Inflammaging

Last updated

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

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]

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 complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

<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">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<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.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory. Age-associated immune deficiency is found in both long- and short-lived species as a function of their age relative to life expectancy rather than elapsed time. It has been studied in animal models including mice, marsupials and monkeys. Immunosenescence is a contributory factor to the increased frequency of morbidity and mortality among the elderly. Along with anergy and T-cell exhaustion, immunosenescence belongs among the major immune system dysfunctional states. However, while T-cell anergy is a reversible condition, as of 2020 no techniques for immunosenescence reversal had been developed.

<span class="mw-page-title-main">Toll-like receptor 9</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.

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 alarmin because they serve as a warning sign for the organism to alert it of 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.

<span class="mw-page-title-main">Inflammasome</span> Cytosolic multiprotein complex that mediates the activation of Caspase 1

Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of gasdermin D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. Additionally, inflammasomes can be incorporated into 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.

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.

PANoptosis is an inflammatory cell death pathway. Genetic, molecular, and biochemical studies identified extensive crosstalk among the molecular components across cell death pathways in response to a variety of pathogens and innate immune triggers, leading to the conceptualization of PANoptosis. PANoptosis is defined as a unique innate immune inflammatory cell death pathway driven by caspases and RIPKs and regulated by multi protein PANoptosome complexes. PANoptosis is implicated in driving innate immune responses and inflammation in disease. PANoptosome formation and PANoptosis occur during pathogenic infections, including bacterial, viral, and fungal infections, as well as during inflammatory diseases and can be beneficial in the context of cancer.

