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Chronic Inflammation

Extensive data generated over the past 25 years shows a robust relationship between –physical frailty and modest elevations in inflammatory mediators including C-reactive protein (CRP),  white blood cell count (WBC), neutrophils, Interleukin 6 (IL6) (Leng et al., 2007; Walston et al., 2002; and Soysal, 2016).  This modest elevation in inflammatory mediators is often called chronic inflammation (CI).  Many of the earliest biology focused studies of frailty were cross sectional evaluations of the relationship between inflammatory markers and frailty status or future frailty status.  These results were often dismissed as “epidemiological phenomena,” meaning that the elevations could have been related to ongoing chronic disease states or other issues independent of frailty status.  However, subsequent studies have consistently demonstrated significant relationships between patterns of elevated inflammatory cytokines in midlife and the subsequent development of frailty (Leng et al., 2007; Walston et al., 2002; and Walker et al., 2018).   

Others, including a longitudinal study of CRP and fibrinogen and incident frailty reported an association between elevated levels of these inflammatory markers and the onset of frailty among women, but not among men (Gale et al., 2013). 

Importantly, there is now considerable evidence that increased inflammatory cytokines actually drive many of the biological changes thought to drive frailty, including loss of satellite cells in skeletal muscle and neurological tissue, mitochondrial dysfunction, glucose intolerance, and chronic anemia. (Ferrucci and Fabbri, 2018).  Chronic inflammatory mediators also likely further dysregulate the immune system, driving additional propensity towards inflammatory pathway activation and ultimately pathophysiological cellular and tissue based changes.   Additionally, chronic inflammation drives the conversion of tryptophan to a series of neurotoxic intermediates that may drive muscle weakness and physical frailty (Westbrook et al., 2020).   

CI is also likely stimulating critical biological pathways that drive the strong relationships between physical frailty, chronic disease states, mild cognitive impairment, Geriatric syndromes, and adverse health outcomes (Ferrucci and Fabbri, 2018).  For example, an association between preoperatively elevated markers (IL-6, CRP) and postoperative-onset delirium has been found in multiple studies (Capri et al., 2014; Pol et al., 2014; and  Vasunilashorn et al., 2015).  Additionally, cortisol and DHEA-S, studied as markers frailty and of the state of stress on the hypothalamic-pituitary-adrenal axis, are impacted by chronic inflammation and have been predictive of delirium incidence among hospitalized older adults (Rigney et al., 2010) and predicting postoperative delirium (Cerejeira et al., 2013). 

 In summary, CI appears to play a critical role in the development of physical frailty as well as driving a number of molecular, cellular, and tissue based changes that help account for the marked vulnerability to stressors and adverse health outcomes observed in frail, older adults.