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7-Ketocholesterol as a Contributing Cause of Multiple Age-Related Diseases

One noteworthy difference between the biochemistry of young and old individuals is a greater presence of oxidative molecules, resulting from dysfunctional cells, inflammatory processes, and other issues. As a consequence, there are also many more oxidized molecules, changed from their original structure and now either broken or actively harmful. Cells clear out this sort of oxidative damage constantly, and are quite efficient at this sort of maintenance until levels of oxidization become high, but they nonetheless struggle with some particularly toxic or resilient oxidized molecules, even in smaller amounts. A good example of the type is 7-ketocholesterol, a form of oxidized cholesterol. It is primarily understood as an important contributing cause of atherosclerosis via its detrimental effects on the macrophages responsible for clearing lipids from blood vessel walls, but there is evidence for it to contribute to other age-related conditions as well.

Cholesterols exist both inside and outside of the cell, as they are important components of all cellular membranes, but these and other nonpolar substances are transported in the plasma via lipoproteinparticles. Low density lipoprotein (LDL) is the principle carrier of cholesterol to peripheral tissue. All of the components of LDL are susceptible to oxidation to produce an oxidized form of LDL (OxLDL). OxLDL has been linked to a variety of pathologies. Oxidation of the cholesterol in LDL produces several oxidation products including 7-ketocholesterol (7KC), which is the most abundant oxysterolpresent in OxLDL. We believe that it is important to distinguish between the effects of OxLDL and that of unsequestered 7KC, as many studies fail to account for this important difference in how 7KC interacts with the cell. OxLDL is not the only source of 7KC within the body. 7KC can be produced endogenously by a series of oxidation or, much less commonly, enzymatic reactions. It can also be ingested directly in food, however the liver is well equipped to process and rid the body of exogenous toxins, so 7KC is not acutely poisonous to ingest. However, endogenously produced, unsequestered 7KC can wreak havoc inside of most cells. Unesterified 7KC can be found within membranes of organelles where it disrupts fluidity and signaling pathways, causing cellular damage via multiple stress-response pathways. These stress-response pathways induce a vicious cycle by increasing the population of reactive oxygen species, which in turn increases the oxidation of cholesterol and production of 7KC. Particularly in people with already-compromised cholesterol pathways, 7KC buildup can be overwhelming and cause significant damage to membranes, pathways, and overall cell function. 7KC is the most abundant oxysterol in both oxLDL particles and atherosclerotic plaques, indicating the significant role 7KC plays in the progression of atherosclerosis. 7KC has been shown to induce macrophage reprogramming, foam cell formation, and oxiapoptophagy in a multitude of cell types. In atherosclerotic plaques, this results in the deposition of calcium-laden apoptotic bodies, leading to subsequent calcification of the blood vessel. It has been shown that oxysterols are likely a cause of altered brain cholesterol metabolism which is an integral part of Alzheimer's disease, Parkinson's disease, and other aspects of neurological aging. It is not yet fully understood whether 7KC can cross the blood-brain barrier, but 7KC is highly toxic to neuronal cells and should certainly form spontaneously inside of them with age. Additionally, 7KC is implicated in macular degeneration as it is a major component of the drusen within the retina. 7KC can also damage the liver by disrupting membrane rafts and fenestrations. Lastly, 7KC is also characterized in congenital disorders such as sickle cell, Niemann Pick, and other lysosomal storage disorders. Ambiguous links between many of these diseases, particularly atherosclerosis and neurodegeneration, further implicates 7KC as an unexplored target in many diseases. We propose that 7KC could be an effective therapeutic target due to its implication in a wide variety of diseases. Although the abundance of 7KC has not yet been strongly correlated to aging or the severity of different pathologies, there is clear evidence to show its destructiveness in biological systems. As more studies are conducted on toxic oxysterols in aging and disease, we hope that more will become known about 7KC abundance in different cells and tissues. This would increase the potential of 7KC as a therapeutic target for various diseases, especially those specifically associated with aging. Considering nonenzymatic oxysterol accumulation, particularly 7KC, as an integral factor in disease progression could change the way we identify and treat these diseases, offering new and possibly broadly effective therapeutics.
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