With age comes a myriad of mental and physical changes that no one looks forward to, such as aches and pains, forgetfulness, and dulled senses. However, when it comes to our health, the most sinister change of all may be the increased risk of developing chronic diseases, such as cancer, diabetes, cardiovascular disease, and neurological disorders. The 2017 – 2018 Canadian Community Health Survey, conducted by the Government of Canada, estimated that 75% of Canadians aged over 65 years have at least one chronic disease and over 33% have two or more chronic diseases. These chronic conditions not only account for greater than 60% of deaths in the country, but also lead to significant loss in quality of life.
What exactly are the changes that occur in our body that make us more disease prone as we age? Underlying observable physical and behavioural changes, our body is also aging at the cellular and molecular level. Our immune cells are therefore not exempt from age-associated changes. In healthy, normal circumstances, our immune cells act as sentinels and caretakers of the body – they detect and eliminate dangerous compounds, prevent tissue damage, and guard against external threats like infection-causing pathogens. Yet in our aging bodies, these immune cells slowly become “senile” and start making mistakes, ultimately becoming less efficient at protecting us. Slowly but surely, these “senile”, error-prone immune cells cause low-grade, chronic inflammation, which is a strong contributor to the development of chronic diseases. Based on this observation, scientists very aptly refer to this age-associated inflammatory phenomenon as “inflammaging”.
Given the complexity of the immune system and its relationship to our overall health, simply eliminating inflammation to treat aging could lead to unforeseen consequences. While detrimental in some cases, inflammation is an essential component to our survival. Acute inflammation is critical for fighting pathogens and repairing injured tissues. In a healthy, young individual, acute inflammation involves a delicate balance between pro- and anti-inflammatory factors that simultaneously trigger and control the scale of the immune response. However, aging immune cells often fail to meet the metabolic demands required to maintain this equilibrium. Consequently, these aging cells tip the balance in favour of pro-inflammatory components, increasing the likelihood of chronic inflammation that persists even in the absence of infection or external threat.
There are multiple theories that link aging immune cells to their increased propensity for triggering chronic inflammation – and some key models are highlighted here.
Changes to the immune cell repertoire
Our immune system can be broadly categorized into two main types – innate and adaptive immune cells. Innate immune cells survey the body in a non-specific manner and are the first to respond to a pathogen, while the adaptive subtypes develop immunological memory towards specific pathogens or insults. This repertoire of cells is constantly replenished by stem cells in the red bone marrow. As we get older, red bone marrow is progressively replaced by fat, which creates yellow bone marrow instead. This yellow bone marrow provides limited nutrients for stem cells and thereby pushes stem cells to produce more innate immune cells than adaptive. Increased production of innate immune cells is undesirable since these cells have a low threshold for activation and are the main drivers of chronic, low-grade inflammation.
Oxidative stress
Excessive stress for prolonged periods of time is also an activator of immune cells. This includes oxidative stress within cells. As mitochondria become less efficient with age, they produce less usable forms of energy, such as ATP, and more potentially harmful byproducts, like reactive oxygen species, which can accumulate in our bodies over time and activate immune cells.
DNA damage
At the ends of our chromosomes exist structures made up of DNA and proteins, called telomeres, which protect the chromosome ends from getting damaged and are required for cell division. Over time, the shortening of telomeres and the accumulating mutations in our chromosomes result in DNA damage accumulation, including in immune cells, which triggers a DNA damage response that also results in inflammation.
Altered ability to recycle cellular machinery
Under healthy circumstances, innate cells are responsible for eating and recycling potentially harmful or damaged components circulating throughout the body, including dying or cancerous cells. Similar to how we experience wear and tear at the organ and tissue level, innate cell machinery also experiences wear and tear. With age, cells lose their recycling capacity, which leads to an accumulation of toxic substances in our body and thereby activating inflammatory mechanisms.
Lifestyle interventions hold promise in counteracting inflammaging and can promote healthy aging that prolongs life and delays the onset of disease. For example, exercise can serve as a natural anti-inflammatory remedy by reducing stress and promoting healthy metabolism. A healthy diet – consisting of foods high in antioxidants and low in saturated fats – paired with moderate restriction can also limit inflammation. Diet can achieve these benefits by promoting healthy metabolism of immune cells and maintaining a diverse gut microbiota that produce anti-inflammatory metabolites. Studies involving individuals who have lived past 100 years have provided valuable insight into the efficacy of such interventions and validate that longevity can co-exist with inflammaging if accompanied by appropriate anti-inflammatory mechanisms.
All in all, inflammation is a key driver of aging, age-related disease, and subsequent death. Anti-aging therapies and prevention of immune cell aging remain active and rapidly growing areas of research. However, while certain interventions may delay the effects of inflammaging and promote longevity, there does not yet exist a cure for aging itself or age-associated chronic diseases. Until such a breakthrough is made, and we discover the so-called “Elixir of Life”, we can only ask ourselves: “Will our immune system, which has been protecting us throughout most of our lives, ultimately lead to our demise?”
References:
https://www.nature.com/articles/s41574-018-0059-4
https://www.nature.com/articles/s41392-023-01502-8
https://pubmed.ncbi.nlm.nih.gov/20549353/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4963991/#B34
https://www.sciencedirect.com/science/article/abs/pii/S1568163721001690?via%3Dihub
https://pmc.ncbi.nlm.nih.gov/articles/PMC6146930/
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