Chronic Inflammation as Proximate Cause of a Large Fraction of Age-Related Disease

This popular science article discusses at length the chronic inflammation that is characteristic of the old, and its role as a proximate cause of age-related disease. Inflammation is a necessary part of the immune response to injury and pathogens, and when present in the short term it is vital to the proper operation of bodily systems. But when the immune system runs awry in later life, and inflammatory processes are constantly running, then this inflammation corrodes metabolism, tissue function, and health.

The causes of excess, constant inflammation are both internal and external to the immune system. Internally, the supply of new immune cells falls off with age as the thymus atrophies and hematopoietic stem cell populations decline; this leads to an immune system made up of increasingly damaged, malfunctioning cells. Externally, much of the inflammation of aging is the result of signals secreted by lingering senescent cells, and removal of this inflammation is a primary reason why senolytic therapies produce rejuvenation and longevity when tested in animal models. Addressing these causes of inflammation will be an important aspect of rejuvenation therapies in the years ahead.

In 2007, researchers already knew that exercise reduces the risk of cardiovascular disease as much as cholesterol-lowering statin drugs do. By analyzing biomarkers in the blood of 27,055 women participating in a long-term study, and other objective measures, they hoped to tease out how much of the benefit was attributable to improved blood pressure, to lower body weight, or to something else. "We were actually surprised that reduced inflammation was the biggest explainer, the biggest contributor to the benefit of activity, because we hadn't hypothesized that. We knew that regular exercise does reduce inflammation over the long term, but we also knew that acute exercise transiently increases inflammatory biomarkers during and immediately after exertion." About a third of the benefit of regular exercise, they found, is attributable to reduced inflammation. The anti-inflammatory effect of exercise was much greater than most people had expected. That raised another question: whether inflammation might also play a dominant role in other lifestyle illnesses that have been linked to cardiovascular disease, such as diabetes and dementia.

In 2017, two cardiologists, who suspected such a link, published the results of a human clinical trial which involved more than 10,000 patients in 39 countries, and was primarily designed to determine whether an anti-inflammatory drug, by itself, could lower rates of cardiovascular disease in a large population, without simultaneously lowering levels of cholesterol, as statin drugs do. The answer was yes. But the researchers went a step further, building into the trial additional tests seeking to clarify what effect the same anti-inflammatory drug, canakinumab, might have on illnesses seemingly unrelated to cardiovascular disease: arthritis, gout, and cancer. Only the researchers themselves, and their scientific colleagues, were unsurprised by the outcome. Lung cancer mortality dropped by as much as 77 percent. Reports of arthritis and gout also fell significantly.

In medicine, believing something is true is not the same as being able to prove it. Because the idea that inflammation - constant, low-level, immune-system activation - could be at the root of many noncommunicable diseases is a startling claim, it requires extraordinary proof. Can seemingly unconnected illnesses of the brain, the vasculature, lungs, liver, and joints really share a deep biological link? Evidence has been mounting that these common chronic conditions - including Alzheimer's, cancer, arthritis, asthma, gout, psoriasis, anemia, Parkinson's disease, multiple sclerosis, diabetes, and depression among them - are indeed triggered by low-grade, long-term inflammation. But it took that large-scale human clinical trial to dispel any lingering doubt: the immune system's inflammatory response is killing people by degrees.

Now the pertinent question is why, and what can be done about it. The pharmaceutical industry is deeply interested in finding ways to stop inflammation with medicines like canakinumab, an orphan drug that blocks a specific pro-inflammatory pathway called IL-1beta. But some researchers suggest that the inflammatory process - a normal and necessary part of the natural immune response - has itself has been misunderstood. Scientists know that the process can be turned on and off, but have only recently understood that this doesn't mean normal physiology will resume once the inflammation caused by infection, injury, or irritant has been shut down. Instead, the restoration of health is an active phase of the inflammatory process itself, facilitated by a little-known class of molecules called pro-resolving mediators - the protectins, resolvins, maresins, and lipoxins - brimming with marvelous, untapped, regenerative capacities.



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