In recent news, researchers have identified CD47, mainly of interest in cancer therapies up until this point, as a potential therapeutic target to diminish the vicious circle of mechanisms that causes fatty plaques to grow in blood vessel walls. Everyone suffers from this problem as they age, and it leads to the condition known as atherosclerosis. The plaques start as tiny areas of inflammation, spawned by an overreaction to damaged lipid molecules, but this can spawn a cycle of ever greater inflammation, futile immune system intervention, and cell death that produces a growing graveyard of cell debris and fats. The resulting plaque narrows and remodels its blood vessel, contributing to vascular stiffening and consequent hypertension that in turn results in other forms of cardiovascular disease. Ultimately, one or more plaques grow fragile and fragment, rupturing or blocking blood vessels to cause a stroke, heart attack, or similar likely fatal event.
The SENS rejuvenation research point of view here, as for all age-related disease, is to focus on root causes or other important differences between young and old tissues, and consider how to revert or block these changes in a narrow, targeted manner. For example, the damaged lipids that seed lesions in blood vessel walls arise in part as the end result of a lengthy Rube Goldberg chain of events that starts with forms of mitochondrial DNA damage. Therefore allotopic expression gene therapy to duplicate mitochondrial genes in the cell nucleus, and thus ensure that they can continue to supply necessary proteins even if damaged in the mitochondria, should reduce incidence of atherosclerosis. That experiment lies perhaps five to ten years in the future at the present time, depending on funding. Another SENS approach is to clear out the worst of the waste compounds in plaques that can overwhelm and kill the macrophage immune cells that are drawn in to clean up the mess. Macrophage death is an important component of the vicious cycle that causes plaques to grow once established, making it a beacon of inflammation that draws in immune cells to their death. If the cell death could be cut down, then the immune system could successfully clean up atherosclerotic plaques. Similarly, making macrophages much more resilient would also be helpful, and for exactly the same reasons.
At a high level the progression of atherosclerosis is fairly well understood, with the vicious cycle of inflammation and immune cell death sitting at the heart of it. At the detailed level of cellular mechanisms, however, there is a steady process of new discoveries as researchers find and map the blind spots. For example, the smooth muscle cells in blood vessel walls are now known to play a more active role than was once thought, and, considered overall, the various types and states of cells involved are not at all as clearly demarcated as was the case a decade ago. It is a complex process. That complexity is a good reason to focus in on specific mechanisms likely to disrupt the cycle - that cells arrive to clean up the mess, become overwhelmed, die, and add to the debris. Anything that keeps macrophages alive and working efficiently to remove the compounds making up the plaque should be beneficial.
Normally, as a cell approaches death, its CD47 surface proteins start disappearing, exposing the cell to macrophages' garbage-disposal service. But atherosclerotic plaques are filled with dead and dying cells that should have been cleared by macrophages, yet weren't. In fact, many of the cells piling up in these lesions are dead macrophages and other vascular cells that should have been cleared long ago. Researchers performed genetic analyses of hundreds of human coronary and carotid artery tissue samples. They found that CD47 is extremely abundant in atherosclerotic tissue compared with normal vascular tissue, and correlated with risk for adverse clinical outcomes such as stroke.
Much of what's now known about CD47's function stems from pioneering work in cancer research. In the late 1990s and early 2000s, researchers first identified CD47 as being overexpressed on tumor cells, which helps them evade destruction by macrophages. They went on to show that blocking CD47 with monoclonal antibodies that bind to and obstruct the protein on tumor cells restores macrophages' ability to devour those cells. Phase-1 clinical safety trials of CD47-blocking antibodies in patients with solid tumors and blood cancers are now underway.
In a laboratory dish, anti-CD47 antibodies induced the clearance of diseased, dying and dead smooth muscle cells and macrophages incubated in conditions designed to simulate the atherosclerotic environment. And in several different mouse models of atherosclerosis, blocking CD47 with anti-CD47 antibodies dramatically countered the buildup of arterial plaque and made it less vulnerable to rupture. Many mice even experienced regression of their plaques - a phenomenon rarely observed in mouse models of cardiovascular disease. Looking at data from other genetic research, the scientists learned that surplus CD47 in atherosclerotic plaques strongly correlates with elevated levels, in these plaques, of a well-known inflammation-promoting substance called TNF-alpha. Further experiments showed that TNF-alpha activity prevents what would otherwise be a progressive decrease of CD47 on dying cells. Hence, those cells are less susceptible to being eaten by macrophages, especially in an atherosclerosis-promoting environment. "The problem could be an endless loop in which TNF-alpha-driven CD47 overexpression prevents macrophages from clearing dying cells in the lesion. Those cells release substances that promote the production of even more TNF-alpha in nearby cells."