Mitochondrial Aging Promotes Inflammation

文摘:

Abstract: Mitochondrial Aging Promotes Inflammation Aging is often associated with a progressive decline in health resulting in a decline in the quality of life that limits healthspan, defined as number of years spent in good health. One critical goal of aging research is to increase “healthspan”. This goal is especially important because according to CDC, the number of US adults aged >65 or older will more than double to approximately 71 million by the year 2030, and present healthspan data project an untenable drain on our healthcare system in addition to the obvious personal burden. Of the many cellular processes that decline with age, mitochondrial dysfunction is especially important because numerous studies show a link between failing mitochondria and the development of age-associated diseases. This proposed project will evaluate age associated mitochondrial translocation of STAT3(mitoSTAT3) as the driver of an aberrant addictive dependence of aging CD4+ T cells on oxidative phosphorylation(oxphos) and impaired upregulation of the aerobic glycolysis to promote inflammation. Our data shows that CD4+ T cells from lean normoglycemic older adults (avg age 62 yrs) produce higher amounts of proinflammatory Th17 cytokines compared to cells from lean normoglycemic younger adults (avg age 32 yrs). We experimentally established that this proinflammatory profile was secondary to an aberrant mitochondrial respiratory profile, lower glycolysis and impairment in autophagy, the cellular recycling process known to decline with age. We observed that T cells from older subjects had higher mitoSTAT3, which is known to drive oxphos dependence in many cell types. We also observed that mitochondrial translocation of STAT3 occurred in an autophagy dependent manner. Genetic inhibition of autophagy in T cells from younger subjects, promoted mitochondrial translocation of STAT3, resulting in a bioenergetic and inflammatory profile that mimicked that of aging T cells. Hypothesis: Preventing aging induced mitochondrial translocation of STAT3 improves T cell function and alleviates inflammation. We will utilize the newly developed small molecule inhibitors of mitoSTAT3 to either directly inhibit mitochondrial translocation of STAT3 or indirectly by promoting autophagy and thereby limit mitoSTAT3. We hypothesize that the metabolic reprogramming promoted by limiting mitoSTAT3, would result in higher glycolysis and lower oxphos dependence, improved T cells function and would alleviate inflammation. We will establish cause and effect by manipulating mitoSTAT3 using genetic and pharmacological gain-and-loss of function approaches. This mechanistic work will map the role of mitoSTAT3 in the regulation of T cell metabolism and inflammation during aging and has therapeutic implications towards the goal of improving health span. .