References

  1. ↑ "BioRender". BioRender. Retrieved 29 November 2021.
  2. 1 2 3 Alberro, Ainhoa; Iribarren-Lopez, Andrea; Sáenz-Cuesta, Matías; Matheu, Ander; Vergara, Itziar; Otaegui, David (23 February 2021). "Inflammaging markers characteristic of advanced age show similar levels with frailty and dependency". Scientific Reports. 11 (1): 4358. Bibcode:2021NatSR..11.4358A. doi:10.1038/s41598-021-83991-7. ISSN   2045-2322. PMC   7902838 . PMID   33623057. S2CID   232039252.
  3. ↑ Fulop, T., Larbi, A., Pawelec, G., Khalil, A., Cohen, A. A., Hirokawa, K., ... & Franceschi, C. (2021). Immunology of aging: the birth of inflammaging. Clinical reviews in allergy & immunology, 1-14. PMID   34536213 PMC   8449217 doi : 10.1007/s12016-021-08899-6
  4. ↑ Dugan, B., Conway, J., & Duggal, N. A. (2023). Inflammaging as a target for healthy ageing. Age and Ageing, 52(2), afac328. PMID   36735849 doi : 10.1093/ageing/afac328
  5. 1 2 3 Rea, Irene Maeve; Gibson, David S.; McGilligan, Victoria; McNerlan, Susan E.; Alexander, H. Denis; Ross, Owen A. (9 April 2018). "Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines". Frontiers in Immunology. 9: 586. doi: 10.3389/fimmu.2018.00586 . ISSN   1664-3224. PMC   5900450 . PMID   29686666.
  6. ↑ Montecino-Rodriguez E, Berent-Maoz B, Dorshkind K (March 2013). "Causes, consequences, and reversal of immune system aging". The Journal of Clinical Investigation. 123 (3): 958–65. doi:10.1172/JCI64096. PMC   3582124 . PMID   23454758.
  7. ↑ Lee, B.C.; Yu, K.R. (2020). "Impact of mesenchymal stem cell senescence on inflammaging". BMB Reports. 53 (2): 65–73. doi:10.5483/BMBRep.2020.53.2.291. ISSN   1976-670X. PMC   7061209 . PMID   31964472.
  8. ↑ Lyamina, S.; Baranovskii, D.; Kozhevnikova, E.; Ivanova, T.; Kalish, S.; Sadekov, T.; Klabukov, I.; Maev, I.; Govorun, V. (2023). "Mesenchymal Stromal Cells as a Driver of Inflammaging". International Journal of Molecular Sciences. 24 (7): 6372. doi: 10.3390/ijms24076372 . ISSN   1422-0067. PMC   10094085 . PMID   37047346.
  9. 1 2 3 Yazdi, Amir S.; Ghoreschi, Kamran (2016). "The Interleukin-1 Family". Regulation of Cytokine Gene Expression in Immunity and Diseases. Advances in Experimental Medicine and Biology. Vol. 941. pp. 21–29. doi:10.1007/978-94-024-0921-5_2. ISBN   978-94-024-0919-2. ISSN   0065-2598. PMID   27734407.
  10. ↑ Latz, Eicke; Duewell, Peter (1 December 2018). "NLRP3 inflammasome activation in inflammaging". Seminars in Immunology. 40: 61–73. doi:10.1016/j.smim.2018.09.001. ISSN   1044-5323. PMID   30268598. S2CID   52890879.
  11. ↑ Sebastian-Valverde, Maria; Pasinetti, Giulio M. (June 2020). "The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process". Cells. 9 (6): 1552. doi: 10.3390/cells9061552 . PMC   7348816 . PMID   32604771.
  12. ↑ Swanson, Karen V.; Deng, Meng; Ting, Jenny P.-Y. (August 2019). "The NLRP3 inflammasome: molecular activation and regulation to therapeutics". Nature Reviews Immunology. 19 (8): 477–489. doi:10.1038/s41577-019-0165-0. ISSN   1474-1733. PMC   7807242 . PMID   31036962.
  13. ↑ Malik, Ankit; Kanneganti, Thirumala-Devi (1 December 2017). "Inflammasome activation and assembly at a glance". Journal of Cell Science. 130 (23): 3955–3963. doi:10.1242/jcs.207365. ISSN   1477-9137. PMC   5769591 . PMID   29196474.
  14. 1 2 Franceschi C, Campisi J (2014). "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases". Journal of Gerontology: Biological Sciences . 69 (Supp 1): s4–s9. doi: 10.1093/gerona/glu057 . PMID   24833586.
  15. ↑ Chatterjee, Nimrat; Walker, Graham C. (June 2017). "Mechanisms of DNA damage, repair and mutagenesis". Environmental and Molecular Mutagenesis. 58 (5): 235–263. doi:10.1002/em.22087. ISSN   0893-6692. PMC   5474181 . PMID   28485537.
  16. ↑ Zuo; Prather; Stetskiv; Garrison; Meade; Peace; Zhou (10 September 2019). "Inflammaging and Oxidative Stress in Human Diseases: From Molecular Mechanisms to Novel Treatments". International Journal of Molecular Sciences. 20 (18): 4472. doi: 10.3390/ijms20184472 . ISSN   1422-0067. PMC   6769561 . PMID   31510091.
  17. ↑ Gordleeva, Susanna; Kanakov, Oleg; Ivanchenko, Mikhail; Zaikin, Alexey; Franceschi, Claudio (1 October 2020). "Brain aging and garbage cleaning". Seminars in Immunopathology. 42 (5): 647–665. doi:10.1007/s00281-020-00816-x. ISSN   1863-2300. PMID   33034735. S2CID   222235623.
  18. ↑ Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu (March 2012). "Inflammaging: disturbed interplay between autophagy and inflammasomes". Aging. 4 (3): 166–175. doi:10.18632/aging.100444. ISSN   1945-4589. PMC   3348477 . PMID   22411934.
  19. ↑ Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (October 2018). "Inflammaging: a new immune-metabolic viewpoint for age-related diseases". Nature Reviews. Endocrinology. 14 (10): 576–590. doi:10.1038/s41574-018-0059-4. hdl: 11585/675065 . PMID   30046148. S2CID   50785788.
