Inflammaging - What is it about and why is it important?

To tackle longevity effectively, we need to talk about a concept called inflammaging. This is a really important concept to be aware of as it is something that you might not be aware of, but over time can do real long lasting damage to your body.

In this post, we will discuss your immune system, gut microbiome, immunosensecence and your metabolic capability and how this all adds up together in the concept of inflammaging.

Inflammaging can be thought of as a chronic, low-grade inflammation that develops with advanced age. Now it is regarded as ‘sterile’ meaning there is no active or overt evidence of infection or inflammation raging in your body but rather a low grade indolent process that persists for months and years.

The theory is that this long-term chronic indolent process actually leads to the development and clinical manifestations of age-related pathologies. People have attributed inflammaging as one of the processes that may contribute to diseases such as metabolic syndrome, type 2 diabetes, cancers, coronary artery disease, and Alzheimer’s just to name a few.

We also now have a lot of evidence to support the notion that inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

Link to our immune system

Now it is thought that inflammaging results in this chronic, overstimulation of our innate immune system. Let’s first define what is an immune system. An immune system is basically the body’s defence mechanism against outside pathogens, and comprises both innate ( which is nonspecific) and acquired (which is specific) components. The acquired type is what you might develop after getting a vaccine. Whereas the innate immune response is mainly the focus on what we will discuss in this post. The immune system is an intricate defence system that is highly conserved across vertebrate species, and has, from an evolutionary perspective, undergone strong pressures to maximize survival to allow procreation.

But before we dive too deep into the details, let’s first describe what is inflammation?

Inflammation is essential process that our immune system develops in order to protect against viral and bacterial infection, as well as noxious stimuli. It is an integral part of the healing process. Essentially, it is the body’s own defence system against things that are in your body that may be harmful. Now in the short term, it is obviously advantageous for your body to be able to conjure up the inflammatory process to fight against for example a bacterial infection. Once the infection is cleared then the inflammation process then subsides and vanish. Now the thinking about inflammaging is that if there is persisting low grade inflammation process, then this could be harmful and detrimental to your body.

We know that the various network dynamics of inflammation changes with age, and factors such as genes, lifestyle, and environment contribute to these changes over time. But let’s first take a zoom out and examine this from an evolutionary perspective.

In prehistoric times, starvation and infection by a pathogen pose as severe risks to survival. Inflammation may have served a protective role in human survival when food and water were scarce and even if they were present, they may be highly contaminated with pathogens lie bacteria. There is this interesting observation known as ‘postprandial inflammation’. Actually, what happens after we eat is that our innate immune system gets activated and you can see this when you measure the various immune related biomarkers in your blood. It is a well known phenomenon. This is because your immune system is being primed to try to detect and sense pathogenic nutrients so that it can react to it and stopping it from being to take hold and propagating to the rest of the body. What also happens is that one of the hormone leptin also changes in terms of its synthesis, which contributes to a decrease in food intake. This is to decrease the likelihood of ingesting another pathogen as well as preserving receptors critical for pathogen sensing, from sensing pathogenic nutrients instead.

The Metabolic Link

Scientists believe there is a pretty close link of inflammaging with insulin resistance. Think of insulin resistance as a condition that basically perturb the normal glucose homeostasis and preferentially tells your body not to use glucose but rather fat as the main substrate, and basically preserving glucose as the only substrate for the brain. This basically reduces the amount of glucose inside your cells, in order to optimise the glucose to your brain. This is advantageous in scenarios of starvation or infection, where this protects to supply of vital nutrients in glucose to the brain during times of stress. Why, because during tough times, we still need to be able to think straight otherwise, we cannot survive.

Nowadays we see this same phenomenon in the context of someone who has so-called ‘metabolic inflexibility’ meaning that their body has been trained to utilise fat much early on rather than glucose as the main substrates for energy.

Low grade, or what we term basal physiological inflammation is probably helpful to us until around middle age. However, after that, it is thought that a combination of loss of function of some of the core sensing structures in our immune system, as well as increase in stimulation (for example, from chronic infection like cytomegalovirus, or external factors like over-nutrition), can then drive the physiological level of inflammation to a little higher becoming the level of so called inflammaging, where this can cause damage to our body.

For example, during ageing, it has been observed that a diet rich in saturated fatty acids activates pattern recognition receptors, and together with debris from dead cells (necroptosis), work to activate an inflammatory response that is similar to that seen during an infection.

A major focus in ageing research is the identification of the stimuli that fuel inflammaging. If you are found to have chronic infections that will definitely contribute to this. For example, CMV or cytomegalvirus infection. CMV often persists as a lifelong infection, which can alternate between reactivation and latency, and the infection can simultaneously alter lipid and glucose metabolism. If you have chronic teeth infection, or medically termed as periodontitis, can also linger and persists for long periods, and can have low grade inflammation. But beside these, scientists also think that cell debris, misplaced self molecules and misfolded and oxidized proteins are major contributors to inflammaging.

