Unraveling the metabolic underpinnings of frailty using multicohort observational and Mendelian randomization analyses

Jonathan K.L. Mak, Laura Kananen, Chenxi Qin, Ralf Kuja-Halkola, Bowen Tang, Jake Lin, Yunzhang Wang, Tuija Jääskeläinen, Seppo Koskinen, Yi Lu, Patrik K.E. Magnusson, Sara Hägg, Juulia Jylhävä

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Identifying metabolic biomarkers of frailty, an age-related state of physiological decline, is important for understanding its metabolic underpinnings and developing preventive strategies. Here, we systematically examined 168 nuclear magnetic resonance-based metabolomic biomarkers and 32 clinical biomarkers for their associations with frailty. In up to 90,573 UK Biobank participants, we identified 59 biomarkers robustly and independently associated with the frailty index (FI). Of these, 34 associations were replicated in the Swedish TwinGene study (n = 11,025) and the Finnish Health 2000 Survey (n = 6073). Using two-sample Mendelian randomization, we showed that the genetically predicted level of glycoprotein acetyls, an inflammatory marker, was statistically significantly associated with an increased FI (β per SD increase = 0.37%, 95% confidence interval: 0.12–0.61). Creatinine and several lipoprotein lipids were also associated with increased FI, yet their effects were mostly driven by kidney and cardiometabolic diseases, respectively. Our findings provide new insights into the causal effects of metabolites on frailty and highlight the role of chronic inflammation underlying frailty development.

Original languageEnglish
Article numbere13868
Issue number8
Publication statusPublished - Aug 2023
Publication typeA1 Journal article-refereed


  • biomarkers
  • frailty
  • Mendelian randomization
  • metabolomics
  • twins

Publication forum classification

  • Publication forum level 2

ASJC Scopus subject areas

  • Ageing
  • Cell Biology


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