Healthy Skeletal Muscle, Healthy Brain: Are Kynurenine Metabolites the Link?

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ABSTRACT There is increasing evidence that sarcopenia is a risk factor for Alzheimer’s disease and related dementias (ADRD), but the potential mechanisms are unknown. The significance of this gap was highlighted at the 2019 NIA-sponsored U13 Osteoporosis & Soft Tissue Disorders Conference where improved understanding of the relationship of skeletal muscle and cognitive impairment was identified as a priority. As recently updated by the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia is defined as the aging- related accumulation of adverse muscle changes that culminates in muscle failure and is best characterized by poor muscle strength. Age-related sarcopenia and ADRD may be mechanistically linked by dysregulated kynurenine metabolism in skeletal muscle. Kynurenines are tryptophan metabolites with neurotoxic or neuroprotective effects. Activity-induced skeletal muscle contraction may protect against ADRD by decreasing accumulation of neurotoxic kynurenines in the brain, with effects regulated by activity-induced muscle contractions. In this study, I propose to measure plasma concentrations of kynurenine metabolites in a community-dwelling older adults to determine the relationship between physical activity, skeletal muscle strength, and neurocognitive outcomes at baseline and after two years. My central hypothesis is that physical inactivity leads to skeletal muscle alterations and sarcopenia, characterized functionally by poor muscle strength and molecularly by accumulation of neurotoxic kynurenines. Accumulation of neurotoxic kynurenines increases ADRD risk, which is reflected by greater concentrations of plasma neurofilament light (NfL) – a biomarker of neurodegeneration – and poorer cognitive performance. If the relationship between physical activity, skeletal muscle strength, and cognitive performance is mediated by neurotoxic kynurenine metabolites, that will support further studies investigating therapies directed to skeletal muscle to treat ADRD. Fortunately, I have the unique opportunity to address this research question by leveraging an existing cohort of older adults with baseline and two-year observational measures of actigraphy-based physical activity, physical performance, and cognition as well as plasma available for kynurenine determination. The goal of this project is closely aligned with the GEMSSTAR objective to support junior physician-scientists bridging geriatrics and medical subspecialties – in this case, neurology and neuropsychology – to become future leaders in aging research. Completion of these aims will support my professional development objectives, outlined within this GEMSSTAR application, by developing cross-specialty expertise in two common, co-occurring geriatric syndromes: sarcopenia and ADRD. I will develop expertise in the selection, use, and analysis of neuropsychological assessments and refine my neuroscience mentoring and collaborative networks. Results of this work will serve as preliminary data for a subsequent career development award to evaluate whether interventions that promote neuroprotective metabolites have beneficial effects on cognitive function and ADRD biomarkers. Taken together, this project and GEMSSTAR support will be critical in furthering my development at as transdisciplinary leader in aging-research.