Epigenetics and Inflammageing
Ageing is associated with an increased risk of developing a large number of inflammatory rheumatic diseases. Many features of both the adaptive and innate immune systems change with increasing age, leading to a state of increased activity termed inflammageing. In the adaptive system, changes include reduced generation of high-affinity antibodies after immunization and reduction in the naive T cell population. Innate immune system changes include both higher systemic levels of proinflammatory cytokines and increased lipopolysaccharide (LPS)-induced production of TNF and IL-6 by macrophages. Age-related functional changes occur in granulocytes, including decreased chemotaxis, phagocytosis and superoxide generation in response to danger signals. Neutrophils of elderly individuals exhibit decreased expression of CD16 (FcγRIIIa) and have alteration of mitogen-activated protein kinase (MAPK) activation, contributing to the inability of GM-CSF to decrease caspase-3 activation, leading to reduced clearance of apoptotic neutrophils. These studies suggest a complex pattern of age-related changes in gene expression in different immune cells that may result in an increased risk of inflammatory disorders (Fig. 2).
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Figure 2.
Ageing is associated with epigenetic drift with resultant increased risk of inflammatory conditions.
Environmental exposures during life affect the epigenetic signature of genes resulting in a gradual loss of control of gene expression in different tissues. These changes in immune and inflammatory cells result in the development of inflammageing with increased risk of age-related inflammatory diseases.
There is evidence suggesting a role of epigenetic drift in inflammageing. Age-related divergence of the epigenetic signature in peripheral blood has been reported in monozygotic twins; the patterns of global and gene-specific DNA methylation are similar in early life, however, older twins (age >50 years) have marked differences, particularly if they were separated early in life. A longitudinal study of the methylation status of 1505 CpG motifs in 807 genes reported changes in immune genes, including IL-10 and IL-16. Levels of methylation of CpG motifs in the TNF promoter gradually decease with age, by ~1.4% per decade in macrophages, and may be a mechanism of the age-related increased systemic levels of this key proinflammatory cytokine. Inflammation per se can lead to alteration in the epigenetic signature via the effects of reactive radicals oxidizing 5-methylcytosines to 5-hydroxymethlycytosine, with subsequent loss of methylation. Conversely the production of reactive halogen molecules, such as HOCl and HOBr, by activated leucocytes can result in the incorporation of halogen cytosine into DNA with subsequent increased methylation.