Metabolism is the complex web of chemical reactions related to energy generation that an organism must maintain and regulate in order to sustain life. These chemical reactions store and spend the energy needed for physiological functions. These reactions also construct, maintain, and dismantle pools of chemical building blocks needed for cell and tissue homeostasis. Multiple metabolic factors likely play a role in the development of frailty, including mitochondrial function, nutrition, energy homeostasis and life-style factors (Picca et al., 2020). This complexity poses a challenge to research on the relationship between frailty, symptoms of declining weight, strength and energy, and changes in the metabolic processes that normally support such functions.

In the age of “Omic” technologies (systems for measuring and analyzing a large number of variables in a single experiment), methods for measuring many metabolites at once (metabolomics) provide new and important insights into the complexities of how living systems work (Pan et al., 2020). By simultaneously detailing the flux of hundreds of lipids, amino acids, carbohydrates, and nucleic acids, metabolomics can generate an “integrated” signal that reflects all the diverse factors affecting metabolism, including genetic background, physiologic function, and environmental exposures such as diet and pollutants.

Several potential metabolic pathways mediating the increasing frailty risk seen in aging have been proposed from metabolomics and other analyses:

  •  In a mouse model of frailty, metabolites in the kynurenine pathway were differentially detected and these pathway abnormalities, including elevation of the kynurenine/tryptophan ratio, correlate with inflammatory markers such as IL-6 and soluble TNF-αR as well as measures of muscle strength and weight loss in mice (Westbrook et al., 2020). Similar correlations were observed in frail vs non-frail older humans as determined by the physical frailty phenotype.
  • Several metabolites in the kynurenine pathway have been identified as toxic to cells and particularly to neurons. In the same study, in both frail mouse muscle tissue histology and motor neuron cell cultures, exposure to kynurenine pathway metabolites was associated with signs of neuron degeneration (Westbrook et al., 2020).
  • Dysregulation in carnitine metabolism correlated with frailty index scores based on deficit accumulation in a large cohort of older adults (Rattray et al., 2019). Carnitines are involved in energy generation through fatty acids oxidation (β-oxidation)—a form of mitochondrial energy generation. Genetic defects in this pathway are associated with dysfunction of the mitochondrial electron transport chain and myopathy. Age-associated dysfunctions in this pathway might play a similar role in loss of energy production and muscle strength in frailty (Ferrucci and Zampino, 2019).
  • Other metabolic studies have also suggested a role for changes to mitochondrial function in physically frail older adults. In a recent study using phosphorus (31P) magnetic resonance (MR) imaging, physically frail older adults had faster rates of decline in skeletal muscle high-energy phosphate during physical exertion compared to healthy middle-aged individuals and non-frail older adults (Lewsey et al., 2020). This rate of decline on MR imaging correlated with shorter 6-minute walk distance, and lower peak oxygen consumption during cardiopulmonary exercise – findings that support a role for impaired mitochondrial function in frail older adults.
  • Another metabolomic study by Westbrook and colleagues identified some differences in glycolytic, TCA, and TCA cycle derived neurotransmitters (glutamate and GABA) in frail as compared on non-frail older adults (Westbrook et al., in press). In this case it is important to note that altered demand as well as altered metabolite supply or maintenance could affect TCA and glycolytic intermediates.
  •  Vitamin E is an antioxidant also found to be reduced in those with increased Deficit Accumulation Index (DAI) scores (Rattray et al., 2019). Declines in Vitamin E and its metabolites might lead to increased cellular damage by reactive oxygen species (ROS) (Pan et al., 2021).

While these important cross-sectional associations have been identified, cause and effect cannot be understood. More work is needed to evaluate the changes in metabolites in humans using longitudinal cohorts. Further mechanistic work is also needed to confirm the precise mechanisms by which TCA cycle, glycolysis, kynurenine, carnitine, and vitamin E metabolites mediate frailty in aging animals. Such mechanistic studies can support the development of interventions that modify these pathways and which could perhaps slow or reverse frailty.


Pan, Y., Ji, T., Li, Y., & Ma, L. (2020). Omics biomarkers for frailty in older adults. In Clinica Chimica Acta (Vol. 510, pp. 363–372). Elsevier B.V.

Picca, A., Calvani, R., Cesari, M., Landi, F., Bernabei, R., Coelho-Júnior, H. J., & Marzetti, E. (2020). Biomarkers of physical frailty and sarcopenia: Coming up to the place? In International Journal of Molecular Sciences (Vol. 21, Issue 16, pp. 1–16). MDPI AG.

Westbrook, R., Chung, T., Lovett, J., Ward, C., Joca, H., Yang, H., Khadeer, M., Tian, J., Xue, Q. L., Le, A., Ferrucci, L., Moaddel, R., de Cabo, R., Hoke, A., Walston, J., & Abadir, P. M. (2020). Kynurenines link chronic inflammation to functional decline and physical frailty. JCI Insight, 5(16).

Rattray, N. J. W., Trivedi, D. K., Xu, Y., Chandola, T., Johnson, C. H., Marshall, A. D., Mekli, K., Rattray, Z., Tampubolon, G., Vanhoutte, B., White, I. R., Wu, F. C. W., Pendleton, N., Nazroo, J., & Goodacre, R. (2019). Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty. Nature Communications, 10(1).

Ferrucci, L., & Zampino, M. (2020). A mitochondrial root to accelerated ageing and frailty. In Nature Reviews Endocrinology (Vol. 16, Issue 3, pp. 133–134). Nature Research.

Lewsey, S. C., Weiss, K., Schär, M., Zhang, Y., Bottomley, P. A., Jake Samuel, T., Xue, Q. L., Steinberg, A., Walston, J. D., Gerstenblith, G., & Weiss, R. G. (2020). Exercise intolerance and rapid skeletal muscle energetic decline in human age-associated frailty. JCI Insight, 5(20).

Westbrook, R., Zhang, C., Yang, H., Tian, J., Guo, S., Xue, Q. L., Walston, J.D., Le, A., Abadir, P. M. Metabolomics-based Identification of Metabolic Dysfunction in Frailty. Journal of Gerontology: Series A. In press.

Pan, Y., Li, Y., & Ma, L. (2021). Metabolites as frailty biomarkers in older adults. In Proceedings of the National Academy of Sciences of the United States of America (Vol. 118, Issue 1). National Academy of Sciences.