Impact of abnormal steroid metabolome on cellular senescence, frailty and cognition

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PROJECT SUMMARY/ABSTRACT Mild autonomous cortisol secretion (MACS) is diagnosed in up to 50% of patients with adrenal adenomas1, affecting 1-2% of adult population. MACS is diagnosed based on abnormal cortisol following dexamethasone suppression; however, 24h urine cortisol concentrations are usually normal. As we recently showed in the work sponsored by the current NIDDK K23 award, patients with MACS demonstrate higher incidence of fractures and report more falls and symptoms of muscle weakness. In our preliminary data we show that when assessed by a comprehensive multi-steroid panel, patients with MACS demonstrate a unique steroid signature that is similar to aging adults without adrenal adenomas. We further found that patients with MACS demonstrate lower cognition and increased frailty and increased senescence biomarkers. Our overall objective of this project is to understand the link between the abnormal steroid signature and cognitive function, overall frailty, and biomarkers of cellular senescence. In Aim 1, the domains and the extent of cognitive impairment will be characterized in patients with MACS, and the association of cognitive function to accelerated adrenal aging, as measured by the steroid metabolome will be determined. In Aim 2, the association of cognitive impairment with frailty, advanced glycation products, and biomarkers of senescence will be determined. The proposed research will take advantage of the current structure and detailed characterization of subjects enrolled as part of the K23 NIDDK award as well as another ongoing prospective study of patients with overt hypercortisolism. The exceptional resources and institutional support at Mayo Clinic, outstanding multi- disciplinary mentorship and collaborative team, will allow advancement in understanding the steroid signature associated with cognitive decline that may serve as a diagnostic and prognostic biomarker of cognitive impairment and frailty.