Inflammation rises in aging to promote age-associated diseases including type 2 diabetes, cardiovascular disease, and cognitive decline and is thus recognized as a significant cause of death across the globe. Metformin broadly alleviates age-associated inflammation, or inflammaging. The proposed project will identify mechanisms of metformin action on age-associated changes in CD4+ T cell function. Focus on this cell type is justified by data herein that used bioinformatics to uncover a Th17 cytokine profile preferentially produced by CD4+ T cells from sexagenarians. This inflammaging profile is strikingly similar to the profile that characterizes a major challenge to healthspan, type 2 diabetes. Our new data show that physiologically achievable amounts of metformin ameliorate the Th17 inflammaging profile by improving mitochondrial bioenergetics and/or autophagy in CD4+ T cells from older subjects. Metformin concurrently increased non-mitochondrial glycolysis and thus lactate production, but had none of these effects on cells from younger subjects. Data herein challenge dogmas that glycolysis fuels inflammation, and raise the possibility that metformin can target either one of the two required inflammatory pathways to lower age-related inflammation. We will test the central hypothesis that metformin ameliorates a Th17 inflammaging profile through targeting one of two critical mechanisms, non-mitochondrial autophagy or excessive mitochondrial OXPHOS, to increases lactate and block age-related Th17 cytokine production. We will analyze CD4+ T cells from overweight/obese subjects 60-85 yrs of age, with cytokine profiles as our primary outcome. Some studies will use cells from younger adults to test conclusion from aged cells. We will inhibit/activate each step of the hypothesized pathway in cells stimulated in the presence/absence of metformin, and measure effects on downstream elements with rigorous statistical and bioinformatic tests to query similarities/differences in cytokine profiles. This approach will establish cause/effect relationships amongst metformin and mechanisms that drive age-related inflammation. Finally, comparison of mechanistic changes in T cells from older subjects exposed to metformin in vitro and in vivo, the latter from people who take metformin as part of their clinical care, will establish clinical relevance of our in vitro mechanistic work to meet our main objective: to pinpoint mechanisms by which metformin lowers inflammaging en route to improving healthspan.
Numerous studies support the premise that inflammation, as indicated by circulating pro- inflammatory cytokines, rises in aging and triggers age-related health declines. Drugs with anti- inflammatory actions such as metformin are being investigated as means to promote the length of one's life spent in good health. To better understand the anti-inflammatory actions of metformin, we will define molecular mechanisms underlying metformin's impact on inflammatory cells from older subjects, and compare those outcomes to cells from people who take metformin as part of their clinical care.
