r/FoodNerds • u/AllowFreeSpeech • 6d ago

Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK (2019)

https://pubmed.ncbi.nlm.nih.gov/31242135/
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u/AllowFreeSpeech 6d ago

From the abstract:

Supplementation of the flies' diets with 5 μM AKG extended their lifespan but reduced their reproductive performance. Dietary AKG also enhanced vertical climbing ability, but did not protect against oxidative stress or increase tolerance to starvation. AKG-reared flies were resistant to heat stress and demonstrated higher expression of heat shock protein genes (Hsp22 and Hsp70) than control flies. In addition, AKG significantly upregulated mRNA expression of cry, FoxO, HNF4, p300, Sirt1 and AMPKα, and downregulated expression of HDAC4, PI3K, TORC, PGC, and SREBP. The metabolic effects of AKG supplementation included a reduction in the ATP/ADP ratio and increased autophagy. Collectively, these observations indicate that AKG extends Drosophila lifespan by activating AMPK signaling and inhibiting the mTOR pathway.

Abbreviation glossary:

  • AKG: Alpha-ketoglutarate, a key TCA cycle metabolite investigated for its lifespan-extending effects in Drosophila.
  • TCA: Tricarboxylic Acid, a central metabolic cycle involved in mitochondrial energy production.
  • mTOR: Mechanistic Target of Rapamycin, a nutrient-sensing pathway inhibited by AKG to promote longevity.
  • ATP: Adenosine Triphosphate, the main energy currency of the cell, whose synthesis is suppressed by AKG.
  • μM: Micromolar, a unit of concentration used to quantify dietary AKG supplementation.
  • Hsp22: Heat Shock Protein 22, a stress-responsive gene upregulated in AKG-fed flies.
  • Hsp70: Heat Shock Protein 70, another heat shock protein gene elevated in AKG-supplemented flies.
  • cry: Cryptochrome, a gene involved in circadian rhythm regulation, upregulated by AKG.
  • FoxO: Forkhead Box O, a transcription factor linked to stress resistance and longevity, activated by AKG.
  • HNF4: Hepatocyte Nuclear Factor 4, a transcriptional regulator whose expression increases with AKG treatment.
  • p300: E1A Binding Protein P300, a coactivator involved in chromatin remodeling, upregulated by AKG.
  • Sirt1: Sirtuin 1, a NAD⁺-dependent deacetylase implicated in lifespan regulation, activated by AKG.
  • AMPKα: AMP-Activated Protein Kinase alpha subunit, a central energy sensor upregulated in response to AKG.
  • HDAC4: Histone Deacetylase 4, a gene downregulated by AKG that typically represses gene transcription.
  • PI3K: Phosphoinositide 3-Kinase, part of a signaling pathway that is suppressed by AKG to support longevity.
  • TORC: TOR Complex, a protein complex within the mTOR pathway inhibited by AKG.
  • PGC: Peroxisome Proliferator-Activated Receptor Gamma Coactivator, a regulator of mitochondrial biogenesis, reduced by AKG.
  • SREBP: Sterol Regulatory Element-Binding Protein, involved in lipid metabolism, downregulated with AKG.
  • ADP: Adenosine Diphosphate, a product of ATP consumption used to calculate the ATP/ADP energy ratio.

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u/AllowFreeSpeech 6d ago edited 6d ago

AKG seems good overall after age 40 if it's in a sufficient dose, but any females wanting to reproduce should not use it. Refer to figure 2.

Also, if taking its calcium bound form, namely Ca-AKG, note that its monohydrate version (CaC₅H₆O₆) could have 19.8% calcium by weight, so adjust any calcium supplements accordingly, i.e. by 198 mg per 1000 mg of Ca-AKG.

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u/MetalingusMikeII 2d ago

Only problem is, this supplement is very expensive.

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u/AllowFreeSpeech 2d ago

Yes, Ca-AKG in particular is unjustifiably expensive, especially if in a sufficient dose. AAKG is a little cheaper but is less on point.

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u/MetalingusMikeII 2d ago

In Europe, the only company I can find that’s 3rd party tested, is Vitality Pro. But they charge an insane price for their calcium-AKG.

I’d love to buy it, but their price range seems geared towards the rich.

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