Forms of autophagy function to remove unwanted, excess, or damaged structures and other molecules in the cell. These materials are delivered to a lysosome, a membrane packed with enzymes capable of dismantling near every macromolecule a cell will encounter, producing raw materials for reuse. Autophagy is quite clearly connected to tissue function and aging in a number of ways. It appears to decline in quality with age, leading to downstream problems in cell and tissue function as worn and damaged component parts accumulate. Upregulation of autophagy for long periods of time is a feature of numerous interventions, such as calorie restriction and calorie restriction mimetics, that result in slowed aging.
In today's research materials, the team involved in developing autophagy-upregulating small molecule therapies at Life Biosciences discuss evidence for chaperone-mediated autophagy to be relevant in atherosclerosis. In atherosclerosis, fatty deposits build up in blood vessels as a result of macrophages becoming less capable of returning excess cholesterol to the blood stream. The chronic inflammation and oxidative stress of age disrupts the ability of macrophages sufficiently to allow atherosclerotic plaques to form in the first place, but once formed the plaque is a hostile environment that overwhelms macrophages with excess cholesterol.
Anything that improves macrophage resilience can help. It is actually not that hard to significantly slow the growth of atherosclerotic plaque in mice, and many methods work well. Small differences sustained over time add up. Reversal of atherosclerosis is a much harder problem, and the work involving increased autophagy noted here is not a demonstration of reversal, but rather just another demonstration of slowed atherosclerosis. In that sense, it is not that exciting; it is on a par with what can be done with drugs like statins that lower blood cholesterol. Lower blood cholesterol over a lifetime can halve the risk of dying due to atherosclerosis in humans, but statins as a treatment applied in old age are nowhere near that good at reducing cardiovascular mortality.
Chaperone-mediated autophagy (CMA) keeps cells functioning normally by selectively degrading the many proteins that cells contain. In CMA, specialized chaperone proteins bind to proteins in the cytoplasm and guide them to enzyme-filled cellular structures called lysosomes to be digested and recycled. Disrupted CMA allows damaged proteins to accumulate to toxic levels, contributing to aging and - when the toxic buildup occurs in nerve cells - to neurodegenerative diseases including Parkinson's, Alzheimer's, and Huntington's disease.
To investigate CMA's role in atherosclerosis, researchers promoted atherosclerosis in mice by feeding them a fatty Western diet for 12 weeks and monitoring CMA activity in plaque-affected aortas of the animals. CMA activity initially increased in response to the dietary challenge; after 12 weeks, however, plaque buildup was significant, and virtually no CMA activity could be detected in the two types of cells - macrophages and arterial smooth muscle cells - that are known to malfunction in atherosclerosis, leading to the buildup of plaque within arteries. Feeding the high-fat diet to mice totally lacking in CMA activity produced even stronger evidence of CMA's importance: plaques nearly 40% larger than those in control animals that were also on the high-fat diet.
The researchers genetically "upregulated" CMA in mice that were fed a pro-atherosclerotic, high-fat Western diet and later compared them with control mice fed the same diet for 12 weeks. The CMA-boosted mice had greatly improved blood lipid profiles, with markedly reduced levels of cholesterol compared with the control mice. Plaque lesions that formed in the genetically altered mice were significantly smaller and milder in severity compared with plaques in control mice.
Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to pro-atherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression.