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Review
. 2018 Apr 9:9:586.
doi: 10.3389/fimmu.2018.00586. eCollection 2018.

Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines

Irene Maeve Rea  1   2   3 , David S Gibson  2 , Victoria McGilligan  2 , Susan E McNerlan  4 , H Denis Alexander  2 , Owen A Ross  5   6   7
Affiliations
Review

Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines

Irene Maeve Rea et al. Front Immunol. .

Abstract

Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called "inflamm-aging." Despite research there is no clear understanding about the causes of "inflamm-aging" that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer's disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with "inflammageing" or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.

Keywords: SASP; age-related diseases; aging; autophagy; cytokine dysregulation; inflamm-aging; inflammation resolution; redox.

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Figures

Figure 1
Figure 1
Inflammation pathway to resolution. An illustration of the sequence of key processes (in capitalized text), cells and molecules involved in reaction to injury or infection, and how the inflammatory episode is resolved over time (from left to right). Cells from the innate and adaptive immune system that are involved in cell recruitment, phagocytosis, and clearance processes are highlighted in blue text; key molecules are in italic text.
Figure 2
Figure 2
The arachidonic acid (AA) pathway of inflammation mediators. In the simplified pathway for the eicosanoid metabolic pathway, AA is released from membrane stores by phospholipase 2 (PLA2). AA is metabolized to biological mediators by three enzymatic pathways: cyclooxygenase, lipoxygenase, and cytochrome P450. Each pathway contains enzyme-specific steps that result in a wide variety of bioactive compounds that drive the pro-inflammatory (prostaglandins) response. After lipid mediator class-switching at the height of inflammation, the pro-resolving mediators-lipoxins begin to drive inflammation resolution. Eicosapentaenoic acid and docosahexaenoic acid-derived from dietary sources produce the E-series of resolvins and D-series of resolvins, maresins, and protectins, respectively, which are important pro-resolving mediators in progressing the resolution of inflammation.
Figure 3
Figure 3
(A) The ubiquitin–proteasome pathway of protein degradation. Three different sets of enzymes—E1, E2, and E3, identify and categorize proteins in order to link ubiquitin or ubiquitin complexes to the damaged proteins. The ubiquitin-protein complexes pass through the proteasome where they are degraded and discharged as free amino acids into the cytoplasm. (B) The autophagy pathway of degradation of damaged organelles and pathogens. The autophagy system degrades larger aggregated proteins and cellular organelles, such as mitochondria, peroxisomes, and infectious organisms. The process involves membrane formation, fusion, and degradation. A small separate membrane called a phagophore forms and then forms the autophagosome that fuses with the lysosome. The autophagosome contents are degraded by lysosomal hydrolases.
Figure 4
Figure 4
Mitochondrial reactive oxygen species (ROS) and nod-like receptor 3 (NLRP3) activation of inflammation pathway. Mitochondrial ROS from damaged mitochondria triggers the inflammasome NLRP3, stimulating NF-κB and the IL-1β and IL-18-mediated inflammatory cascade. The adapter protein ASC mediates innate signaling by bridging the interaction between the damage recognition receptor and the NF-κB caspase-1 inflammasome complex.
Figure 5
Figure 5
Cytokine dysregulation and NF-κB inflammation pathway. This reshaping of cytokine expression pattern with a progressive tendency toward a pro-inflammatory phenotype has been called “inflamm-aging” and is found associated with age-related diseases. Several molecular pathways have been identified that trigger the inflammasome and stimulate the NF-κB and the IL-1β-mediated inflammatory cascade of cytokines.
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References

    1. Ter Horst R, Jaeger M, Smeekens SP, Oosting M, Swertz MA, Li Y, et al. Host and environmental factors influencing individual human cytokine responses. Cell (2016) 167(4):1111e–24e.10.1016/j.cell.2016.10.018 - DOI - PMC - PubMed
    1. Govindaraju D, Atzmon G, Barzilai N. Genetics, lifestyle and longevity: lessons from centenarians. Appl Transl Genom (2015) 4:23–32.10.1016/j.atg.2015.01.001 - DOI - PMC - PubMed
    1. Rea JNM, Carvalho A, McNerlan SE, Alexander HD, Rea IM. Genes and life-style factors in BELFAST nonagenarians: nature, nurture and narrative. Biogerontology (2015) 16(5):587–97.10.1007/s10522-015-9567-y - DOI - PMC - PubMed
    1. Liu Y-Z, Wang Y-X, Jiang C-L. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci (2017) 11:316.10.3389/fnhum.2017.00316 - DOI - PMC - PubMed
    1. Abe K, Hashimoto Y, Yatsushiro S, Yamamura S, Bando M, Hiroshima Y, et al. Simultaneous immunoassay analysis of plasma IL-6 and TNF-α on a microchip. PLoS One (2013) 8(1):e53620.10.1371/journal.pone.0053620 - DOI - PMC - PubMed

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