Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice


A CaAKG-supplemented diet extends lifespan of middle-aged female mice

AKG supplementation extends healthspan of both female and male mice

AKG compresses morbidity. Reduction in frailty is more dramatic than lifespan extension

AKG reduces chronic inflammation and induces IL-10 in T cells of female mice



The link between AKG and DNA methlation was mentioned in this thread

I have been doing a lot of reading around Krebs metabolites (Citrate/AKG) and how they get out of the mitochondria.

AKG is interesting because it sort of exists in a pool including Glutamine and Glutamate in the cytosol.

It comes out of the mitochondria as part of the Malate-Aspartate shuttle so appears in the cytosol together with ATP. Arguably as Citrate links to the Mitochondrial Membrane Potential you can say high AKG indicates a high energy state whereas high citrate indicates a high power state.

Not all Krebs metabolites are positive. Malate is generally swapped back into the mitochondria when citrate or AKG come out.

AIUI DNA methylation indicates a lower probability of transcription of genes. Hence if you have more AKG you have less methylation and a greater range of mRNA. However, even if you use citrate to acetylate the histone and AKG to demethylate the DNA you still need ATP to make the proteins (and make the mRNA).

Hence it is quite logical that AKG and Citrate will help to compress morbidity. You will need more efficient mitochondria to extend lifespan and also to minimise senescence.


Excellent. I already supplement Ca-AKG, Citrate (Magnesium) and Malate (Citrulline Malate).

Now, the question is whether I’ll live to 150 or not. :wink:

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I have wondered about malate. Obviously higher levels of malate enable higher levels of citrate and AKG to leave the mitochondria. Hence arguably it should improve gene transcription.

Supplementing AKG (which I think is disassociated possibly into Glutamine and then absorbed into the cells) and Citrate has the potential to increase cytosolic levels. Citrate I know does this. The arguments on AKG are that it cannot get through the cell boundary, but there were reports that labelled carbon gets into cells.

The serum half life of AKG is really short (about 5 mins), but that’s not the issue. The issue is getting increased cytosolic levels of AKG.

Because these are metabolites, however, material amounts are needed to move the dial.


This is one of the papers I used. If people wish to read up on this this one may be useful:

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@John_Hemming Yes, dosing is the question, and maybe the problem. I have stopped chasing every new “extends life in X” because it always seems like the equivalent dose is impossible or impossibly expensive for the gamble in effectiveness vs side effects. Maybe I’ve just gotten bored of chemicals, and am missing out.

What are the best bets now …in which a modest dose is very likely to move the needle?


The point about the metabolites is that moving the needle is not easy with a modest dose as you start with a certain endogenous concentration and to change that requires a lot of inputs.

At the moment I am messing around with dosing to get an idea of impact. However, there are side effects from too high dosing (scores of grams) because of the cations.

Hence I keep going with my weekly blood tests and checking things out. It would be nice if there were other people willing to do frequent blood tests as it would be easier to work things out.