Novel biomarkers of frailty in middle-aged and older females

The burden of frailty and its associated health complications, including cardiovascular disease, is becoming a critical health concern. Frailty is a multifactorial physiological decline that increases vulnerability to health stressors. Blood-based biomarkers have been suggested as a means of identifying frailty declines earlier. Specifically, myokines, muscle-derived cytokines involved in inter-organ communication, have emerged as potential biomarkers of frailty given the deterioration in muscle health seen in this population. This dissertation investigates the association of myokines with frailty through a series of studies utilizing both univariable and multivariable analyses. Chapter 2 of this thesis discusses the application of frailty assessment to the clinical setting. Chapter 3 and 4 examine the association of univariable systemic myokine concentrations related to muscle to phenotypic frailty using data from a cohort study examining novel cardiovascular disease risk factors. These works identified fractalkine/CX3CL1 as being associated with frailty, potentially indicating early immune dysregulation. IL-6, IL-15, TNF alpha, myokines associated with inflammation, and Leptin, which plays a role in metabolism, were associated with cardiovascular disease risk. Chapter 5 utilizes a multivariable design to examine myokines associated with frailty in a larger data set analyzed from the WARM Hearts cohort study for both a phenotypic assessment of frailty and a frailty index. The stepwise multivariable regression analysis identified BDNF, FABP-3, OSM and osteocrin in the model for the frailty index. These data support the association of myokines related to inflammation and metabolic function with frailty, as well as with cognition. In contrast, only SPARC, a myokine related largely to muscle function and mass, added to the model predicting Fried score. These preliminary works support the notion of myokines acting as biomarkers of frailty with those involved in inflammation and metabolic function seeming to be most likely to add value to such a model. Future work should further elucidate the physiological role myokines regulate in the human body, determine the optimal means of measuring myokines in a clinically feasible method, health interventions to modulate their expression and release, and clinical outcomes following this modulation.