Sarcopenia is a common co-morbidity in aging, and its presence sets the clinical stage for disability and fall risk which are both conditions of grea public health significance. The mechanisms behind why sarcopenia develops, and thus how to mitigate its development, are not fully elucidated. We propose to investigate a novel pathway that involves reduced gastrointestinal (GI) motility and thus barrier function in aging. We hypothesize that aging-related reduction in GI muscular propulsion results in altered mucosal-microbial interactions and greater microbial translocation (MT) into the circulation. MT provides systemic circulatory source of bacterial inflammatory stimuli which incites insulin resistance (IR) in muscle. IR inhibits anabolic signaling, which over time will contribute to loss of muscle mass. IR is commonly seen with aging, and had been proposed to cause inflammation. We posit that MT is a proximal event in frailty development, inciting inflammation and IR early, which in turn inhibits the maintenance of normal muscle mass. Vervet monkeys are an excellent model of healthy aging, demonstrating most common age-related co-morbidities within a 25 year lifespan including recent preliminary data indicating reduced GI motility and increased MT. Monkeys at the Vervet Research Colony are known-aged animals that have had equivalent life-long environmental exposures, and are housed in large corrals that allow opportunities to feed and exercise normally. We will measure GI motility by radiographic tracers in young and old monkeys and relate these to MT and inflammation biomarkers in plasma. We will also do a 6-week interventional study in aged monkeys to increase and decrease GI motility using available pharmaceutical agents. Main outcomes will be MT markers and mucosal integrity by measurement of the appearance of large-molecule fluorescent tracers in plasma after oral administration. The pharmacological agents chosen do not affect intestinal content or mucosal characteristics. This study will allow us to prospectively examine MT and inflammatory status as a function of GI motility. Muscle biopsies in young and old monkeys will be assessed for fiber type and size, insulin signaling and anabolic response to insulin infusion, with these endpoints related to MT. Finally, muscle function will be assessed as walking speed, activity levels, and muscle size by computed tomography, and the relationship with MT and inflammation described in young and old monkeys. With the studies we have proposed in healthy aging monkeys, we will demonstrate that normal aging is associated with greater indices of MT from the gut, and that this source of systemic inflammation leads to a decline in physical function. These studies will provide proof of concept regarding the association between age, MT, and physical function and generate excellent preliminary data to support a larger application in which we will propose to modify GI motility and MT in young and old monkeys using both pharmacological and dietary interventions. We will then prospectively evaluate muscle mass and physical function over a significant period of time as a result of variable intestinal function.

R21AG049160

2015-04-15

2018-03-31