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Metabolomics-Based Identification of Metabolic Dysfunction in Frailty

Westbrook R, Zhang C, Yang H, Tian J, Guo S, Xue QL, Walston J, Le A, Abadir PM
The Journals of Gerontology: Series A 2022 77(12):2367-2372

Bibliography

PubMed
PMID 36580380
PubMed Central
PMC9799179
DOI
10.1093/gerona/glab315
Funding
Supported by the Johns Hopkins University Claude D. Pepper Older Americans Independence Center/NIA (P30AG021334), NIH grants UH3 AG056933, R01AG046441, K23 AG035005 and S10 1S10OD025226-01, the BrightFocus Foundation, the Nathan W. and Margaret T. Shock Aging Research Foundation/Nathan Shock Scholar in Aging, and the American Federation for Aging Research.
Competing interests
None declared.

Study snapshot

DesignCross-sectional targeted and untargeted serum metabolomics study.
ModelCommunity-dwelling adults aged 20-97 years.
Sample146 participants: 45 young adults and 101 older adults; older group included 29 frail and 72 nonfrail participants.
InterventionNo supplementation; observational serum metabolomics.
DurationCross-sectional.
EndpointsSerum alpha-ketoglutarate and TCA-cycle metabolites; Frailty status; Grip strength; Walking speed; Inflammatory cytokines

What the study showed, in plain terms

This human metabolomics study is important because it directly challenges the often-repeated claim that circulating AKG falls sharply with age.

Serum alpha-ketoglutarate was significantly higher in older adults than in young adults, and both frail and nonfrail older groups had higher AKG than young participants. The authors explicitly noted that the previously suggested ten-fold decline with age was not apparent in their cohort.

The study is cross-sectional and does not prove that higher AKG causes frailty or that supplementation is harmful. It shows that age-related AKG biology is context-dependent and cannot be reduced to a universal decline narrative.

Key findings

  • Serum AKG was significantly elevated in older adults versus young adults.
  • The reported age-related ten-fold decline in plasma AKG was not observed in this cohort.
  • AKG correlated positively with IL-6 after age adjustment, while broader TCA-cycle dysregulation accompanied aging and frailty.

What this study can and cannot tell us

  • Cross-sectional design cannot establish causality.
  • Participants were not fasted, which can affect circulating metabolites.
  • Serum concentration is not the same as tissue-specific AKG availability or flux.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology