New research uncovers and replicates the mechanism by which a ketogenic diet curbs brain inflammation. The findings pave the way for a new drug target that could achieve the same benefits of a keto diet without having to actually follow one.
The keto diet is focused on reducing the amount of carbohydrates as much as possible and increasing the amount of fat.
Besides its weight loss-related benefits, recent studies have pointed to many other advantages. For instance, Medical News Today recently covered research suggesting that the diet may increase longevity and improve memory in old age.
However, the mechanism by which a keto diet may benefit the brain in these illnesses has been a mystery. The new research - which was led by Dr. Raymond Swanson, a professor of neurology at the University of California, San Francisco - suggests that it may do so by reducing brain inflammation.
In the new study, Dr. Swanson and team show the molecular process by which the keto diet reduces brain inflammation. The researchers also identify a key protein that, if blocked, could create the effects of a keto diet.
This means that a drug could be designed to reduce inflammation in patients who cannot follow a keto diet because of other health reasons.
The findings were published in the journal Nature Communications.
A keto state lowers brain inflammation
A keto diet changes the metabolism, or the way in which the body processes energy. In a keto diet, the body is deprived of glucose derived from carbs, so it starts using fat as an alternative source of energy.
In the new study, Dr. Swanson and his colleagues recreated this effect by using a molecule called 2-deoxyglucose (2DG).
The 2DG molecule stopped glucose from metabolizing and created a ketogenic state in rodents with brain inflammation as well as in cell cultures. Levels of inflammation were drastically reduced - almost to healthy levels - as a result.
"We were surprised by the magnitude of our findings," said Dr. Swanson. "Inflammation is controlled by many different factors, so we were surprised to see such a large effect by manipulating this one factor. It reinforces the powerful effect of diet on inflammation."
The restricted glucose metabolism lowered the so-called NADH/NAD+ ratio. Dr. Swanson explained to MNT what this ratio refers to, saying, "NAD+ and NADH are naturally occurring molecules in cells that are involved in energy metabolism."
"Cells convert NAD+ to NADH, as an intermediary step in generating energy from glucose, and thus increase the NADH/NAD+ ratio," he added.
When this ratio is lowered, the CtBP protein gets activated and attempts to turn off inflammatory genes. As Dr. Swanson told us, "CtBP is a protein that senses the NADH/NAD ratio and regulates gene expression depending on this ratio."
So, the scientists designed a molecule that stops CtBP from being inactive. This keeps the protein in a constant "watchful" state, blocking inflammatory genes in an imitation of the ketogenic state.
Significance of the findings, future research
Speaking to MNT about the clinical implications of the study, Dr. Swanson said, "Our findings show that it is [...] possible to get the anti-inflammatory effect of a ketogenic diet without actually being ketogenic."
"[The keto] diet is difficult to follow [...], especially for people who are acutely ill. Our work identifies a potential drug target that can produce the same effect as [the] ketogenic diet."
Dr. Raymond Swanson
"I think the work also increases the scientific legitimacy of the ketogenic diet/inflammation link," he added.
Dr. Swanson went on to highlight how important it is that the research conducted by he and his team uncovered a causal mechanism rather than simply pointing to an association.
"Most scientists," he told us, "are reluctant to accept cause-effect relationships between events in the absence of a defined mechanism. Here we have provided a biochemical mechanism by which diet affect inflammatory responses."
Dr. Swanson also shared with us some directions for future research. "Our work was very focused on brain trauma," he said, but "next steps will be to expand the list of pro-inflammatory conditions that can be modulated by the CtBP mechanism."
The findings could apply to other conditions that are characterized by inflammation. In diabetes, for example, the excessive glucose produces an inflammatory response, and the new results could be used to control this dynamic.
"[The] ultimate therapeutic goal would be to generate a [drug] that can act on CtBP to mimic the anti-inflammatory effect of [the] ketogenic diet," Dr. Swanson concluded.