Damage to the joint from sever arthritic inflammation often requires a hip replacement.
Inflammation is what gives us that response. It serves as all-purpose protection against invaders and traumatic damage. To take a simple scenario, suppose you are bitten by a cat. First, coagulation factors promote clotting in order to stanch bleeding and prevent germs from spreading from the wound site. A menagerie of phagocytes, which swallow and destroy pathogens, surge out of the bloodstream and squeeze into the affected tissue, engulfing bacteria and secreting cytokines—messenger proteins that send out the call for more responders. The phagocytes also generate reactive oxygen species, unstable compounds that chew up bacteria as well as damaged human tissue.
At the same time, other switches get flipped throughout the body, modifying everything from metabolism to cell growth, via other cytokines, such as IL-6 and tumor necrosis factor–a, and things like CRP, which mark bacteria for destruction. The specialized adaptive immune response eliminates any remaining germs.
So far, so good. But the inflammation response can kick in even when there’s no invader. Atherosclerosis, or hardening of the arteries, is a classic example. In response to fatty deposits on the walls of the arteries, a type of phagocyte called a macrophage identifies the growing lesions as trouble spots and infiltrates them, swelling and destabilizing the deposits. Those lesions can then break open, resulting in the formation of a blood clot that can clog blood vessels and cause heart attacks. The more active the macrophages are, the more CRP is in the bloodstream, and the more likely the lesions will break open, block your arteries, and kill you.
The evidence that inflammation is behind other diseases is indirect, but it is mounting. Researchers have long known that in patients with Alzheimer’s, the areas of the human brain clogged with senility-associated plaques also bristle with inflammatory cells and cytokines. Modern research has found that cytokines block memory formation in mice. In diabetes, inflammation and insulin resistance apparently track together, and drugs that effectively restore insulin sensitivity also appear to reduce inflammatory factors like IL-6 and CRP. Inflammation is also being investigated by a group at Leiden University in the Netherlands as a culprit in declining lung function, in osteoporosis, and in old-age depression. Even the weakness of old age may have an inflammatory cause: Ferrucci has found that inflammatory activity breaks down skeletal muscle, leading to the loss of lean muscle mass. Being fat makes all these diseases strike earlier, and that seems to be at least in part because fat cells spur more inflammation.
These findings have provided researchers with a totally new appreciation of how subtly inflammation can work and how wildly awry it can go over time. It’s not about “a massive infection or a welt the size of an egg because you got hit in the head with a two-by-four,” Tracy says. “Inflammation also goes on at a much lower level.” As it simmers in the background, over years and decades, collateral damage accumulates—in the heart, in the brain, everywhere. Harvey Jay Cohen, chairman of the department of medicine and director of the Center for the Study of Aging at Duke University Medical Center, likens inflammation to “little waves lapping on the shore. It’s a relatively low level of activity, one that sustained over time wears away at the beach and stimulates other bad events.”
Evolution has designed into us a cruel trade-off: What saves us in the short term kills us over the long haul. As we get older, acute episodes of inflammation tend to turn into chronic ones, perhaps because the regulation of the immune system becomes less efficient. Inflammatory factors in the blood can increase two- to fourfold. Chronic infections may be partly to blame. Although we usually don’t know it, nearly all adults are infected with the Epstein-Barr virus, and at least 60 percent of us with cytomegalovirus. These two pathogens can stay in our bodies in a latent state, hiding out in our cells. But Ronald Glaser, a viral immunologist at Ohio State University Medical Center and his research partner (and wife), psychologist Janice Kiecolt-Glaser, think that these viruses are not fully dormant. They’ve found evidence (pdf) that with age, antibodies to these viruses increase, indicating a reawakened virus and an active immune response.
Early experiences may also influence the way that inflammation affects an individual’s aging, says Caleb Finch, a neurobiologist and gerontologist at the University of Southern California. Analyzing historical birth and death records from 19th-century Europe, he and Eileen Crimmins, a gerontologist and sociologist at the University of Southern California, found that longevity is directly related to exposure to childhood disease. Children born during years of high neonatal mortality who survived to adulthood didn’t live as long as those born in healthier years. The reason, he says, is inflammation: A high infectious burden in childhood results in a high inflammatory burden in adulthood, which results in a shorter, sicker life. Conversely, Finch believes that people in affluent countries now live so long because their childhoods are free from diseases like measles, typhoid, malaria, whooping cough, and worms. Without these diseases, people grow bigger and stronger—and live much longer.
Looking beyond provocative findings like those in Finch’s study, Tracy and other researchers on aging say that it may be too simplistic to think of inflammation in terms of straightforward cause and effect. Instead we must think of human biology as a group of interdependent systems. “Is inflammation a response to aging, or is it causing aging or disease?” Tracy asks. “My answer is: Yep, yep, yep. It does all those things. There’s no other way to think about it—it’s both cause and response to what’s going on.”
Inflammation is not uncontested as a theory of aging. There are many competing hypotheses. Yet inflammation reinforces some more than others, potentially establishing a plausible constellation of mechanisms responsible for aging.
