Introduction
Inflammation is an essential immunological defense system to enhance human survival. Acute (short-term) inflammation is a first-line defense against harmful agents, pathogens, toxins, and allergens. However, when acute inflammatory response fails to resolve, more defense components create an unresolved long-term immune response known as chronic inflammation. Chronic inflammation manifests in a low-grade manner for a prolonged time, leading to tissue degeneration. It involves macrophages, lymphocytes, and various other cells. One of the main changes during aging is immune response dysregulation.
Chronic low-grade inflammation follows a different course than acute inflammation. The recruitment of macrophages and lymphocytes replaces the immune cells involved in acute inflammation (neutrophils). These secondary immune cells attempt to eliminate the cause of the inflammation. However, when they fail to resolve the process, it leads to a chronic inflammatory state with the formation of structures such as granulomas. As a result, the consequences are associated with pathological conditions such as autoimmune diseases, fibrosis-related diseases, cancer, and other degenerative diseases.
What Is Inflammaging?
C. Franceschi termed the age-related phenomenon of a progressive increase in pro-inflammatory status. Inflammaging is manifested by increased pro-inflammatory cytokines commonly observed during aging. It impairs the ability to initiate an efficient immune response to antigens or environmental stimuli. Various animal and human studies exhibit elevated steady-state levels of inflammatory mediators, acute phase proteins (APPs), clotting factors, stress hormones, and oxidative stress. According to this hypothesis, these alterations in the immune system contribute to the development of organ-specific inflammatory diseases such as atherosclerosis, Alzheimer’s disease, and diabetes mellitus.
What Are the Sources of Chronic Inflammation in Aging?
Chronic low-grade inflammation contributes to natural processes in aging tissue and various age-related pathologies, including the nervous and musculoskeletal systems. Many tissues in aged individuals are chronically inflamed. The possible sources of chronic inflammation during aging are:
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Cell Debris/ Immunoglobulin Accumulation: Debris and immunoglobulin (antibodies that protect against pathogens) accumulate due to inappropriate cell elimination and trigger the immune system leading to persistent inflammation. Among the determinants of aging, mitochondrial (a cell organ that produces energy) dysfunction is a factor. The consequences of age-related failing mitochondrial quality include the release of mitochondria-derived damaged molecules. Cell-free circulating mitochondrial deoxyribonucleic acid (DNA) has recently become an intensive research topic because of its possible involvement in aging and degenerative diseases.
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The Gut Mucosa and Microorganisms: The oral and gut mucosal barrier against bacterial invasion deteriorates with age. The gut microorganisms of aged individuals have decreased diversity. Further, anti-inflammatory microorganisms are diminished in older individuals. On the other hand, inflammatory and pathogenic microorganisms increase with age. Therefore, changes in the gut microbiota in aged people can increase susceptibility to infectious agents.
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Cell Aging: Cell aging is an irreversible cell cycle arrest due to various mechanisms. These include stress and inflammatory mediators. The number of aged cells increases with age in several organs. These cells secrete multiple inflammatory mediators generating low-grade inflammation. This theory has been proposed recently as the primary source of inflammaging in age-related diseases such as atherosclerosis, cancer, and diabetes.
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Immunosenescence: Immunosenescence is the age-related dysregulation of the immune system. It is marked by a persistent inflammatory response. Immunosenescence increases susceptibility to cancer, autoimmunity, and infections. On the other hand, it decreases the response to vaccination and hampers wound healing. Chronic inflammatory disease can augment the “immunosenescence” process. The mechanisms that underlie persistent aging-associated inflammation remain unclear but may alter the number and functions of immune cells.
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Clotting and Anti-clotting System: Increased clotting and clot-dissolving activity in elderly individuals can lead to enhanced inflammation in age-related diseases, such as atherosclerosis and lung fibrosis. The concentrations of various clotting factors increase with the physiological process of aging. Raised fibrinogen (clotting factor I) levels are a primary risk factor for clotting disorders and have been shown to increase with advancing age. Further, clotting factor X is found at high levels in human atherosclerotic plaques. Thus, increased blood and local clotting factors during aging might account for the higher cardiovascular risk in older people.
What Are the Various Age-Related Diseases Linked to Chronic Inflammation?
Metabolic disorders, including obesity, insulin resistance, type 2 diabetes mellitus, and fatty liver disease, are associated with chronic inflammation. Metabolically active tissues such as adipose (fat) tissue, liver, muscle, and pancreas are common sites of inflammation in aging. Proinflammatory factors interrupt normal tissue function, as seen in insulin resistance. Chronic inflammation in adipose tissue is well documented and contributes to increased inflammation. Therefore, it indicates an important link between obesity and inflammation. Fatty liver disease is also linked to inflammation.
The chronic inflammatory process also plays a pertinent role in the pathogenesis of atherosclerosis (plaque buildup on walls of blood vessels). White blood cell recruitment and increased proinflammatory cytokines occur in the early stages of plaque formation. Further, inflammatory pathways promote the thrombotic complications of atherosclerosis responsible for stroke and myocardial infarction (MI).
Chronic inflammation is linked to aging in various neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Lewy body dementia. Further, several proinflammatory cytokines are implicated in dementia and cognitive decline. Recent evidence indicates the harmful role of microglia (brain-specific macrophages) in dementia. It further highlights the importance of the immune-inflammation link. It is because microglial activation relates to a primary inflammatory state and causes white blood cell invasion into the brain, which amplifies inflammation.
Another crucial disease involving chronic inflammation is cancer. Interest has increased in this respect after discovering that inflammation plays a role in cancer progression. Inflammatory cells are indispensable components in cancer formation, cancer cell proliferation, survival, and migration. Concerning cancer progression, it is vital to note that cancer cells also share common signaling molecules with the immune system, including cytokines (inflammatory mediators) and cell adhesion molecules. Hence, evidence suggests that inflammatory mediators are a crucial factor in the initiation and progression of cancer. Activated mediators stimulate the production of proinflammatory cells and inhibit cancer cell death.
Conclusion
Inflammation should subside immediately after the elimination of the pathogen to allow normal tissue to heal. However, low-grade and persistent inflammation occurs in many older individuals, leading to organ degeneration. There is strong evidence that the development of age-related conditions such as cancer, heart disease, Alzheimer’s disease, type II diabetes mellitus, and osteoporosis are associated with low-grade elevation of circulating inflammatory mediators. Although aging is a complex process involving environmental and genetic factors, interventions addressing selectively destroying aging host cells will offer improved therapeutic opportunities.
