Key Points:
- Inflammation is a response to stressors that leads to age-related disability after reaching a specific threshold.
- Repeatedly triggering a mild inflammatory response via various interventions can “reverse” inflammaging.
Due to the nuances of the original description being lost, “inflamm-aging” is often erroneously described as chronic, sterile, low-grade inflammation. However, while the original description characterizes chronic, sterile low-grade inflammation as an inevitable consequence of aging, it is not the sole determinant of age-related disability. That is, whether inflammation leads to disability is genetically determined by our capacity to cope with stressors. Still, we can augment our capacity to cope with stressors through several interventions.
Original Description of Inflammaging
The term “inflammaging” was coined by Italian researcher Claudio Franceschi, M.D., in a seminal 2000 publication that described a new hypothetical framework for how aging progresses. Inflammaging builds on the idea that our survival depends on how well our body defends against stressors, including external (e.g., pathogens, ultraviolet radiation, and adverse people) and internal (e.g., DNA damage and free radicals) stressors. According to the framework, our ability to resist external and internal stressors dictates our health and longevity.
In their original description, Franceschi and his collaborators argue that white blood cells called macrophages are central mediators of handling stressors. Macrophages, integral to the immune system, are responsible for engulfing and destroying pathogens and dysfunctional material such as damaged cells. They are also recruited to injured tissues, where they are involved in tissue repair. In response to stressors, macrophages secrete an assortment of molecules, including the stress hormone cortisol and several pro-inflammatory molecules.
Over time, as more macrophages are activated in response to stressors, the secretion of pro-inflammatory molecules increases too. As such, the level of pro-inflammatory molecules circulating throughout the body, what Franceschi and collaborators call pro-inflammatory status, increases with age.
In addition to the progressive elevation in macrophage activation, aging brings a quantitative reduction in the immune system as a whole. Specifically, the tissues that generate new immune cells (e.g., thymus, bone marrow, spleen, lymph nodes) degenerate and shrink. According to Franceschi and collaborators, this leads to a “reshaping” of the immune system that serves to maintain normal function into adulthood. However, as the effects of stressors accumulate, the reshaping of the immune system decreases, promoting pervasive inflammation in old age.
Coping with Stressors
Coping capacity is an often-overlooked nuance of the inflammaging theory. Each of us is equipped with an inherent capacity to cope with stressors, which is determined by the efficacy of our biological defense systems. However, this capacity varies between individuals, as some of us can cope with higher levels of accumulated stress than others. According to Franceschi and collaborators, this capacity determines the threshold by which we transition from successful aging—aging without disability—to unsuccessful aging—aging with disability (e.g., chronic diseases). This threshold is the breaking point of our capacity to cope with stressors, whereby the accumulation of stress and inflammation overtakes our biological defenses.
The coping threshold helps explain why centenarians, people who live to 100 and beyond, have high levels of inflammation like older adults in their 70s and 80s, but are often not burdened with chronic disease. It is hypothesized that centenarians harbor more genes that increase the robustness of their biological defense systems and lack “frailty genes” that weaken biological defenses. Their increased capacity to cope with stressors allows centenarians to live longer without disability. It follows that we each have our own genetically-determined capacity to cope that decides our threshold against disability.
Contributors to Inflammaging
Over the past quarter century, new discoveries have shaped the field of aging biology. As a testament to its validity, the inflammaging framework seamlessly incorporates new findings, building on its original conception in 2000. Some of the most studied processes contributing to inflammaging are senescent cells, the gut microbiome, and dysfunctional mitochondria.
Senescent Cells
In response to stressors, otherwise normally functioning cells become senescent cells. Senescent cells fail to serve their original function and contribute to inflammaging by secreting pro-inflammatory molecules. With age, senescent cells accumulate, and animal studies show this accumulation underlies many chronic diseases. Along with activated macrophages and the dysregulation of other immune cells, senescent cell accumulation appears to be a major contributor to age-related increases in inflammation.
Gut Microbiome
Within the inflammaging framework, the gut microbiome can be thought of as an immune system organ and potential stressor. It consists of many species of bacteria and other microbes, some of which are beneficial and some of which are harmful to the host organism. The harmful microbes produce large quantities of pro-inflammatory molecules, contributing to body-wide inflammation and inflammaging.
Mitochondria
The role of mitochondria in aging has become more apparent in recent years. They produce the energy necessary for all cells to function, including immune cells. It follows that mitochondrial impairment contributes to immune system deterioration by rendering immune cells less efficient or dysfunctional. Moreover, dysfunctional mitochondria contribute to inflammaging through several mechanisms, including the generation of excessive levels of free radicals, which trigger the release of pro-inflammatory molecules.
Reverse Inflammaging?
As per a recent publication, Franceschi and collaborators explain that inflammaging should not be thought of as a purely detrimental process that needs to be combated. They say that inflammation should not be looked at as a risk factor for disease that can be reversed to achieve “healthy” aging. Instead, inflammaging should be viewed as an adaptive process that can be optimized.
With that being said, in a 2020 publication, Franceschi and collaborators relay an anti-aging strategy for optimizing inflammaging that revolves around nutrition and physical activity. Notably, they say that,
“Strategies aimed at reducing inflammaging by acting on the immune response (systemic reduction of stress/antigenic burden, eradication of chronic infections, vaccinations, and treatment with anti-inflammatory drugs) have yet to offer definitive proof of their capacity to delay aging as well as the onset of age-related diseases. At variance, dietary interventions and physical activity fit much better into the conceptual framework of hormesis.”
Hormesis
Hormesis is the process in which exposure to stressors that are damaging at higher doses induces an adaptive beneficial effect at lower doses. Within this conceptual framework of hormesis, mild-intensity stressors can have beneficial effects if repeated, as demonstrated by caloric restriction (consuming fewer calories) and fasting (not consuming calories), for example. Physical activity is also a form of mild stress that, if repeated, is beneficial. This means that the activation of our biological defense systems, including inflammation, can benefit health and longevity when activated repeatedly in small doses.
Thus, the goal should not be to reverse inflammaging, but to activate it in small doses consistently, according to Franceschi and collaborators. This means adopting a routine that incorporates regular exercise and bouts of fasting or caloric restriction. Getting adequate sleep to recover from such exercise and fasting is also recommended.
Comments