Tier 4 — mechanistic

α-Ketoglutarate inhibits autophagy

Baracco EE, Castoldi F, Durand S, Enot DP, Tadic J, Kainz K, Madeo F, Chery A, Izzo V, Maiuri MC, Pietrocola F, Kroemer G
Aging (Albany NY) 2019 11(11):3418-3431

Bibliography

PubMed
PMID 31173576
PubMed Central
PMC6594794
DOI
10.18632/aging.102001
Funding
Supported by European and French cancer/aging research programs, ERC and associated academic grants; NAWI Graz and BioTechMed-Graz also supported the work.
Competing interests
Guido Kroemer and Frank Madeo disclosed being scientific cofounders of Samsara Therapeutics.

Study snapshot

DesignMechanistic cell-culture, metabolomics and yeast experiments comparing membrane-permeable AKG esters.
ModelHuman and mammalian cell systems plus yeast; no oral supplementation cohort.
SampleLaboratory experiments across multiple cell systems; no clinical cohort.
InterventionDimethyl-, trifluoromethylbenzyl- and octyl-AKG esters used to manipulate intracellular AKG.
DurationAcute laboratory exposure protocols.
EndpointsAutophagic flux; Cellular metabolism; ATP and metabolite changes; mTOR-related signaling

What the study showed, in plain terms

This mechanistic study is important because it complicates the simplistic claim that AKG is an autophagy activator.

Different cell-permeable AKG esters produced different metabolic effects, and intracellular AKG could inhibit starvation-induced autophagy under the tested conditions.

It does not test oral Ca-AKG in people, but it shows that the AKG-autophagy relationship is context- and formulation-dependent.

Key findings

  • Intracellular AKG could suppress starvation-induced autophagy in the tested laboratory systems.
  • Different AKG esters were not biologically interchangeable.
  • Mechanistic effects depended on how AKG was delivered into cells.

What this study can and cannot tell us

  • In-vitro/mechanistic evidence rather than oral supplementation.
  • Cell-permeable AKG esters are not equivalent to calcium alpha-ketoglutarate supplements.
  • Results should not be translated into a clinical recommendation to use or avoid Ca-AKG for autophagy.

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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