Defining the landscape and mechanisms of redox regulation of metabolism during aging

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PROJECT SUMMARY: Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). Despite the longstanding links between ROS dysregulation and aging, technological limitations have resulted in a persistent absence of information on the exact protein cysteines are modified by ROS that explain the molecular basis for this dysfunction in vivo. Using the cysteine-phospho tag (CPT) proteomics technology that I developed, I have determined that a fundamental remodeling of protein cysteine oxidation networks occurs with caloric restriction (CR) in aging. Building on this, I will determine the functional role of redox regulation of newfound protein networks that are linked to the lifespan and healthspan benefits of CR in aging. I have also extended Oximouse to diversity outbred (DO) mouse populations to recapitulate the genetic diversity of human population, in search for redox signaling targets that have high translational potential. Preliminary data from this effort has identified conserved redox signaling targets on proteins that may have critical implications in age-dependent decline of thermogenesis leading to age-related obesity. I will study metabolic redox signaling nodes underlying longevity- modifying interventions and delineate the mechanisms through which these targets are redox-regulated with age that lead to a decline in thermogenic activity. The proteomics data will provide a rich resource for the community to explore ROS and aging. The mechanistic studies will validate redox signaling nodes that can potentially be manipulated to extend lifespan and healthspan, in line with the mission of the National Institute of Aging. Objectives: (1) Defining mitochondrial cysteine oxidation mechanisms underlying the health benefits of CR. (2) Determining adipose metabolic redox signaling nodes underlying longevity-modifying interventions. (3) Investigating the mechanisms of redox control in age-related obesity. The first two objectives will be completed during the K99 phase, and the last objective will be carried out during the R00 phase. This work builds on a redox proteomics technology that I developed, which quantifies absolute cysteine redox modification stoichiometry at orders of magnitude deeper proteome coverage than previous methods. From this big data, I will mechanistically validate individual redox signaling nodes that have important roles in metabolism and longevity. I will be mentored by Drs. Chouchani and Gygi, who are experts in the fields of ROS biology, metabolism, animal physiology, and mass spectrometry (MS)-based proteomics. I will additionally learn from my collaborators/consultants, Drs. Mair, Gladyshev, Banks, Gupta, and Spiegelman, who have extensive expertise in aging, animal physiology, and metabolism. The rich scientific environment at DFCI and HMS adds fuel to my enthusiasm to establish myself as an independent investigator. My unique skillset will allow me to develop novel technologies to study the biology of aging in a “big-data” driven manner, then select targets for mechanistic validation to provide insights for future translational therapeutic development.