or least-hated) vegetable. Rotate through everyone’s favorite at dinnertime. Toss in a salad, and you’re well on your way to reducing your atherosclerosis risk. Cut back on the red meat, as well. Keep meat portions small (the size of a deck of cards). Lean, skinless poultry is a great choice. Don’t use the excuse, “at my age, changing my lifestyle won’t make any difference. In fact, adopting a healthy lifestyle in middle age reduces the risk of death from atherosclerosis by two-thirds, (WebMd, 2005-2013). Diseases caused by atherosclerosis are the most common cause of death in the U. S. Since atherosclerosis is so widespread and so dangerous, you might ask: Why don’t we test everyone with the best tests we have? The one test that can directly show blocked arteries is called angiography. Angiography is an “invasive” test: * A thin tube is inserted inside an artery in the leg or arm. * It is then threaded through the body’s maze of branching arteries. Injected dye shows arteries — and any blockages — on a monitor, (WebMD, 2005-2013). In Conclusion, it is a fact that atherosclerosis and age are intimately linked. Its effects on the coronary, cerebral and peripheral arteries and the aorta which results in heart disease, stroke, and peripheral ischemia are the most important cause of disease and disability of old age. If we can figure out a way to control atherosclerosis, then we can save our elderly population. Until we do that however, we need to make sure that we exercise, eat healthy, and visit our doctor regularly.

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