Abstract
Neutrophil dysfunction has been described with age, appears exaggerated in infection, with altered phosphoinositol signaling a potential mechanism. However, functional aging is heterogeneous. Frailty is a negative health status and is more common in older adults. We hypothesized that neutrophil migration may be compromised in frailty, associated with the degree of frailty experienced by the older person. We compared measures of frailty, neutrophil function, and systemic inflammation in 40 young and 77 older community-dwelling adults in the United Kingdom. Systemic neutrophils exhibited an age-associated reduction in the accuracy of migration (chemotaxis) which was further blunted with frailty. The degree of migratory inaccuracy correlated with physical (adjusted hand grip strength) and cognitive (Stroop test) markers of frailty. Regression analysis demonstrated that age, Charlson comorbidity index, and frailty index were able to predict neutrophil chemotaxis. Reduced chemotaxis of neutrophils from frail adults could be reversed using selective PI3K inhibitors. Exposure of neutrophils from young adults to plasma from chronically inflamed frail older adults could not recapitulate the migratory deficit in vitro, and there were no relationships with systemic inflammation and neutrophil dysfunction. Frailty exaggerated the neutrophil deficits seen with advanced age but aspects of the frailty-associated deficit in neutrophil function are rescuable and thus potentially form a therapeutic target to improve outcomes from infection in older adults.
Highlights
Inflammation and immune cell function have been implicated in the pathophysiology of frailty [5]
Neutrophil Chemokinesis Is Preserved With Frailty But Chemotaxis Is Reduced There were no significant differences in the speed of migration in any direction of isolated neutrophils to fMLP or CXCL8 between the 3 groups, frail older adults (FO), healthy older adults (HO), or healthy younger adults (HY) (Supplementary Figure S1A and C)
This study presents novel data on the differential effects of age and frailty on neutrophil function, linking migratory accuracy with global markers of function
Summary
Inflammation and immune cell function have been implicated in the pathophysiology of frailty [5]. Neutrophils are of primary importance during infective challenges, and previous work by our group and others have described neutrophil dysfunction with an individual’s increasing age. This includes reduced phagocytosis to some but not all pathogens [11], a failure to prevent apoptosis in the presence of inflammatory stimuli, reduced neutrophil extracellular. Trap formation [12], and inaccurate migration [13,14] These altered functions have been postulated to represent a marker of biological age [15]. The systemic inflammation associated with aging and frailty might alter neutrophil behaviors, making the cells less responsive to chemotactic cues seen during inflammation and infection. We further hypothesized that PI3K signaling would be implicated in altered neutrophil migration
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