Mitochondrial Aging Promotes Inflammation

PROJECT SUMMARY/ABSTRACT Mitochondrial Aging Promotes Inflammation Aging is often associated with a progressive decline in health, resulting in reduced quality of life that limits health span, defined as the number of years spent in good health. Of the many cellular processes that decline with age, changes in the mitochondria are significant because numerous studies show a link between altered mitochondrial function and the development of age-associated diseases. Our studies, funded by the current R15 award, show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which induces profound changes in mitochondrial structure, dynamics, and function and has a mechanistic link to proinflammatory Th17 cytokine production. Th17 cytokines (IL-17A, IL-17F, IL-21) and Th17 supportive cytokines (IL6, TNFα) are specifically known to promote age-associated pathologies such as Alzheimer's and dementia, diabetes, and several forms of autoimmunity and malignancies. In our studies, mitoSTAT3 increased the OXPHOS dependence of aging T cells and regulated mitochondrial complex II; succinate dehydrogenase (SDH). Limiting mitoSTAT3 using mitochondria-targeted STAT3 inhibitor, Mtcur-1, lowered complex II expression and activity, prevented age-induced changes in mitochondrial structure, dynamics, and function, and reduced proinflammatory Th17 inflammation. Exogenous expression of the constitutive serine phosphorylated form of STAT3, a required phosphorylation for mitochondrial translocation, in T cells from young adults mimicked changes in mitochondrial function in T cells from older adults and promoted the production of Th17 supportive cytokines. The data also showed the involvement of additional key but yet-to-be-identified factors that support Th17 inflammation concertedly with mitoSTAT3. Our recent data point to dysregulation in Nuclear factor erythroid 2-related factor 2 (NRF2) signaling as another potential mechanism in promoting age-related inflammation. The proposed work will evaluate (i) crosstalk between autophagy and mitoSTAT3 and (ii) regulation of metabolism and redox signaling by NRF2 as dominant mechanism(s) of CD4+ T cell inflammation during aging. We will utilize pharmacological and genetic loss-and-gain of function approaches to modulate autophagy mitoSTAT3, NRF2 and related proteins. This mechanistic work will map the age-sensitive regulatory mechanisms and pathways operational in T cells that promote inflammation. The study's overarching goal is to identify pathways and druggable targets for preventing the onset of inflammatory diseases during aging and improving health span.