How our aging immune system goes haywire
Danger stalks the body from without and within. For most of human evolution, the biggest killers have been foreign invaders — not other humans, but the microbial pathogens that mosquitoes inject into us (malaria, dengue, yellow fever) as well as countless other variously transmitted bacterial and viral pests.
But the gears have shifted. Medical and public-health advances have so vastly reduced the death toll from microbes that today’s leading killers spring from within. People are living long enough to acquire debilitating bug-free disorders such as heart disease, strokes, cancer, osteoarthritis, Type 2 diabetes and neurodegenerative syndromes such as Alzheimer’s.
A common element in all of these appears to be inflammation — not the intense, temporary, ad hoc (or, as immunologists say, acute) variety that’s actually helpful when you run a fever while you’re fighting off an infection, but another kind that’s stealthy, steady and pernicious, like a leaky faucet. It doesn’t seem like a big deal until the water bill comes.
With advancing age, there’s an escalating tendency for our immune system to go haywire. It becomes less capable of protecting us against infections and cancer or responding to vaccinations but, paradoxically, increasingly prone to wallowing in a state of vague, nonspecific irritation that’s called chronic low-grade inflammation.
Along with this progression — which immunologists have dubbed “inflammaging” — comes a growing vulnerability to disease.
If we knew why and how inflammaging occurs, we might be able to find ways to forestall or override it. For example, researchers at Stanford and elsewhere are gaining deeper insights into the inflammatory underpinnings of the world’s No. 1 killer, cardiovascular disease, leading to studies testing new treatments. Two huge national trials are now exploring whether anti-inflammatory medications used by patients with autoimmune diseases can prevent heart attacks and strokes.
Similar insights and ideas for treatments are emerging for other diseases of aging, too.
The two arms of the immune system
Many scientists theorize that a big factor in inflammaging, and the susceptibility to many diseases that comes with it, is that one of the immune system’s two arms — the “adaptive” immune system — is increasingly tied behind its back, leaving the other arm — the “innate” immune system — to pick up the slack.
We don’t hear that much about the innate immune system, which is present even in such evolutionary ancient organisms as sponges. We moderns couldn’t live without it, either. This arm of the immune system is fast and powerful, but hasty and somewhat indiscriminate.
We’ve perhaps heard more about the immune system’s slower to respond, but far more targeted, other arm: the adaptive immune system, which evolution has installed in us vertebrates to provide highly selective protection against infections and cancer while sparing healthy tissues. The adaptive immune system consists mainly of cells called lymphocytes.
Stated loosely, any given lymphocyte is narrowly focused on a particular biochemical shape or, in science-ese, “antigen.” Recognizing this specific antigen on a tumor cell or pathogen or in a vaccine, the lymphocyte proceeds to undergo round upon vigorous round of rapid-fire replication. But that lymphocyte will proliferate only in response to the antigen to whose shape it’s attuned.
“A healthy young adult’s body harbors billions of lymphocytes that, in the aggregate, can recognize 100 million different antigens,” says Jorg Goronzy, MD, professor of medicine, whose career has focused on the aging immune system. “But typically only a handful of those billions of lymphocytes are geared to respond to any given antigen.” When a pathogen appears on the scene, this handful has to turn into an army, meaning lymphocytes have to divide like crazy. It takes them days or weeks to fire up to full fighting strength.
“If you had to wait that long to be able to take on a pathogen, you’d be dead,” Goronzy says.
But you don’t. The innate immune system’s various constituent cell types all feature, both internally and on their surfaces, families of “pattern recognition” receptors that sense broad, generic signs of infection and injury: for instance, material smacking of bacterial cell walls, or DNA bearing telltale microbial sequences. These abundant, one-size-fits-all fighter cells can quickly sense the presence of a virus or bacterium and, without bothering to distinguish among the millions of varieties of each or needing to proliferate, respond swiftly, fiercely and wantonly, often inflicting collateral damage on healthy tissue.
That can spell trouble.
It’s not just a single invisible hand steadily turning up the inflammatory dial as the years go by, but many.
Like our closets, our bodies accumulate junk as we age. Garbage that can’t be metabolized piles up within aging cells or gets sloughed off alongside them. One job of innate immune cells known as macrophages (derived from the Greek words for “big” and “eater”) is to ingest and metabolize all that garbage, preventing dead and dying cells from throwing off inflammation-promoting substances. But macrophages’ garbage-gobbling gumption declines with age.
