Metabolomic insight into the link of Intermuscular Fat with Cognitive Performance: The Health ABC Study

There is growing evidence that higher intermuscular fat (IMF) is associated with worse processing speed, measured by the digit symbol substitution test (DSST) in older adults. However, the underlying biological mechanisms are not well understood. Considering that both muscle and the brain are metabolically active organs, we sought to identify metabolites that may explain the IMF-DSST association. We assessed 613 plasma metabolites in 2388 participants from the Health, Aging and Body Composition Study (mean age ± SD: 74.7 ± 2.9 years, 50% men, 63% white), using liquid chromatography-mass spectrometry. We found that higher IMF was associated with worse DSST scores (standardized beta (95% CI): -0.08 (-0.12, -0.03), p<0.001). Sixty-six metabolites were significantly associated with both IMF and DSST. Four of the 66 metabolites attenuated the association by ≥10%: higher levels of adrenic acid (polyunsaturated fatty acid), and lower levels of C20:5 lysophosphatidylcholine (lysophospholipid), 1-methylnicotinamide (vitamin B3-related myokine), and maslinic acid (triterpene) were associated with higher IMF and worse DSST. Together, they explained 41% of the IMF-DSST association. Pathway enrichment analyses identified two significant shared pathways: unsaturated fatty acid metabolism and the citrate (TCA) cycle. This study provides hypothesis-generating evidence that a set of circulating metabolites related to unsaturated fatty acids, energy metabolism, and myokines may partially explain the inverse association of IMF with processing speed. The findings, if further confirmed by independent studies, advance our understanding of molecular pathways underlying muscle-brain crosstalk and raise the possibility of metabolites as potential predictive biomarkers and/or therapeutic targets.