Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis

Researchers have made a discovery that could explain why a low-carb, high-fat diet can promote healthy aging and prevent age-related diseases.
Previous studies have shown that eating less sugar and more healthy fat can protect against type 2 diabetes, Alzheimer’s diseasea nd cancer, but the mechanics behind this metabolic process have been unclear.
Now, researchers have observed a detoxification system in the body which has not previously been identified, and could explain how the body protects itself from the harmful effects of sugar.


The α-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects primarily by reacting with biopolymers such as DNA and proteins.

We now demonstrate that during ketosis, another metabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the ketone body acetoacetate, leading to 3-hydroxyhexane-2,5-dione. This novel metabolite is present at a concentration of 10%–20% of the methylglyoxal level in the blood of insulin-starved patients.

By employing a metabolite-alkyne-tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in human blood. The discovery represents a new direction within non-enzymatic metabolism and within the use of alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon nucleophile.

Johannsen is convinced ketones have a valuable role regarding biological aging.  “Now we have evidence for saying that ketones can minimise the amount of harmful methylglyoxal in living organisms, and that is a discovery that gets noticed, as it involves two of the most debated substances within biological aging and late diabetic complications. Moreover, these substances react with each other.
“One perspective could be to follow a diet with fewer carbohydrates and more fat. The fat helps to encapsulate and destroy the sugars that cause the pain.”
Johannsen added that the findings could be relevant for people with diabetes-related complications such as neuropathy.

Cell Chemical Biology: Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis


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