Inflammaging

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Factors involved in Inflammaging Aging leads to perturbations in cellular homeostasis leading to inflammaging that results in pro-inflammatory cytokine secretion. Inflammaging Schematic Image.jpg
Factors involved in Inflammaging Aging leads to perturbations in cellular homeostasis leading to inflammaging that results in pro-inflammatory cytokine secretion.

Inflammaging (also known as inflamm-aging or inflamm-ageing) is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals. [2] [3] [4]

Contents

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

Inflammasome Activation and Assembly Release of ROS and pro-inflammatory cytokine secretion in response to inflammasome assembly after DAMP / PAMP binding 3 Models of NLRP3 Inflammasome Activation.png
Inflammasome Activation and Assembly Release of ROS and pro-inflammatory cytokine secretion in response to inflammasome assembly after DAMP / PAMP binding

Over-activation of the inflammasome is one mechanism contributing to inflammaging. The inflammasome is a multi-protein complex consisting of a sensor, an adapter, and an effector, that when activated, modulates caspases which cleave cytokines and result in an inflammatory signaling response. [9] [10] [11] Receptors present on the cell surface act as sensors for the detection of damage and pathogens. When activated, this system can go on to elicit pro-inflammatory cytokine secretion and sometimes cell death. [12] [13] Pro-inflammatory cytokines secretion acts as the effector or the response to such stimuli.

Stimuli that can fuel inflammasome assembly include pathogen-associated molecular patterns (PAMPS), damage associated molecular patterns (DAMPS), nutrients, and the microbiota. [14] These various self, non-self, and quasi self molecules are recognized by receptors of innate immune cells, whose promiscuity allows for many different signals to lead to activation and consequently to inflammation. Examples of stimuli that act as PAMPS include viral and bacterial infection, such as cytomegalovirus and periodontitis, respectively. Examples of DAMPS include misfolded and oxidized proteins, cell debris, and self nucleic acids.

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 insufficient sleep, overnutrition, sensory overload, physical inactivity, altered gut microbiome, impaired intestinal epithelial barrier, and chronic stress occurring in any stage of the individual's life. [19] [20] [21] Cytokines with inflammatory properties can also be secreted by fat tissue. [22]

Biomarkers of inflammaging

TNF Mediated Cell Survival and Death Pathway TNF alpha binding to receptors induces apoptosis and necrosis through various signaling pathways. TNF-Mediated Death and Survival Pathways.png
TNF Mediated Cell Survival and Death Pathway TNF alpha binding to receptors induces apoptosis and necrosis through various signaling pathways.

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]

Crystal Structure of TNF-alpha Crystal protein structure of tumor necrosis factor-alpha. TNFa Crystal Structure.rsh.png
Crystal Structure of TNF-alpha Crystal protein structure of tumor necrosis factor-alpha.

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 Il-1a and IL-1B. [25] IL-1B is one of the most prominent mediators of inflammation and its secretion is tightly regulated given its potent nature. [9] IL-1B starts in an inactive form and is induced first by toll like receptors or TNFa and requires a second stimulus by the inflammasome to induce the mature, active form of IL-1B. [9]

Tumor necrosis factor-alpha

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine produced upon acute inflammation and is an important signaling molecule responsible for inducing apoptosis or necrosis. [26] TNF-alpha exerts its effects by binding to various membrane receptors that belong to the TNF Receptor superfamily. With age, TNF-alpha serum levels negatively correlate with T cell function. [27] Additionally, elevated TNF-alpha levels are associated with increased systemic inflammation and contribute to inflammatory diseases like rheumatoid arthritis. [27] TNF-alpha signaling is thought to be up-regulated during inflammaging and contributes to cellular senescence and immune exhaustion.

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 post prandial inflammation, which involves innate immune system activation after ingesting a meal. Additionally, during infection by a pathogen, leptin synthesis changes and a reduction in food intake occurs. [28] This is to decrease the likelihood of ingesting another pathogen as well as preserving receptors critical for pathogen sensing, from sensing pathogenic nutrients instead. Perhaps, this is another reason calorie restriction is beneficial in the treatment of inflammaging. [28]

Cytokine Storm Induced by SARS-CoV2 Infection Infection by SARS-COV 2 leads to COVID-19 Infection resulting in activation of inflammatory phenotypes by cell types in both the central nervous system and within the immune system network Fimmu-11-01648-g002.jpg
Cytokine Storm Induced by SARS-CoV2 InfectionInfection by SARS-COV 2 leads to COVID-19 Infection resulting in activation of inflammatory phenotypes by cell types in both the central nervous system and within the immune system network

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

Adaptive immunity, involving the ability to fight off pathogens, declines with age. [30] Chronic inflammation and immunosenescence, which both increase with advanced chronological age, renders the elderly population more vulnerable to adverse, long term effects of viral infection by SARS-CoV2. [31] Inflammaging alone contributes to 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. [31]

