Kynurenine accumulation drives loss of muscle and bone function with aging

This is a competitive renewal application of our currently funded Program Project (P01) award now titled “Kynurenine Accumulation Drives Loss of Muscle and Bone Function with Aging”. Loss of muscle and bone mass with age are underlying factors contributing to falls and fractures in the elderly, and these fractures are very costly both in terms of financial burden and quality of life. A critical barrier to progress in correcting the problem of muscle and bone loss with aging is a poor understanding of the molecular and cellular mechanisms driving age-related musculoskeletal dysfunction. Major findings from the previous four years of funding include: (1) aging results in increased serum levels of the tryptophan (Trp) metabolite kynurenine (Kyn), a by-product of Trp degradation by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1); (2) elevated Kyn levels in older patients are significantly associated with fragility hip fractures and markers of frailty; and (3) the aryl hydrocarbon receptor (AhR), which is activated by Kyn and its downstream metabolites, likely mediates the effects of Kyn on muscle and bone. Our central hypothesis is that AhR activation by Kyn and its metabolites with aging induces muscle and bone loss. Four individual projects, focused on Kyn-AhR interactions with the aging musculoskeletal system, comprise this application. The proposal also includes three Core facilities that will provide essential support to the Projects: an Administrative Core (Core A) that will serve to coordinate the activities of the different projects, supervise recruitment and mentoring of junior aging researchers including medical students from Puerto Rico, and provide biostatistics and bioinformatics support; a Functional Outcomes Core (Core B), which will provide resources for body composition (DXA), bone and muscle histomorphometry, bone imaging and RNAscope, bone mechanical testing, muscle functional testing, and mouse gait assessments; and a Cellular Aging Core (Core C) which will measure inflammatory cytokines associated with the senescence-associated secretory phenotype (SASP) and provide bone- and muscle-derived stem cells to all investigators, as well as perform assays of mitochondrial function, mitophagy, and autophagy in muscle and bone cells. The project has three specific aims: Aim 1 will test the hypothesis that age-related increases in AhR signaling by Kyn and its metabolites alter musculoskeletal stem cell function and muscle-bone crosstalk; Aim 2 tests the hypothesis that specific interventions that either reduce Kyn accumulation with aging or inhibit AhR signaling with aging can prevent age- related changes in muscle and bone stem cell function; and Aim 3 will determine the mechanism(s) by which increased activation of the Kyn-AhR pathway leads to musculoskeletal dysfunction in a sex-specific manner. The long-term impact of this Program Project will be the identification and development of new targets and countermeasures for preventing or reversing musculoskeletal aging.