The role of Interleukin-6 in age-related frailty syndrome

Aging is accompanied by chronic low-grade inflammation – a term which relates to increase in serum levels of cytokines such as interleukin 6 (IL-6), TNF-α and acute phase proteins such as C-reactive protein. Multiple studies in humans have shown that IL-6 most reliably increases with aging. Frailty is a geriatric syndrome characterized by decrease in physical ability and increased vulnerability to stressors. One of the most consistent findings in frail subjects is an elevation of serum IL-6 but we lack research which delineates is this a causational relationship. We developed a mouse model with inducible IL-6 expression (IL-6TET-ON/+ mice) that enables overexpression of IL-6 following stimulation with doxycycline (dox) administrated in food. IL-6 induction was dose dependent and led to increase in frailty as measured by 30-point murine clinical frailty index. Mice induced to express high levels of IL-6 quickly displayed an increase in frailty index, decrease in muscle grip strength and loss of fat. Mice induced to express 3–4 fold increase in IL-6 similar to frail humans displayed similar changes after months of induction. We measured IL-6 levels in serum and various tissues (gut, muscle, adipose, spleen) of aged (28-month-old) frail mice and adult controls as well as dox fed IL-6TET-ON/+ mice. We observed that IL-6 levels were increased in serums and spleen homogenates of aged mice and IL-6TET-ON/+ mice but not in other tissues. We determined that neutrophils were the main producers of IL-6 and their numbers were higher in spleens of aged and IL-6TET-ON/+ mice compared to adult controls. We conclude that elevated IL-6 serum levels are directly associated with age-related frailty and that spleen neutrophils are likely the main producers of IL-6.