Inflammaging
Inflammaging (also known as inflamm-aging or inflamm-ageing) is a chronic, sterile, low-grade
Inflammation is essential to protect against viral and bacterial infection, as well as noxious stimuli. It is an integral part of the healing process, though prolonged inflammation can be detrimental. The network dynamics of inflammation change with age, and factors such as genes, lifestyle, and environment contribute to these changes.[5] Current research studying inflammaging is focused on understanding the interaction of dynamic molecular pathways underlying both aging and inflammation and how they change with chronological age.
Characteristics
Fine control and modulation of the immune system response becomes fragile and less precise with age, as seen with other bodily systems.[5] 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.[6] 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 contributes to "inflammaging."[5] The secretome of senescent mesenchymal stem and stromal cells (MSCs) exhibits immunomodulatory effects and serves as a driver in inflammaging-related diseases.[7][8] All together, this contribues to a less efficient immune system response to pathogens and chronic, systemic inflammatory phenotypes.
Causes
Inflammaging is a complex and systemic issue, likely a result of several factors.
Inflammasome activation
Over-activation of the
Pro-inflammatory cytokines secretion acts as the effector or the response to such stimuli.Stimuli that can fuel inflammasome assembly include
Generation of reactive oxygen species
In addition to inflammasome activation, with age, cellular components accumulate reactive oxygen species (ROS). These free radicals can damage DNA, lipid, and protein and is able to drive cellular senescence. This is accompanied by a loss in efficiency of DNA damage repair mechanisms.[15] This results in pro-inflammatory cytokine secretion, which contributes to low grade, chronic inflammation in the absence of pathogen or damage, but rather in response to damaged self molecules like oxidized nucleotides.[16]
SASP phenotype
Senescent cell populations increase with age and secrete a pro-inflammatory cocktail of chemicals, a condition known as senescence-associated secretory phenotype (SASP).[14] Cells with the SASP are characterized by being in cell cycle arrest, releasing inflammatory factors, and possessing a particular morphology. These cells promote tissue degeneration and are able to spread to other regions by way of the inflammatory secretory molecules released.[17] This contributes to inflammaging as inflammatory secretion contributes to innate immune activation and exhaustion.
Functional decline in autophagy and mitophagy
Another contribution to inflammaging is a decline in effective autophagy and mitophagy capacity. This is an essential process for cellular housekeeping that prevents protein aggregation and accumulation of damaged mitochondria that produce large quantities of reactive oxygen species.[18] A loss of effective autophagic processes leads to aggregation of damaged proteins. As inflammasome precision declines with age, these aggregates, normally degraded, can be recognizes as a pathogen and lead to an inflammatory response. This contributes to inflammaging and is also involved in many neurodegenerative diseases as well.
Other factors
Other possible factors that may lead to inflamm-aging include
Biomarkers of 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.[2] 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 .[23]
Biomarkers of immuno-senescence also exist and involved changes to T cells, CD4/CD8 ratios as well as the SASP phenotype. Altogether, these biomarkers may not be translationally relevant to clinical outcomes. The generation of more reliable biomarkers of inflammation and aging is of interest in current research.
Interleukin 6
IL-6 is pro-inflammatory in nature and can be produced by many cells of the immune system as well as non-immune cells, like fibroblasts.[24] This cytokine has been identified in many organs such as the lungs, adipose tissue, muscle, and brain. The concentration of this cytokine is usually very low or non-detectable in young adults though levels increase in old age and are very high in the elderly.[2] Moreover, elevated IL-6 has also been associated with disability and mortality in older adults. High serum levels are associated with cognitive impairment, low locomotion, and depression.[24]
Interleukin 1
The interleukin 1 family consists of both pro and anti inflammatory mediators and there are 9 genes that encode different forms of interleukin 1, like
Tumor necrosis factor-alpha
Evolutionary consideration
While inflammation is capable of having negative implications, evolutionarily insight explains how inflammation has served as a layer of protection. It has been proposed that immune, metabolic, and endocrine systems co-evolved.[28]
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 highly contaminated. This explains
These same inflammatory processes may be detrimental towards humans in current society where over-nutrition is readily available. While inflammatory adaptations have evolved to promote survival in times of food deprivation, it does not appear that such adaptations have evolved in periods of over-nutrition.[29] In current times, natural selection does not favor those who are spared from inflammaging, as this occurs at ages past the reproduction window.
Inflammaging and COVID-19
Available evidence indicates that SARS-CoV2 enters the
Inflammaging and COVID-19 infection may lead to worse outcomes and contribute to the development of neurodegenerative disease in aged individuals.
Cardiovascular diseases
Inflamm-aging, has been linked to a higher risk of cardiovascular diseases and has been increasingly recognized as a determinant of cardiovascular outcome.[32][33][34][35]
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