THE ROLE OF INTERLEUKIN-6 AND ITS AFFECTS ON FRAILTY

Abstract

Frailty represents a clinical state of increased vulnerability to stressors and declined ability to rebound from an adverse event, resulting in a high risk of adverse clinical outcomes. These outcomes include disability, hospitalization, and death, and disproportionally affect the older population. The most consistent laboratory finding in patients who are characterized as frail in an elevation in serum Interleukin- 6 (IL-6). At this time, we lack the information of whether this elevation represents a causal connection. In order to investigate the role this cytokine plays in aging and frailty, we generated a new mouse model of inducible IL-6 expression, that allowed us to overexpress IL-6 with doxycycline (Dox) containing food, Titration experiments revealed that the IL-6 induction in our model was Dox-dose dependent. These preliminary experiments also allowed us to identify the Dox dose that elevated IL-6 to levels observed in old and frail mice, which in turn correspond to levels seen in frail humans. We next showed that IL-6 elevation to levels found in frail mice and humans directly led to an increase in the frailty index and a decrease in muscle grip strength. Non-transgenic littermate mice fed Dox chow were used as controls and failed to induce frailty, demonstrating that Dox alone, in the absence of the IL-6 elevation, did not lead to frailty. Aged wild type (wt) mice and young induced transgenic mice demonstrated increased IL-6 levels in the serum and spleen, but not in other tissues. Additionally, the induced transgenic mice exhibited selective elevation of IL-6 levels, but no increase in other cytokines. Our research demonstrated that elevated IL-6 serum levels were directly associated with age-related frailty and when IL-6 was induced early on, this singlehandedly resulted in an early onset of frailty.