Inflammageing

The concept of inflammageing, a state of discrete chronic inflammation, has been discussed in depth in Chap. 1. In brief, it is characterised by an age related immune imbalance with increased pro-inflammatory cytokines such as IL-6, CRP, TNFa and decreased IL-10, an anti-inflammatory cytokine.

A positive association has been demonstrated between IL-6 and CRP with frailty on multiple occasions in different frail populations [41-43, 53]. High levels of IL-6 predict disability and mortality, which are significant outcomes in frailty, in older community dwelling adults [54-56]. PBMCs from frail older adults produce greater amounts of IL-6 on stimulation compared to non-frail counterparts [57].

Inflammatory and immunological biomarkers of frailty have been used in a variety of settings to predict poor outcomes [28,58] The Biomarker Frailty Index incorporates markers of inflammation and immunesenescence as well as haematological and genetic markers. This model is associated with mortality and at low levels of frailty is better than the frailty index at predicting mortality [28].

Investigation of the individual components of sarcopenia and frailty has demonstrated an association with inflammageing and inflammageing predating a loss of physical function. Cross-sectional studies have demonstrated both an association of high levels of IL-6 and TNFa with low muscle mass and strength [59] and low levels of CRP with high grip strength [60]. Longitudinal studies have shown that higher levels of IL-6 predict reduction in fat free mass, a hallmark of sarcopenia [61]. Higher levels of IL-6 and CRP at baseline equate to a two- to threefold greater risk of losing more than 40 % of grip strength over a 3-year follow up [62]. TNFa mRNA and protein levels are higher in frail older adults. It was also demonstrated that this could be reversed with an exercise program, which correlated with an increase in muscle strength [63].

The frailty murine model, IL-10 knock out mouse, has increased levels of IL-6 at 50 weeks and phenotypically displays increased muscle weakness and decreased activity levels in comparison to the wild type [51]. In murine models the exogenous administration of TNFa results in anorexia and weight loss in the mouse [64, 65].

In centenarians IL-6 -174 GG genotype, associated with higher plasma levels of IL-6, is under represented and IL-10 -1082 CC, associated with higher plasma levels of IL-10, are over-represented [46].

The limited data available demonstrates that frailty is associated with a state of chronic inflammation. There is also evidence that inflammageing predates a diagnosis of frailty suggesting a causative role.

 
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