SARS-CoV2 Virus Corona virus resulting in COVID-19 SARS-CoV-2 without background.png
SARS-CoV2 VirusCorona virus resulting in COVID-19

Available evidence indicates that SARS-CoV2 enters the central nervous system through the lymphatic system and the virus was confirmed present in the capillaries and neuronal cells of the frontal lobe of COVID-19 patients. [31] This is corroborated with evidence demonstrating that SARS-CoV2 was present in cerebral spinal fluid of infected patients which displayed severe neurological symptoms. Viral infection is capable of inducing neuroinflammation through neuro-immune interactions. While aging is the most significant risk factor in the development of neurodegenerative diseases like Alzheimers, Parkinson's, and Amyotrophic lateral sclerosis, chronic, low-grade inflammation and immunosenescence may be aggravated by a viral infection, worsening the aging phenotype and contributing to the development of neurodegenerative disease. For example, neuroinflammation has been shown to contribute greatly to the severity and pathogenesis of Parkinson's disease. Infection by the H1N1 virus was shown to contribute to Parkinson's disease development. [31]

Inflammaging and COVID-19 infection may lead to worse outcomes and contribute to the development of neurodegenerative disease in aged individuals.

Cardiovascular diseases

Inflammaging has been linked to a higher risk of cardiovascular diseases and has been increasingly recognized as a determinant of cardiovascular outcome. [32]

Related Research Articles

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function.

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Neuroimmune system</span>

The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Caspase 1</span> Protein-coding gene in the species Homo sapiens

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

Immune dysregulation is any proposed or confirmed breakdown or maladaptive change in molecular control of immune system processes. For example, dysregulation is a component in the pathogenesis of autoimmune diseases and some cancers. Immune system dysfunction, as seen in IPEX syndrome leads to immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX typically presents during the first few months of life with diabetes mellitus, intractable diarrhea, failure to thrive, eczema, and hemolytic anemia. unrestrained or unregulated immune response.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune and neurodegenerative disorders, and coronary heart disease.

Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmins because they serve as warning signs to alert the organism to any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern recognition receptor. Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs) sensing microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP, is a type of NOD-like receptor. NOD-like receptors are a type of pattern recognition receptor that are found in the cytosol of the cell, recognizing signals of antigens in the cell. NLRP proteins are part of the innate immune system and detect conserved pathogen characteristics, or pathogen-associated molecular patterns, such as such as peptidoglycan, which is found on some bacterial cells. It is thought that NLRP proteins sense danger signals linked to microbial products, initiating the processes associated with the activation of the inflammasome, including K+ efflux and caspase 1 activation. NLRPs are also known to be associated with a number of diseases. Research suggests NLRP proteins may be involved in combating retroviruses in gametes. As of now, there are at least 14 different known NLRP genes in humans, which are named NLRP1 through NLRP14. The genes translate into proteins with differing lengths of leucine-rich repeat domains.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

<span class="mw-page-title-main">Thirumala-Devi Kanneganti</span> Indian immunologist

Thirumala-Devi Kanneganti is an immunologist and is the Rose Marie Thomas Endowed Chair, Vice Chair of the Department of Immunology, and Member at St. Jude Children's Research Hospital. She is also Director of the Center of Excellence in Innate Immunity and Inflammation at St. Jude Children's Research Hospital. Her research interests include investigating fundamental mechanisms of innate immunity, including inflammasomes and inflammatory cell death, PANoptosis, in infectious and inflammatory disease and cancer.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

PANoptosis is a unique, innate immune, inflammatory, and lytic cell death pathway driven by caspases and RIPKs and regulated by multiprotein PANoptosome complexes. The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer. Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes, have been characterized so far.

<span class="mw-page-title-main">Alzheimer's disease and COVID-19</span>

Studies have shown that Alzheimer's disease (AD) patients are at an increased risk of morbidity and mortality from SARS-CoV-2, the virus that causes COVID-19. AD is the most common cause of dementia worldwide and is clinically defined by amyloid beta plaques, neurofibrillary tangles, and activation of the brain's immune system. While COVID-19 has been known to more severely impact elderly populations, AD patients have been shown to have a higher rate of SARS-CoV-2 infection compared to cognitively normal patients. The disproportionate risk of COVID-19 in AD patients is thought to arise from an interplay of biological and social factors between the two diseases. Many common biological pathways are shared between COVID-19 and AD, notably those involved in inflammation. Genetic factors that put individuals at risk for AD, such as the APOE4 genotype, are associated with worse outcomes during SARS-CoV-2 infection. Cognitive impairment in AD may prevent patients from following proper public health guidelines, such as masking and social distancing, increasing their risk of infection. Additionally, studies have shown cognitively normal COVID-19 patients are at an increased risk of AD diagnosis following recovery, suggesting that COVID-19 has the potential to cause AD.

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