PROJECT ABSTRACT The aging population will double to 2 billion by 2050. Natural lung aging is associated with progressive changes at molecular and physiological levels, causing a decline in lung function and impaired immunological responses. To avoid cumulative damage, lung-resident cells rely on a robust homeostatic balance of stress response pathways; however, at a certain tipping point(s) (point of no return), aging finally overwhelms these control mechanisms leading to an increased oxidative environment and irreversible damages. Our data indicate that lung tissue in the elderly (in humans and mice) has high inflammation and oxidative stress baselines, leading to dysfunction of critical innate soluble and cellular components driving host susceptibility to respiratory infections [e.g., Tuberculosis (TB) and Coronavirus disease 2019 (COVID-19)]. Defining when and how these changes occur in the lung at the cellular and molecular levels is critical to understanding age-associated lung-specific pathologies and aging in general. Our data link mitochondrial dysfunction to cumulative oxidative stress in the lung of the elderly, where interventions that reduce lung oxidative stress can reverse susceptibility to respiratory diseases. Mitophagy (mitochondrial autophagy) is also impaired at this stage, resulting in increased accumulation of oxidative stressors in cells. We now hypothesize that aging-associated mitochondrial dysfunction and impaired mitophagy is central to the collapse in pulmonary control of mycobacteria. Using the well-accepted mouse model of aging, this application aims to determine whether aging-associated mitochondrial dysfunction drives increased oxidative stress in lung cells, generating a permissive lung environment for respiratory infections such as Mycobacterium tuberculosis, the causative agent of TB. Completing the F99 phase will facilitate my transition to the postdoctoral phase (K00 phase) by providing robust intellectual and technical training and, consequently, contributing to my goal of becoming an independent researcher in the biology of Aging field.