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 ≥ 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.

The authors have declared no competing interest.

This work was supported by the National Institute on Aging Contracts N01AG62101, N01AG62103, and N01AG62106; National Institute on Aging Grant R01AG028050; and National Institute of Nursing Research Grant R01NR012459. This work was also supported in part by the Intramural Research Program of the National Institute on Aging, Baltimore, Maryland, USA. Metabolomics in the Health ABC study were supported by National Institute on Aging Grant R01AG059729. VLM is funded by the Melvyn Rubenfire Professorship in Preventive Cardiology. ABN is supported by the Pittsburgh Pepper Center P30 AG024827 and the UPMC Endowed chair in Geroscience. MMM is supported by the National Institute on Aging K01AG075143. Richard Xu is supported by the National Institute on Aging T32 Training Grant in Population Neuroscience of Aging and Alzheimer's Disease (5T32AG055381).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This multi-site study recruited Medicare patients from Pittsburgh, Pennsylvania and Memphis, Tennessee with the University of California, San Francisco as the coordinating unit. All participants gave informed consent, and each participating institution's human subject review board approved the protocol.

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Researchers may request Health ABC data from the NIA website at https://www.nia.nih.gov/healthabc-study. Analytical methods and R code for this study are available from corresponding author upon reasonable request.

https://www.nia.nih.gov/healthabc-study