Meanwhile, chronic viral infections we accumulate — cytomegalovirus, Epstein-Barr virus, herpesviruses — are constantly challenging the immune system to a fight. Bacteria, trillions of which happily inhabit our intestines (where they usually do us much more good than harm) poke through our older, and therefore leakier, gut linings into the circulation, angering our innate immune system, which doesn’t know them and doesn’t like them. The body becomes an increasingly pro-inflammatory environment.
As we get older, our adaptive immune system gradually goes to seed. We end up with not enough different kinds of lymphocytes, and too many of some of the kinds that we do have. Every battle against a microbial foe or incipient tumor leaves behind milling masses of surplus immune warrior cells with time on their hands. That can foster autoimmune disease. A team led by Cornelia Weyand, MD, professor of medicine and chief of that department’s division of immunology and rheumatology, has identified a kind of lymphocyte whose job it is to keep other lymphocytes in check. This regulatory lymphocyte acts as a sort of military policeman that quiets down the adaptive immune system after it has been, however justifiably, in a state of battle readiness. With time, this class of regulatory lymphocytes begins to fail, leaving us with continuous, simmering inflammation. Weyand’s group has tied deficits in these cells’ capacity to do their policing to the likelihood and severity of strongly age-related autoimmune diseases such as giant-cell arteritis, a condition affecting one in 500 older people but never seen in people under age 50. The team is now analyzing blood from patients with cardiovascular disease to see if similar regulatory lymphocyte deficits play a major part in that far more common condition, as well. (Preliminary evidence suggests this may be the case, Weyand says.)
Meanwhile, as we age, it’s harder for the adaptive immune system to respond to novel pathogens. Our remaining lymphocytes — having encountered life’s continuing barrage of troubles — are increasingly dedicated to recognizing and responding to specific “remembered” antigens they’ve previously encountered, and less flexible in their aggregate ability to recognize and respond to novel antigens that characterize new tumor cells or pathogens. Also, lymphocytes in this jaded, battle-hardened state are more prone to spontaneously secrete inflammatory factors than when in their “naïve” state.
In short, there are many ways for people’s immune systems to go astray with age.
A case in point
Between a quarter and a third of all deaths in the United States are traceable to impaired flow of oxygen-rich blood to the heart (coronary heart disease) or the brain (stroke). The underlying process, atherosclerosis — the gradual buildup of plaques in our arteries — was once thought to be the simple result of eating too much fat, which was believed to coat the insides of our arteries and congeal into plaques that thicken over time, impeding circulation.
“But you don’t just gradually have circulatory shrinkage until you finally gasp for breath,” says Weyand. “Heart attacks and strokes occur all of a sudden. Why?”
Fatty substances are indeed a prime constituent of an arterial plaque, but there’s more than fat deposition going on there. For one thing, plaques are stuffed with a variety of dead or near-dead smooth-muscle and endothelial cells associated with blood-vessel walls.
Those plaques also contain lots of immune cells — chiefly macrophages, those “big eaters” that devour invading bacteria, debris and dead cells left behind after injury or infection.
Mature macrophages generally assume one of two personae. The gentler ones, called M2 macrophages, nibble dead cells and extracellular detritus, releasing healing factors that encourage new cell growth and stimulate blood flow, and otherwise overseeing tissue repair.
“Our body turns over more than 100 billion cells per day, every day,” says Nicholas Leeper, MD, associate professor of vascular surgery and of cardiovascular medicine. “Those cells all need to be cleared before they undergo a kind of death in which they release inflammatory material.” All hail the M2 macrophages.
So-called M1 macrophages, on the other hand, are pugnacious, proactive and perhaps a bit paranoid. They blow the whistle on infectious pathogens or suspected tumor cells, recruiting other types of immune cells to the scene and squirting out pro-inflammatory signaling proteins that act both locally and systemically to ramp up the entire immune system to high-alert status. They also attack the pathogens or tumor cells directly.
Cardiovascular catastrophes — heart attacks and strokes — now appear to be tripped off by macrophages, the very immune cells charged with clearing plaques.
