The Ketogenic Diet: A Powerful Molecular Signaling Therapy for the Brain

Estimated reading time: 6 minutes

You may not realize it, but the ketone body BHB, produced when following a ketogenic diet, is a powerful molecular signaling agent. In this blog post we are going to take a look at the effects of BHB on your neurons and the genetic pathways impacted. So, let’s dive into the fascinating world of ketone body signaling. 🌊

Researchers recently examined the effects of BHB on basal autophagy, mitophagy, and mitochondrial and lysosomal biogenesis in healthy cortical cultured neurons. It’s important to note that this study was conducted in a petri dish, not on living organisms. Nevertheless, the findings are truly intriguing.

Results show that D-BHB increased mitochondrial membrane potential and regulated the NAD⁺/NADH ratio. D-BHB enhanced FOXO1, FOXO3a and PGC1α nuclear levels in an SIRT2-dependent manner and stimulated autophagy, mitophagy and mitochondrial biogenesis.

Gómora-García, J. C., Montiel, T., Hüttenrauch, M., Salcido-Gómez, A., García-Velázquez, L., Ramiro-Cortés, Y., … & Massieu, L. (2023). Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy–Lysosomal Pathway. Cells, 12(3), 486. https://doi.org/10.3390/cells12030486

You can learn more about these important mitochondrial functions in this blog post I wrote.

Mitochondrial Health and a Ketogenic Diet

First, let me clarify that this study was using D-BHB. DBHB is the bio-identical ketone to the ketone your body produces when it breaks down fat into a ketone. If you want to learn more about D-BHB you may want to read this blog article I wrote on that very topic!

β-Hydroxybutyrate – Are BHB salts all created equal?

Let’s get back to what they found!

Results showed that D-BHB exposure improves mitochondrial function and stimulates autophagy, mitophagy and mitochondrial biogenesis through the upregulation of transcription factors in a variety of genes.

Upregulation of transcription factors means that the amount or activity of certain proteins is increased, which can increase the expression of the genes they regulate.

Which genes did they see D-BHB have an effect?

FOX01 and FOX03a

FOXO1 and FOXO3a are transcription factors that play important roles in a wide range of cellular processes, including cell differentiation, metabolism, and stress response. They found D-BHB exposure upregulates the expression of FOXO1 and FOXO3a. These are pathways that promote the expression of genes involved in mitochondrial and lysosomal biogenesis. Why is this important?

Because upregulation of FOXO1 and FOXO3a by D-BHB enhances the ability of neurons to improve energy metabolism, reduce oxidative stress, and enhance cellular waste clearance.

FOXO1 and FOXO3a are known to activate and promote the expression of genes involved in mitochondrial biogenesis, such as PGC-1α, NRF1, and TFAM.

PGC-1α, NRF1, and TFAM are all genes that encode for proteins of the same name. When these genes are expressed, the resulting proteins (PGC-1α, NRF1, and TFAM) work together to promote a bunch of molecular signaling goodness I am wanting to tell you about!

PGC-1α

PGC-1α, or peroxisome proliferator-activated receptor gamma coactivator 1-alpha, is a protein that plays a critical role in creating and maintaining healthy mitochondria in neurons. It accomplishes this by promoting the production of new mitochondria and enhancing the ability of existing mitochondria to produce energy.

PGC-1α promotes the production of new mitochondria in neurons by turning on genes that are involved in mitochondrial biogenesis, the process by which new mitochondria are created. This process is critical for ensuring that neurons have enough mitochondria to support their high energy demands. Additionally, PGC-1α enhances the ability of existing mitochondria to produce energy by turning on genes involved in oxidative phosphorylation, the process by which ATP is produced.

Furthermore, PGC-1α is known to regulate the production of antioxidant enzymes that protect mitochondria from oxidative stress. Oxidative stress is a type of stress that can damage mitochondria and other cellular components and can lead to neuronal dysfunction and cell death.

D-BHB, a biologically produced ketone body that people produce on a ketogenic diet, helps PGC-1α work better to make more mitochondria and helps those mitochondria function better. And as if that wasn’t enough, it helps you make the antioxidants you need to reduce oxidative stress.

NRF1

NRF1, or nuclear respiratory factor 1, is a transcription factor that plays an essential role in the creation and maintenance of healthy mitochondria. It acts by turning on genes that produce proteins needed for mitochondrial function. This process is important for ensuring that the mitochondria can produce energy efficiently.

Mitochondria are complex organelles that require a variety of proteins to function properly. Some of these proteins are produced in the nucleus of the cell and then transported to the mitochondria. NRF1 helps coordinate this process by turning on genes that produce these proteins. These proteins include the ones required for energy production and those involved in the maintenance of the mitochondrial structure and the regulation of mtDNA replication.

NRF1 is critical for mitochondrial function because it regulates the expression of genes involved in oxidative phosphorylation, a process that is necessary for the production of ATP, the main energy currency of the cell. It is also involved in the regulation of mitochondrial biogenesis, the process by which new mitochondria are created.

In addition to its role in mitochondrial function, NRF1 has also been implicated in the regulation of cellular stress responses. It is involved in the activation of genes that protect cells from oxidative stress, a type of stress that can damage the mitochondria and other cellular components.

D-BHB, a biologically produced ketone body that people produce on a ketogenic diet, helps NRF1 work better to make more mitochondria, regulate energy production and help protect your brain from oxidative stress.

TFAM

TFAM, which stands for mitochondrial transcription factor A, is a protein that plays a critical role in creating and maintaining healthy mitochondria. It accomplishes this by promoting the replication of mtDNA. TFAM binds to mtDNA and acts as a kind of “master regulator” for mtDNA replication. When TFAM is present, it signals the cell to make more copies of mtDNA.

Replication of mtDNA is crucial for the creation of new mitochondria. As cells grow and divide, they need to create new mitochondria to support their increased energy needs. If mtDNA replication does not occur properly, the cell may not be able to create enough new mitochondria, leading to decreased energy production and potentially harmful effects on the cell.

D-BHB, a biologically produced ketone body that people produce on a ketogenic diet, helps TFAM ensure that new mitochondria can be created.

Conclusion

So I want to be clear about what this means. This means that a ketogenic diet is a powerful gene-signaling, metabolic therapy for the brain.

This is exponentially more powerful molecular signaling than you will ever get with blueberries and salmon. How do I know this?

Because lots of people have gone the blueberry and salmon route and have not had a rescue of mood and cognitive function near the level they experience with a ketogenic diet.

You probably already tried the blueberry and salmon route, or you wouldn’t be a visitor on my blog. I want you to know that it isn’t your fault that the blueberries and salmon didn’t do enough.

You just hadn’t found all the ways you could feel better yet.

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References

Cuenoud, B., Hartweg, M., Godin, J. P., Croteau, E., Maltais, M., Castellano, C. A., … & Cunnane, S. C. (2020). Metabolism of exogenous D-beta-hydroxybutyrate, an energy substrate avidly consumed by the heart and kidney. Frontiers in Nutrition, 13. https://pubmed.ncbi.nlm.nih.gov/32140471/

Gómora-García, J. C., Montiel, T., Hüttenrauch, M., Salcido-Gómez, A., García-Velázquez, L., Ramiro-Cortés, Y., … & Massieu, L. (2023). Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy–Lysosomal Pathway. Cells, 12(3), 486. https://doi.org/10.3390/cells12030486