Inflammatory Aging

As we get older, our immune system gradually breaks down. This process is called immunosenescence. That explains why, for example, pneumonia, the tenth most common cause of death among 50-year-olds and those in their early 60s, moves up to eighth place among those over 65. That is also why latent viruses can reappear, for example chickenpox, which breaks out as shingles after having slept for half a century. That also explains why vaccines no longer work as well when we get old. The annual flu shot is only about 50 percent effective in those who need it most.

On the other hand, activated immune cells in 80-year-olds send significantly more pro-inflammatory signals. This suggests that two disadvantages come together here—the decline of the part of the immune system that fights local infections, and the worsening of nonspecific overreactions that can lead to inflammation. This mounting increase in the pro-inflammatory state is now recognized as one of the main characteristics of the aging process and was officially presented in 2000 in a concept called “inflammaging,” a chronic, silent inflammation that in older people may be responsible for further decline and the onset of disease.

CRP becomes more common with age and is associated with lower life expectancy, poorer physical and cognitive performance, reduced vitality, and a series of age-related diseases such as Alzheimer’s, Parkinson’s, cardiovascular disease, diabetes, and chronic kidney disease. Presumably, inflammatory aging also plays a key role in degenerative disc disease of the spine and the loss of muscle mass.

CRP is the most thoroughly studied inflammatory biomarker for predicting remaining lifespan. Higher CRP levels in the blood can increase the risk of dying prematurely by 42 percent. Interleukin 6 (IL-6), the most important trigger for the production of CRP, may be an even better predictor. Interleukins are chemical messengers that serve to communicate between (inter-) white blood cells (-leukocytes).

When we are young, IL-6 in the blood is low, down to the threshold of detectability, but by 50 or 60 levels begin to rise. Since it is a strongly pro-inflammatory substance, high levels are among the most meaningful predictors of illness and death in older people. Researchers looked at single blood samples from healthy people over 65 and found that their risk of death over the next five years was as high as 40 percent if their IL-6 levels were in the highest quarter, but less than 10 percent if the levels were in the lowest quarter. Even at extremely advanced ages, IL-6 seems to be a predictor. In those over 100 with an IL-6 level in the lowest third, it is three times more likely that they will live almost another five years than in those in the highest third. IL-6 appears to be more a cause than a consequence of life-threatening diseases, because those who are genetically prone to higher IL-6 levels do not have a very high life expectancy.

Save Your Skin

What do you think is the largest of our organs? Maybe the lungs, the liver, or the intestines? Each of these weighs about five pounds. Our skin, by contrast, tips the scales at about 20 pounds. What does skin have to do with inflammatory aging?

As early as 45, we lose moisture from the outermost layer of skin as the skin’s barrier function begins to decline. Gaps in this protective wall can then trigger inflammation that sloshes into the bloodstream. Could a skin cream seal in moisture and prevent this inflammation? When old mice were rubbed with petroleum jelly three times a day for ten days, inflammatory markers decreased not only in their skin but throughout the body. In 2019, that prompted a study to test this in humans.

Older men and women (average age 78) were randomized to apply 3 milliliters (about two thirds of a teaspoon) of a moisturizing skin cream twice daily for one month. Amazingly, blood levels of inflammatory markers such as IL-6 not only fell much more than in control participants who did not moisturize their skin, but dropped almost to those of an average 32-year-old. That is, moisturizing lotion could be a simple way to limit systemic inflammation.

Hot and greasy!

Inflammation is seen as an important indicator and driver of aging, but where does inflammatory aging come from in the first place? Chronic infections such as Epstein-Barr virus or cytomegalovirus (CMV) have been proposed, but preindustrial populations of farmers or hunter-gatherers do not appear to have suffered from inflammatory aging, even though they were highly exposed to infections. We have already discussed two suspects in inflammatory aging: the accumulation of advanced glycation end products (chapter on glycation) and senescent cells that spit out SASP (chapter on cellular senescence). The age-related decline in autophagy (autophagy chapter) also leads to what one might call trash buildup.

Perhaps our immune system begins to react to the cellular debris that accumulates with age, which has led to speculation about whether inflammatory aging—and even part of the aging process itself—could be a complicated autoimmune, autoinflammatory reaction. That would fit with the fact that two years of moderate calorie reduction reduces inflammatory markers such as CRP by 40 percent. This sensational anti-inflammatory effect could have been the result of increased autophagy that cleared out pro-inflammatory cellular junk, or simply a consequence of weight loss.

Dozens of studies have found that obesity is strongly associated with increased inflammatory markers in the blood, for example CRP. But is the inflammation the cause or the consequence of excess weight? In the past, fat tissue was thought to be a passive storage site for excess fat, but today we know that it plays an active role in producing pro-inflammatory chemicals. Fat tissue can expand so quickly that it even outpaces its own blood supply and develops oxygen deficiency. (You can insert an electrode directly into a thick belly and measure how far oxygen levels can drop compared to people with a healthy body weight.) This oxygen deficiency is thought to contribute to the death of fat cells. But that is not good; dead fat cells attract inflammatory cells like macrophages, a type of circulating white blood cell as found in pus, that try to clear away the debris. In fact, belly biopsies from people with obesity show macrophages swarming throughout the fat.

Then the macrophages stick and fuse into giant cells, characteristic of chronic inflammation, as is seen in resistant infections like tuberculosis or around foreign bodies that the body cannot get rid of. All of this happens while components of inflammation spill over into the general circulation. Obesity thus appears to lead to systemic inflammation, not the other way around.

Not fit for human consumption

Dietary cholesterol can also contribute to inflammation in body fat that pours into the bloodstream. In humans, body fat is a large cholesterol store. Fat cells accumulate free cholesterol in large amounts that cannot be broken down by the cells and is toxic in high concentrations.