Fight Aging!

Atherosclerosis is the growth of fatty plaques in blood vessel walls, eventually growing to the point of narrowing vessels to reduce blood flow. Rupture of a plaque can cause a downstream blockage, and this is the cause of heart attack and stroke. As a result, atherosclerosis is the largest cause of human mortality. This remains the case even today because present approaches to the treatment of atherosclerosis do not reliably produce any sizable reduction in plaque size, and are very slow to remove enough plaque lipids to reduce risk of rupture by stabilizing the plaque structure. Available approaches have near entirely focused on reducing inflammation and lowering the transport of cholesterol via LDL particles, but this only modestly slows plaque growth and modestly reduces risk of rupture. New approaches capable of reversing the disease are very much needed.

Like every other dysfunction in the body, atherosclerosis interacts with other aspects of aging and age-related disease processes. In today's open access paper, researchers conduct a tour of some of the better explored relationships between atherosclerosis and other common age-related conditions. In some cases there are shared mechanisms driving both conditions, in other cases there is good reason to think that one condition helps to accelerate the development of the other. Certainly, even without the ability of atherosclerosis-induced reduction of blood flow to make other conditions worse, there is reason enough for greater funding to be devoted to new approaches to treatment.

Association between atherosclerosis and the development of multi-organ pathologies

Atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) has long been known to be associated with the development of various multiorgan pathologies characterised by chronic inflammation, oxidative stress, and dyslipidaemia. However, the significant advances made over the past decade have greatly expanded our understanding of how atherosclerosis-associated pathological changes affect the metabolism of vascular cells in different tissues and organs. It is challenging to distinguish the specific pathways affected by atherosclerosis, as many of the adverse effects associated with atherosclerosis are also attributed to the manifestation of other closely related conditions (such as metabolic syndrome, diabetes mellitus, obesity and others) that share common risk factors with atherosclerosis (primarily hypertension, dyslipidaemia, smoking, advanced age, stress, genetic factors and many others).

A strong association has been established between atherosclerosis and ischemic stroke, with napkin-ring sign plaques, a 'spotty' pattern of plaque calcification, and elevated serum levels of aldosterone, C-reactive protein, and ELAVL1 protein being potent stroke biomarkers. Interestingly, atherosclerosis and Alzheimer's disease have been shown to promote each other through several pathways. Notably, the well-studied C/EBPβ/AEP signalling pathway has been demonstrated to connect atherosclerosis and AD through ApoE-mediated vascular dysfunction. Additionally, the ε4 allele of the ApoE gene has been associated with more severe forms of atherosclerosis and a higher rate of cognitive decline in Alzheimer's disease.

Furthermore, chronic kidney disease (CKD) and atherosclerosis have been shown to exacerbate one another. Kidney dysfunction increases the accumulation of certain uraemic toxins, which impair the antioxidant system, increase reactive oxygen species (ROS) generation and promote oxidative damage, thereby exacerbating vascular dysfunction and the development of atherosclerosis. On the other hand, the rupture of atherosclerotic plaques can release cholesterol crystals into the bloodstream, which can become lodged in arterioles, leading to ischaemia and infarction in various tissues and organs, including the kidneys. Similarly, atherosclerosis and kidney stones have been linked through dyslipidaemia and oxLDL accumulation. Atherosclerosis-like responses to inflammation and perivascular calcification have been shown to promote kidney stone formation. Kidney stones, in turn, up-regulate a wide range of atherosclerosis-promoting genes (such as adhesion molecules, extracellular matrix molecules and pro-inflammatory cytokines), which increase the risk of ASCVD.

The role of atherosclerosis in pancreas dysfunction has been mechanistically explained by atherosclerosis-mediated reductions in blood flow to the pancreas, which causes islet hypoxia and β-cell dysfunction. Finally, dyslipidaemia, hypertension, endothelial dysfunction and a hypercoagulable state have been proposed as the major risk factors linking thyroid dysfunction and ASCVD. In vivo and in vitro experiments have demonstrated that thyroid hormones directly activate the expression and production of pro-inflammatory cytokines and adhesion molecules. In particular, TSH has been shown to aggravate vascular inflammation and promote atherosclerosis development.

The results discussed suggest that regular monitoring and timely treatment of atherosclerosis-related vascular risk factors may be a valuable strategy for treating and preventing Alzheimer's disease, pancreas and thyroid dysfunctions, kidney stones, and CKD. On the other hand, the pathologies of many organs may manifest through ASCVD, complicating diagnosis and treatment and potentially leading to life-threatening conditions. Overall, further studies deciphering the diverse mechanisms by which atherosclerosis is associated with multiple organ pathologies would help generate new therapeutic strategies to mitigate the adverse effects of atherogenesis on other organs.