ABSTRACT/SUMMARY: Patients who survive an Intensive Care Unit (ICU) hospitalization will likely experience new or worsened physical, mental, and/or cognitive impairments (termed Post-Intensive Care Syndrome (PICS)). The most vulnerable to long-term physical and cognitive impairments are older adults (>60 y) because of pre-existing age-related physical frailty or cognitive frailty. Both of which increase a survivor’s likelihood of developing Alzheimer’s diseases and related dementias. However, although advances in critical care treatments have reduced mortality rates among older adult ICU survivors, roughly 67% suffer PICS. Yet, identification of at-risk older adults during admittance is likely difficult because of the 1) homogeneity in the clinical presentation of patients with pre-existing age-related physical frailty and critical illness compared to those suffering from only critical illness and 2) many patients arrive severely debilitated making administration of physical function or other volitional assessments difficult. Therefore, it is essential that new biomarkers to guide early diagnosis, prognosis, and disease monitoring are identified. To this point, tryptophan derivatives, particularly kynurenines and nicotinamide family (e.g., NAD+), have been shown to mediate the relationship between chronic inflammation and physical impairment or signal accelerated aging, respectively. However, it remains unknown if similar associations exist in older adult ICU patients and the prognostic utility of elevated neurotoxic tryptophan metabolites relative to neuroprotective tryptophan metabolites to predict adverse health outcomes while in the ICU. Thus, to fill this knowledge gap I have design three studies to explore the associations between tryptophan derivatives, musculoskeletal health, and cognitive function pre-, intra-, and post-ICU stay. Skills gained during this fellowship will provide be a better understanding of frailty and muscle-brain crosstalk, via the kynurenine pathway, that occurs during an ICU stay and how it may influence long-term physical and cognitive health.