The Impact of Insulin Sensitivity on the Potential of Metformin to Delay Age-related Inflammation

Inflammatory diseases limit healthspan, defined as the length of one’s life spent in good health. We propose an ancillary study on deidentified samples from a recent NIA-funded trial Antecedent Metabolic Health and Metformin (ANTHEM) that will define traits of healthy people who would benefit from metformin intervention before onset of age-related health risks like chronic inflammation. ANTHEM queries an unexpected outcome of dual interventions of metformin and exercise: metformin improved metabolic health over exercise alone in overweight/obese insulin resistant subjects, but metformin blunted exercise-mediated improvements in metabolic health of otherwise similar insulin sensitive subjects. ANTHEM tests the impact of baseline metabolic health on the effects of metformin monotherapy on insulin sensitivity and skeletal muscle mitochondria by recruiting overall healthy subjects to address the general paradigm that lifespan enhancers must start prior to onset of age-related co-morbidities for maximal benefit. The proposed work will add an inflammation arm to ANTHEM. The primary endpoint of our ancillary study will be cytokine profiles, a bioinformatic combination of cytokines that revealed a previously unappreciated Th17 profile that naturally develops systemically with age. This profile is similar to the systemic profile in type 2 diabetes, and thus suggests a mechanistic link between inflammation and this major challenge to healthspan. Metformin-mediated repair of mitochondrial bioenergetics, in combination with improved non-mitochondrial autophagy, lowered the Th17 profile in samples from older subjects. In contrast, metformin lowered IL-10 production by cells from younger subjects, arguably increasing inflammation. Our unique approach to defining “inflammation” thus clarified mechanisms of metformin action, while echoing concepts from the exercise study summarized above: metformin may benefit subjects with sub-clinical health challenges while having a negative effect on healthier people. We will apply similar approaches to query metformin’s effect on inflammation by analyzing deidentified ANTHEM samples to test the hypothesis that metformin intervention in healthy subjects with naturally low insulin sensitivity reduces cytokines known to fuel chronic inflammation, by improving mitochondrial bioenergetics and increasing non- mitochondrial autophagy in immune cells. The secondary hypothesis is that metformin will have either a negative or no impact on immune cells from highly insulin sensitive subjects. Mechanistic insights into metformin action on immune cells will be analyzed relative to changes in body composition, aging biomarkers, glycemic control, and skeletal muscle outcomes collected for ANTHEM. Parallel ex vivo manipulation of mitochondrial function and autophagy in immune cells will establish cause/effect relationships amongst metformin, cell physiology, and cytokine profiles. Success with the proposed project coupled with ANTHEM outcomes will define traits of people who would benefit from preventative metformin, and perhaps more importantly, to identify those who may be harmed by proactive metformin use.