Immune and metabolic dysfunction during aging in human cohorts

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Old age is associated with a high prevalence of metabolic alterations like type 2 diabetes mellitus (DM) and preOM 0ointly 'dysglycemia'), and with an immunologic decline associated with higher risk of developing and dying from lung infections like pulmonary tuberculosis (PTB). These immune-metabolic alterations are accompanied by failure in other organ systems (lung, brain, skeletal muscle), leading to increased morbidity and mortality. Understanding these interactions and detecting them early is critical for delaying, preventing or restoring an individual's organ system health. The underlying mechanisms for immunometabolic alterations are unknown, but our joint studies in humans and mice with and without Mycobacterium tuberculosis (M.tb) infection provide support for the role of oxidative stress and associated inflammation as a driver. Accordingly, in our Hispanic human cohort, we find that systemic oxidative stress is higher in TB or DM patients, and exacerbates age effects. We hypothesize that aging-related immunometabolic changes that drive organ failure are largely originated from impaired mitochondria-driven oxidative stress pathways. We will test these hypotheses, conducting snap-shot and longitudinal studies in humans. We will identify the age at which these changes initiate and the most affected pathway, focusing on monocytes attained from relatively non-invasive specimens. i.e., blood. These studies will take advantage of a well-defined Hispanic clinical cohort at the Texas-Mexico border and our established team of field investigators. In Aim 1, we will determine: i) when altered measures of mitochondria-induced oxidative stress and immune dysfunction are first detected in blood and monocytes during the process of aging, to identify the most effective age for interventions. In Aim 2, we will determine the impact of host biological perturbations (dysglycemia and PTB) on these outcomes. We will further evaluate if PTB may serve as a new model of accelerated aging, given its association with inflammation and oxidative stress. Overall, results will provide the foundation for future clinical testing selected interventions in-vivo and monitoring individualized responsiveness with simple biomarker testing, to promote extended cellular health and organ system healthspan.