ABSTRACT Sickle cell disease (SCD) results in premature aging and early mortality. Although we (using >15 years follow up [f/u]) and others have shown that life expectancy in SCD has improved, adults with SCD still have a life expectancy of only 58 years. Early mortality is associated with SCD-related end-organ damage, especially to the heart, lung, kidneys and central nervous system, as well as with vaso-occlusive event frequency and biomarkers such as sVCAM-1. Most remarkable, however, is that adults with SCD >50 years (now 13% of adults with SCD) have physical function similar to non-SCD adults over the age of 80. While frequency of death peaks in the 5th decade, a subpopulation of patients live into their 70's. Yet little is currently known about how best to evaluate and care for SCD patients over age 50 or predict which patients will achieve that milestone. We hypothesize that multi-omics, by representing several SCD-related and unrelated physiologic processes, strongly determine-by direct and indirect effects-both SCD organ severity and survival. Analysis of these relationships can inform our understanding of the variability in survival and the pace of aging in SCD. Elucidating the multi-omic contributions to SCD severity and mortality will also be critical for developing models of assessment and care for this population. NHLBl's TOPMed program is an extraordinary opportunity to facilitate personalized medicine for SCD, including improving our understanding of factors affecting severity and mortality. Our cohort (OMG-SCD), together with other TOPMed SCD cohorts, total >4000 samples with whole genome sequence (WGS) results and rich clinical data, including organ-function phenotypes and clinical laboratory data; several studies also have survival data. The OMG-SCD cohort also has stored plasma samples, some of which have previously been used to identify proteins associated with kidney damage. Plasma protein activity can be modulated by N-linked glycosylation and thus contributes to health and aging. Yet the role of proteomics and N-linked glycosylation is unexplored in the context of aging in SCD. Discovery of proteomic biomarkers could illuminate the underlying biologic mechanisms of accelerated aging and mortality in SCD. Here, we propose to: (1) Identify novel clinical and 'omic risk factors, including telomere length, mitochondrial copy number, and clonal hematopoiesis, for organ dysfunction and early mortality and (2) Identify proteomic and glycoproteomic biomarkers for premature mortality. Our work is poised to yield significant discoveries regarding the nature of aging and to identify 'omic risk factors of poor prognosis in SCD, thus facilitating precision medicine-guided care models in SCD.