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Abstract Heart failure with reduced ejection fraction (HFrEF) is increasingly treated with medications for type 2 diabetes mellitus (T2DM). Whether metabolic derangements in HFrEF and T2DM are associated with differential outcomes remains unclear. Therefore, understanding molecular pathways in HFrEF and T2DM and their effects on clinical endpoints is important. The FIGHT trial randomized 300 individuals with HFrEF and a recent HF hospitalization to liraglutide (a GLP-1 receptor agonist) versus placebo to assess effects on mortality, HF rehospitalization, and 6-month change in NT-ProBNP. Although the trial showed no clinical benefit of liraglutide, the trial population was highly enriched for individuals with T2DM. Sixty metabolites were quantified via mass spectrometry in plasma from 254 FIGHT participants (N = 147 (57.9%) with T2DM). Principal components analysis reduced the high number of correlated metabolites into uncorrelated factors. The association of factor levels with 90-day changes in 6-min walk distance (6MWD) and NT-proBNP, and with time to mortality or HF hospitalization were evaluated. There were no changes in metabolite factors according to treatment assignment. However, in analyses stratified by T2DM status, changes in five plasma metabolite factors correlated with changes in functional outcomes beyond adjustment: factor 2 (branched-chain amino acids [BCAA]) correlated with changes in NT-proBNP (ρ = − 0.291, p = 4 × 10–4) and 6MWD (ρ= 0.265, p = 0.011); factor 1 (medium-chain acylcarnitines; ρ = 0.220, p = 0.008), factor 4 (long-chain dicarboxylacylcarnitines; ρ = 0.191, p = 0.019), factor 5 (long-chain acylcarnitines; ρ = 0.198, p = 0.017), and factor 8 (urea cycle metabolites; ρ = − 0.239, p = 4 × 10–3), correlated with change in NT-proBNP. Factor 4 was associated with time-to-event (HR = 1.513 [95% CI 1.208–1.896], p = 3 × 10–4) with a trend towards stronger prognostic effect in T2DM (T2DM: p = 1 × 10–3, non-T2DM: p = 0.1). We identified metabolites of BCAA, urea cycle and fatty acid metabolism as biomarkers of HFrEF outcomes, with observed differences in HFrEF patients with T2DM. Such biomarkers might enable future diagnostic or therapeutic interventions in individuals with HFrEF and T2DM. Trial Registration: Clinicaltrials.gov. Identifier: NCT01800968. First posted: February 28, 2013.

Abstract While chronological age is a strong predictor for health-related risk factors, it is an incomplete metric that fails to fully characterize the unique aging process of individuals with different genetic makeup, neurodevelopment, and environmental experiences. Recent advances in epigenomic array technologies have made it possible to generate DNA methylation-based biomarkers of biological aging, which may be useful in predicting a myriad of cognitive abilities and functional brain network organization across older individuals. It is currently unclear which cognitive domains are negatively correlated with epigenetic age above and beyond chronological age, and it is unknown if functional brain organization is an important mechanism for explaining these associations. In this study, individuals with accelerated epigenetic age (i.e. AgeAccelGrim) performed worse on tasks that spanned a wide variety of cognitive faculties including both fluid and crystallized intelligence (N = 103, average age = 68.98 years, 73 females, 30 males). Additionally, fMRI connectome-based predictive models suggested a mediating mechanism of functional connectivity on epigenetic age acceleration-cognition associations primarily in medial temporal lobe and limbic structures. This research highlights the important role of epigenetic aging processes on the development and maintenance of healthy cognitive capacities and function of the aging brain.