Abstract P452: Stem Cells Defect And Alarmins S100A8/A9 Overexpression Associate With Early-stage Frailty And Poor Cardiovascular Health In Older Adults

Abstract

Importance: Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular diseases and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Objective: Here, we studied the association of hematopoietic stem/progenitor cells (HSPCs) and molecular markers of inflammaging with the cardiopulmonary phenotype and prospective adverse events of individuals classified according to levels of frailty. Methods: We conducted one observational study on two patients’ cohorts of older adults characterized for their frailty status examining the abundance (flow cytometry) and gene expression profile (RNAseq) of HSPCs, and the levels of cardiac dysfunction-associated alarmins S100A8/A9 and inflammatory cytokines (ELISA). Results: In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function and increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. We then interrogated the biomarkers in a cohort of 104 frail individuals (average age: 81 years) with multi-domain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. Conclusions and Relevance: Inflammaging resulting from alarmin and pro-inflammatory cytokines in pre-frail individuals is followed by pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 upregulation is activated within HSPCs, identifying a phenotype that drives poor cardiovascular outcomes.