The buildup of dead cells and fatty-plaque components in atherosclerotic lesions should normally be prevented by M2 macrophages’ garbage-disposal service. But with age, their job performance falls off, while M1-types’ activity ramps up. M1 macrophages’ unremitting secretion of inflammatory substances can render plaques brittle, increasing the risk that a chunk will break off and form a clot that can trigger a heart attack or a stroke.
In a study published in The Journal of Experimental Medicine in February, Weyand found that the macrophages of coronary artery disease and stroke patients have a defect that turns them into not only M1s, but sugar-holic M1s to boot. They slurp up too much glucose from the blood, ratcheting their internal metabolic activity into overdrive. That, in turn, prods them into churning out buckets of a pro-inflammatory substance called IL-6, which brings still more angry immune cells to atherosclerotic lesions and perpetuates an inflammatory vicious circle.
In a series of experiments with potential therapeutic implications, Weyand and her colleagues showed that several different biochemical interventions could prevent macrophages’ sugar-high-crazed inflammatory rampage in atherosclerotic lesions. The discovery could give rise to new ways of curing or preventing cardiovascular disease. Tests in mice indicate, for example, that it may be possible to design compounds that prevent defective macrophages from hyper-metabolizing glucose, or that moderate the inflammation-inducing effects of that hyper-metabolism.
Weyand’s got nothing against macrophages, per se. “We can’t live without them,” she says.
Leeper likewise bears no grudge. “Macrophages set out with good intentions,” he says. “We think they’re trying to do the right thing with atherosclerotic plaque, but they choke on it instead.”
In a study published in July in Nature, Leeper discovered an important reason dead cells pile up in atherosclerotic lesions to begin with: They sport a “don’t eat me” signal, in the form of a cell-surface protein called CD47 that deters macrophages’ voracious salvos. Irving Weissman, MD, professor of pathology and of developmental biology, and his colleagues have identified high levels of CD47 on cancer cells as a strategy that tumors use to evade immune attack.
Leeper’s study found, serendipitously, that CD47 is overexpressed on the dying and dead cells in atherosclerotic plaques, obstructing macrophages’ efforts to clear those cells from the scene. When he and his associates blocked this protein with anti-CD47 antibodies, they were able to counter plaque buildup and vulnerability to rupture in several different mouse models of atherosclerosis. Many mice even experienced regression of their plaques.
His team also found that TNF-alpha, like IL-6 an important pro-inflammatory substance, promotes elevated CD47 expression in dying cells in atherosclerotic tissue. Rendered inedible, the cells die in place and secrete still more TNF-alpha-inducing substances. And so forth.
Leeper notes that people with autoimmune disorders characterized by abundant systemic inflammation, such as rheumatoid arthritis or lupus, are at elevated risk for premature cardiovascular disease. But patients taking anti-TNF drugs for rheumatoid arthritis or lupus have fewer heart attacks and strokes than would otherwise be expected for these patients.
It’s already known that aspirin, a nonsteroidal anti-inflammatory drug, lowers cardiovascular risk, and that statin drugs — vaunted for cutting cholesterol production — also exert a pronounced anti-inflammatory effect. But the fact that each of these drugs works by multiple mechanisms makes it hard to prove that it is specifically their anti-inflammatory properties that are producing cardiovascular benefits. Two national trials are enrolling more than 25,000 patients at heightened risk of cardiovascular events to explore whether medications whose effects are known to work only through anti-inflammatory mechanisms can prevent heart attacks and strokes.
In addition, CD47-blocking antibodies are now being administered to cancer patients in early-stage clinical trials underway at Stanford and the University of Oxford. If those antibodies prove safe, they’ll be strong candidates for repurposing to combat cardiovascular disease.
Low-grade chronic inflammation is implicated in not just cardiovascular conditions but cancer, Alzheimer’s and Parkinson’s, Type 2 diabetes and both rheumatoid arthritis and osteoarthritis — age-associated diseases all, with at least one affecting most people age 65 or older. That age — one the great majority of people born in industrialized countries can expect to reach — describes one in seven Americans now and will encompass about one in five in 2030, according to the U.S. Census Bureau. So many leaky faucets spell not only big bills to come, but an inflammaging-fueled flood headed our way. If researchers can find the factors underlying this flood, there’s hope that the right washers and wrenches can stop the drip and help us all live to a healthy old age.