Metabolomic Pathways of Inflammation and Mitochondrial Dysfunction are Related to Worsening Healthy Aging Index and Mortality.

Background: Metabolic-inflammatory states are central to multiorgan mechanisms of aging, but precise functional biomarkers of physiological aging remain less clear.

Methods: In the Health, Aging and Body Composition study, we defined metabolomic profiles of the Healthy Aging Index (HAI), a composite of cardiovascular, lung, cognitive, metabolic, and renal function (0-10, with higher scores indicating poorer health) in a split set design from 2015 older participants (mean age 73.6 years; 50% women; 35% Black). We used standard regression to identify metabolomic correlates of Year 1 and Year 10 HAI, change in HAI over time, and mortality. A metabolite score of HAI was developed using LASSO regression.

Results: We identified 42 metabolites consistently associated with Year 1 and Year 10 HAI, as well as change in HAI: 13 lipids, 4 amino acids, and 4 metabolites of other classes were associated with worse and worsening HAI while 20 lipids and 1 amino acid was associated with better and improving HAI. Most of these associations were no longer significant after additionally adjusting for inflammation biomarkers. A higher metabolite score of Year 1 HAI was associated with greater HAI deterioration over time (hold-out "test" set beta 0.40 [0.15-0.65]) and higher mortality (hold-out "test" set hazard ratio: 1.43 [1.23-1.67]).

Conclusions: A multi-organ healthy aging phenotype was linked to lipid metabolites, suggesting potential pathways related to mitochondrial function, oxidative stress and inflammation. Metabolomics of HAI at older age were related to worsening health and mortality, suggesting potential links between metabolism and accelerated physiological aging.