What about the role of gut microbiome?

Within this framework, the gut microbiome is of particular and crucial importance. We now know that the gut microbiome acts as the boundary between the food that you ingest, you body’s metabolism and the innate immune response. We also know that your gut microbiome changes with ageing, and it actually undergoes profound remodelling with age. There is what we called a symbiosis between the body and the gut bacteria, what we term the ‘host–bacteria symbiosis’. In other words, there is a mutually advantageous coexistence between the two, in that the host gains nutrients from the digestion of certain foods by the gut bacteria and the gut bacteria can also feed on the host’s meals.

A lot of immune cells actually reside at the boundary of this interface which works to essentially protect the body from harmful pathogens, but at the same time, allow nutrients to get through and nourish and feed our body. So you can appreciate that the sensing of these potential pathogens or good nutrients are extremely important, and these are the roles of these immune cells or receptors that sit on the surfaces of cells at these junctions.

Now there is a theory that as we age, our sensing mechanisms go off track, and become less good at sensing what is good, or detecting what is bad. It is thought that one of the reasons why there is increased levels of low grade inflammation is due to the fact that the sensing mechanisms actually erroneously overreact to some of the by-products that might be associated with ageing like cell debris, or some misfolded proteins, for example, which then results in cascade of events that lead to a so called ‘pro-inflammatory' states. This can then perpetuate and persist over several months and years.

Immunosenescence

The decline in immune function with ageing is termed immunosensecence. Remodeling of the immune system in the elderly is thought to be characterized by an inability to control systemic inflammation. With age, the number of lymphocytes being produced decreases, and the composition and quality of the mature lymphocyte pool changes. While the effectiveness of adaptive immune system declines, innate immune mechanisms become overactive and less precise, leading to an increase in pro-inflammatory phenotypes that contribute to "inflammaging." All together, this contributes to a less efficient immune system response to pathogens and chronic, systemic inflammatory phenotypes.

Now another concept that people may be familiar with is called ‘autophagy’. Autophagy is a cellular housekeeping mechanism that is responsible for the removal of dysfunctional intracellular protein via a process called lysosomal degradation. We now know that ageing is associated with decreases in autophagy mechanisms, further contributing to proinflammatory environments. The consequence of a decline of autophagy with age is therefore an increased activation of the inflammasome and greater proinflammatory responses, again promoting the so-called inflammaging. So I hope you can appreciate that all these processes are interconnected. And that is exactly what ageing entity is. Scientists now more and more believe that inflammation plays a crucial role in linking these various processes of ageing, which over time contributes to the process of increased inflammation.

How do we measure inflammaging?

Cytokines are currently used as biomarkers of inflammaging as they are indicative of inflammation and play a large role in the regulation of pro and anti inflammatory immune regulation. Cytokines are small proteins that are secreted by many cell types that are very relevant in the study of aging and longevity. Aging studies show that a healthy balance of pro and anti inflammatory cytokine secretion is associated with successful aging whereas dysregulation of this system results in inflammaging, poor aging phenotypes, and other aging related diseases.

Currently, levels of TNFa, IL-6 and IL-1 can be used as inflammatory biomarkers that indicate frailty, an altered immune system, functional decline and mortality associated with inflammaging. These can actually be measured in clinical practice right now, and can give you a sense of whether there is increased levels of inflammation in your body.

COVID-19 perspective

Now I know everyone has been affected by COVID-19 one way or another and we are also learning about the role of inflammaging and COVID-19. We know, of course, that chronic inflammation and immunosenescence, which both increase with advanced chronological age, renders the elderly population more vulnerable. Now in the context of COVID-19, inflammaging may contribute to a pro-inflammatory cytokine secretion that, in combination with viral infection by SARS-CoV2, may exhaust immune system function, contributing to worse outcomes when fighting COVID-19 in the elderly population. It is one of the reasons scientists think may be responsible for the so-called ‘hyperinflammatory syndrome’ that elderly may get with COVID-19 which contribute to worse outcomes in these patients.

Inflammaging may also contribute to symptom persistence following acute COVID-19, what we now term ‘long-COVID’. Evidence shows that cytokine levels are still increased in patients with long COVID and the maintenance of a low-grade chronic inflammation could be one of the mechanisms that might explain symptom persistence.

So that concludes our summary of what we think inflammaging is. I hope after reading, you can appreciate what an important concept this is, and if you have any questions or comments, feel free to post them in the comment section.

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