The research I'll point out today is an investigation of some of the detailed mechanisms by which the immune cells called macrophages fail in their tasks and as a result cause the bulk of the pathology of atherosclerosis, a disease in which fatty plaques build up in blood vessels. The cardiovascular system deforms and remodels over the years as a result of these deposits, contributing to hypertension and related issues, but the more dangerous outcome is for sections of a plaque to break off and block blood vessels, leading to serious injury or death due to loss of the oxygen supply to critical tissues.
Atherosclerosis starts with very small-scale irritations of the blood vessel wall caused by the presence of damaged lipid molecules, such as those generated by the small population of dysfunctional cells that have been overtaken by broken mitochondria. This population grows with age as ever more mitochondria become randomly damaged in just the right way to spread within their cell, and so does the level of damaged lipids in the bloodstream, from this and other sources. If that was all there was to atherosclerosis, however, we probably wouldn't consider it a significant threat in comparison to everything else that can fall apart in aging. The small battles fought as cells cleaned up damaged lipids probably wouldn't rise to the level of killing people.
The real reason that atherosclerosis is a dangerous medical condition is that macrophages attempt to clean up the lipids and macrophages are weak. They have a limited capacity to digest damaged lipids and other debris resulting from the presence of damaged lipids in a blood vessel wall. Their cellular recycling mechanisms, the lysosomes, become overwhelmed and the macrophage cells die. That creates more debris, which attracts more macrophages. Small areas of damage can thus spiral out of control into battlegrounds marked by growing inflammation and fatty plaques composed of the remains of countless macrophages, lured in to their doom. None of this would happen if macrophages were indomitable, capable of digesting much, much more of the problem lipids and other wastes.
It is possible to create indomitable macrophages? In principle of course. Somewhere in the future lies the mass production of diamondoid medical nanorobots, each thousands of times more effective than evolved cells at a few specific tasks, such as digesting damaged lipids or macrophage remains. But if thinking of the near future, the bounds of the possible are much more limited. Efforts to alter cells to produce better, artificial operational states that do not appear in nature have proven slow and expensive, and produce largely marginal results where there is any success in this direction. The best outcomes to date have come from coercing cells into adopting existing naturally occurring states and patterns of behavior that are more helpful to the present situation - see stem cell medicine, for example. Trying to build a better macrophage, an entirely new state of cellular operation, by iterating on the present design is not likely to stop atherosclerosis, though with great effort it is probably possible to modestly slow its progression.
To my eyes, the better and more cost-effective approach is that of periodic repair after the SENS model for the treatment of aging, which in this case means cleaning up after this macrophage-induced disaster on a regular basis and before the debris builds up to pathological levels. The approach taken to date is to find natural enzymes capable of breaking down the materials of atherosclerotic lesions and plaques. Graveyards are not seeping lipid compounds, so we know that bacteria in the soil can digest these problem molecules. Somewhere in that vast and largely uncharted range of bacterial species can be found the basis for drugs to clear out damaged lipids and the remains of doomed macrophages. This is in fact the longest running SENS rejuvenation research program, and not so long ago the first candidate bacterial enzymes were licensed to Human Rejuvenation Technologies for commercial development; we'll have to wait and see how that goes.
Repair remains a minority position in the research community, though hopefully not for too much longer as good results from other repair approaches such as senescent cell clearance start to emerge. Most researchers would first seek to build a better macrophage, a model with a more resilient garbage disposal system:
In atherosclerosis, plaque builds up on the inner walls of arteries that deliver blood to the body. Researchers suggest this accumulation is driven, at least in part, by processes similar to the plaque formation implicated in brain diseases such as Alzheimer's and Parkinson's. A look behind the scenes in the process of plaque accumulating in arteries, the new study is the first to show that another buildup is taking place. Immune cells attempting to counteract plaque formation begin to accumulate misshapen proteins. This buildup of protein junk inside the cells interferes with their ability to do their jobs. "In an attempt to fix the damage characteristic of atherosclerosis, immune cells called macrophages go into the lining of the arteries. The macrophage is like a firefighter going into a burning building. But in this case, the firefighter is overcome by the conditions. So another firefighter goes in to save the first and is likewise overcome. And another goes in, and the process continues to build on itself and worsen."
The researchers showed that this protein buildup inside macrophages results from problems with the waste-disposal functions of the cell. They identified a protein called p62 that is responsible for sequestering waste and delivering it to cellular incinerators called lysosomes. To mimic atherosclerosis, the researchers exposed the cells to types of fats known to lead to the condition. The researchers noted that during atherosclerosis, the macrophages' incinerators become dysfunctional. And when cells stop being able to dispose of waste, p62 builds up. In a surprise finding, when p62 is missing and no longer gathers the waste in one place, atherosclerosis in mice becomes even worse.
The researchers also found these protein aggregates and high amounts of p62 in atherosclerotic plaque samples taken from human patients, suggesting these processes are at work in people with plaque building up in the arteries. "That p62 sequesters waste in brain cells was known, and its buildup is a marker for a dysfunctional waste-disposal system. But this is the first evidence that its function in macrophages is playing a role in atherosclerosis." In atherosclerosis, and perhaps in the brain disorders characterized by protein accumulation, such evidence suggests it would be better to focus on ways to fix the cells' waste-disposal system for getting rid of the large protein aggregates, rather than on ways to stop the aggregates from forming.
The release of proinflammatory cytokines, such as IL-1β, by macrophages increases the size and number of atherosclerotic plaques. Macrophages in atherosclerotic plaques have a defect in autophagy, a process that eliminates dysfunctional proteins, and it has been shown that p62, a chaperone protein involved in autophagy, sequestered polyubiquitinated proteins in cytoplasmic inclusion bodies in macrophages. Macrophages lacking p62 released more IL-1β, and one of the proteins required for the production of IL-1β partially colocalized with these inclusion bodies.
In a mouse model of atherosclerosis, p62 deficiency increased macrophage infiltration in atherosclerotic plaques and exacerbated atherosclerosis. Thus, enhancing the function of p62 to promote the sequestration of polyubiquitinated proteins could prevent macrophages from exacerbating atherosclerosis.