  20. ↑ Meier J, Sturm A (2009). "The intestinal epithelial barrier: does it become impaired with age?". Digestive Diseases. 27 (3): 240–5. doi:10.1159/000228556. PMID   19786747. S2CID   40407420.
  21. ↑ Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R (July 2003). "Chronic stress and age-related increases in the proinflammatory cytokine IL-6". Proceedings of the National Academy of Sciences of the United States of America. 100 (15): 9090–5. Bibcode:2003PNAS..100.9090K. doi: 10.1073/pnas.1531903100 . PMC   166443 . PMID   12840146.
  22. ↑ Pedersen M, Bruunsgaard H, Weis N, Hendel HW, Andreassen BU, Eldrup E, Dela F, Pedersen BK (April 2003). "Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes". Mechanisms of Ageing and Development. 124 (4): 495–502. doi:10.1016/s0047-6374(03)00027-7. PMID   12714258. S2CID   20234017.
  23. ↑ Fulop, Tamas; Cohen, Alan; Wong, Glenn; Witkowski, Jacek M.; Larbi, Anis (2019), Moskalev, Alexey (ed.), "Are There Reliable Biomarkers for Immunosenescence and Inflammaging?", Biomarkers of Human Aging, Healthy Ageing and Longevity, Cham: Springer International Publishing, vol. 10, pp. 231–251, doi:10.1007/978-3-030-24970-0_15, ISBN   978-3-030-24970-0, S2CID   203442315 , retrieved 27 November 2021
  24. 1 2 Brábek, Jan; Jakubek, Milan; Vellieux, Fréderic; Novotný, Jiří; Kolář, Michal; Lacina, Lukáš; Szabo, Pavol; Strnadová, Karolína; Rösel, Daniel; Dvořánková, Barbora; Smetana, Karel (26 October 2020). "Interleukin-6: Molecule in the Intersection of Cancer, Ageing and COVID-19". International Journal of Molecular Sciences. 21 (21): 7937. doi: 10.3390/ijms21217937 . ISSN   1422-0067. PMC   7662856 . PMID   33114676.
  25. ↑ Kornman, Kenneth S. (February 2006). "Interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging". The American Journal of Clinical Nutrition. 83 (2): 475S–483S. doi: 10.1093/ajcn/83.2.475S . ISSN   0002-9165. PMID   16470016.
  26. ↑ Idriss, H. T.; Naismith, J. H. (1 August 2000). "TNF alpha and the TNF receptor superfamily: structure-function relationship(s)". Microscopy Research and Technique. 50 (3): 184–195. doi:10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H. ISSN   1059-910X. PMID   10891884. S2CID   3003943.
  27. 1 2 Frasca, Daniela; Blomberg, Bonnie B. (February 2016). "Inflammaging decreases adaptive and innate immune responses in mice and humans". Biogerontology. 17 (1): 7–19. doi:10.1007/s10522-015-9578-8. ISSN   1389-5729. PMC   4626429 . PMID   25921609.
  28. 1 2 3 Franceschi, Claudio; Garagnani, Paolo; Parini, Paolo; Giuliani, Cristina; Santoro, Aurelia (October 2018). "Inflammaging: a new immune–metabolic viewpoint for age-related diseases". Nature Reviews Endocrinology. 14 (10): 576–590. doi:10.1038/s41574-018-0059-4. hdl: 11585/736269 . ISSN   1759-5037. PMID   30046148. S2CID   50785788.
  29. ↑ Franceschi, C.; Bonafè, M.; Valensin, S.; Olivieri, F.; De Luca, M.; Ottaviani, E.; De Benedictis, G. (June 2000). "Inflamm-aging. An evolutionary perspective on immunosenescence". Annals of the New York Academy of Sciences. 908 (1): 244–254. Bibcode:2000NYASA.908..244F. doi:10.1111/j.1749-6632.2000.tb06651.x. ISSN   0077-8923. PMID   10911963. S2CID   1843716.
  30. ↑ Bartleson, Juliet M.; Radenkovic, Dina; Covarrubias, Anthony J.; Furman, David; Winer, Daniel A.; Verdin, Eric (September 2021). "SARS-CoV-2, COVID-19 and the aging immune system". Nature Aging. 1 (9): 769–782. doi:10.1038/s43587-021-00114-7. ISSN   2662-8465. PMC   8570568 . PMID   34746804.
  31. 1 2 3 4 Domingues, Renato; Lippi, Alice; Setz, Cristian; Outeiro, Tiago F.; Krisko, Anita (29 September 2020). "SARS-CoV-2, immunosenescence and inflammaging: partners in the COVID-19 crime". Aging (Albany NY). 12 (18): 18778–18789. doi:10.18632/aging.103989. ISSN   1945-4589. PMC   7585069 . PMID   32991323.
  32. ↑ Liberale, L., Badimon, L., Montecucco, F., Lüscher, T. F., Libby, P., & Camici, G. G. (2022). Inflammation, aging, and cardiovascular disease: JACC review topic of the week. Journal of the American College of Cardiology, 79(8), 837-847. PMID   35210039 PMC   8881676 doi : 10.1016/j.jacc.2021.12.017
  33. ↑ Puspitasari, Y. M., Ministrini, S., Schwarz, L., Karch, C., Liberale, L., & Camici, G. G. (2022). Modern Concepts in Cardiovascular Disease: Inflamm-Aging. Frontiers in Cell and Developmental Biology, 10. PMID   35663390 PMC   9158480 doi : 10.3389/fcell.2022.882211
  34. ↑ Ferrucci, L., & Fabbri, E. (2018). Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nature Reviews Cardiology, 15(9), 505-522. PMID   30065258 PMC   6146930 doi : 10.1038/s41569-018-0064-2
  35. ↑ Perrone, M. A., Aimo, A., Bernardini, S., & Clerico, A. (2023). Inflammageing and Cardiovascular System: Focus on Cardiokines and Cardiac-Specific Biomarkers. International Journal of Molecular Sciences, 24(1), 844. PMID   36614282 PMC   9820990 doi : 10.3390/ijms24010844
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.