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Chromatin Regulation in the Mechanisms that Lead to Age-Related Inflammation


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Posted 23 March 2023 - 10:22 AM


Chronic, unresolved, unprovoked inflammation is a feature of aging, a contributing cause of loss of tissue function and all of the common fatal age-related conditions. The biochemistry involved in the regulation of harmful age-related inflammatory signaling is complex, to say the least. There are many contributing causes, such as the signaling of senescent cells, the mislocalization of mitochondrial DNA resulting from mitochondrial dysfunction, and rising levels of other molecular debris from stressed and dying cells. How cells react in detail to inflammatory stimulation is far from fully understood. Researchers are interested in these mechanisms because it is possible that a better understanding might discover targets for intervention that can suppress only unwanted, excess inflammation.

The classic signs of acute inflammation are redness, heat, pain, swelling, and loss of function. Acute inflammation in the absence of infection can also promote wound regeneration or repair, depending on the severity of the tissue damage. In contrast, the chronic, sterile inflammation that results from repeated immune stimulation over time may be the result of the degeneration of a number of receptors that activate the innate immune system in elderly individuals.

A "generic" inflammatory pathway includes Inducers, Sensors, Mediators and Effectors. An example of this pathway in action would be the stimulation of Sensors, such as the Toll-Like Receptors (TLRs) present on macrophages or mast cells by a microbe (Inducer), leading to the production of cytokines (Mediator), which act on target tissues (Effectors) in order to promote the recruitment of pathogen-destroying cells to the affected area. These actions lead to the signs of inflammation through vasodilation, edema, and the presence of pain-promoting prostaglandins in the affected tissue.

Low-grade inflammation is often observed as part of aging. This phenomenon has been termed "inflammaging". In addition to a general decline in function during aging, the nature of the immune system also changes, in a phenomenon known as immunosenescence. This accounts for the reduced ability of the elderly to respond to antigens and correlates with increased susceptibility to infections. The co-ordination of the many processes that contribute to the effective control of the inflammatory response relating to aging is complicated, and the revelation of the mechanisms underlying this control has only recently begun.

It has been found that the production of the correct inflammatory mediator in a timely manner requires exquisite control at the transcriptional level. Importantly, all eukaryotic transcription takes place in the context of the nucleoprotein complex known as chromatin. In this review, we aim to emphasize the roles of chromatin regulation at the intersection between inflammation, aging, and metabolism to deepen our mechanistic understanding of inflammaging while we discuss the possibility of obtaining control over inflammaging and directions for further studies.

Link: https://doi.org/10.3390/ijms221910274


View the full article at FightAging




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