The beginning of a new year is often a time for setting an intention to build new habits. A foundational goal many people share is to improve their health, which typically includes positive changes in diet. Although most would think of shedding pounds or building muscle as the primary outcome of these changes, it turns out that improvements in cognition are another big benefit to eating clean.
To understand why, the key is to think in terms of evolutionary medicine. Throughout most of evolutionary history, humans didn’t have consistent access to food. We would eat to satiety, but then afterward wait until the hunger was motivating enough to seek food again. This process regulates metabolic molecular machinery throughout the body, but importantly also in the brain.
Sugar vs. Fat: How Cells Make Energy
Cells can make energy two different ways: using glucose (sugar) in a process called “glycolysis” or using broken down fatty acids in a process called “ketosis.” Cells use glycolysis to make energy when glucose is available, and if more glucose is available than an organism needs, the glucose is converted into fat for storage. When cells need energy and glucose isn’t available, such as if you may be following a ketogenic or low-carb diet, cells switch to metabolizing fat to ensure that they have a constant supply of energy.
Metabolizing fat also acts as a signal to cells that food may be scarce. Sensing food availability is critical for organisms to survive, and because of this we have evolved adaptive mechanisms in how cells function depending on whether or not food is readily abundant. When food is less available, cells, including neurons, make changes to prevent wasting energy and to improve their efficiency. These protective changes enhance cognition in multiple ways.
Epigenetics of Ketosis
Ketosis increases the activity of a family of transcriptional repressors known as sirtuins. Sirtuins are a class of histone deacetylases (HDACs), or proteins that remove acetyl groups from histones at specific genes to turn off gene expression.
Ketosis increases sirtuin 1 (Sirt1) within the hippocampus, a region of the brain essential for declarative memory formation. On the other hand, loss of Sirt1 can lead to impairments in long-term potentiation and cognition. Li-Huei Tsai’s group found that Sirt1 regulates memory by forming a complex that downregulates microRNA miR-134. This microRNA targets mRNA transcripts for the key learning and memory genes CREB and BDNF, so by keeping miR-134 low, Sirt1 promotes memory formation by keeping CREB and BDNF levels high.
A 2016 study by Heyward et al. found that mice that were chronically overfed had memory impairments and decreased hippocampal Sirt1. Decreased expression of several learning and memory genes, including Sirt1, was associated with an increase in DNA <span class=”glossaryLink ” style=”margin:0;padding:0;border-width:0 0 1px;border-color:initial;border-image:initial;font:inherit;vertical-align:baseline;text-decoration:none !important;border-style:initial initial dotted;” data-cmtooltip=”The addition of a methyl (CH3) group from S-adenosylmethionine to a cytosine nucleotide or lysine or arginine residue.”>methylation.
Interestingly, the researchers also found a decrease in DNA hydroxymethylation that was specific to the Sirt1 gene. DNA methylation underlies longer lasting experience-dependent changes in gene expression. Although the role of hydroxymethylation in the brain is still an area of active investigation, researchers believe that hydroxymethylated DNA attracts different binding partners than methylated DNA, which prevents certain repressive complexes from binding to DNA. It’s also thought that hydroxymethylation acts as an intermediate to facilitate active DNA <span class=”glossaryLink ” style=”margin:0;padding:0;border-width:0 0 1px;border-color:initial;border-image:initial;font:inherit;vertical-align:baseline;text-decoration:none !important;border-style:initial initial dotted;” data-cmtooltip=”The removal of a methyl (CH3) group.”>demethylation.
A third diet-related epigenetic mechanism worth mentioning is that one of the three types of ketones, beta-hydroxybutyrate, is an endogenous HDAC inhibitor itself. Although sirtuins suppress memory repressors, other classes of HDACs suppress memory-enhancing genes. Inhibitors of these HDACs enhance memory and are widely studied for their therapeutic potential. Moses Chao’s team found that beta-hydroxybutyrate increases hippocampal BDNF expression by inhibiting HDAC2 and HDAC3.
The studies described above were carried out in rodents, but there is also data from human studies supporting the cognitive benefits of healthy eating. For example, older adults with Mild Cognitive Impairment showed an enhancement in verbal memory performance after six weeks on a low carb diet. Another study found that, in healthy young adults, a single dose of glucose led to a decrease in performance on cognitive tasks 20 minutes after administration.
The potential epigenetic underpinnings to ketosis and the benefits of cutting back on sugar are still being investigated and there is much more progress to be made. Although resolutions to get fit typically focus on physical wellbeing, we hope that knowledge of the possible neuroepigenetic benefits of healthy eating might be an added incentive to everyone looking to make a positive change in the New Year.
- Mattson MP. 2012. Energy Intake and Exercise as Determinants of Brain Health and Vulnerability to Injury and Disease. Cell Metab. 16(6): 706-22.
- Gao J, Wang WY, Mao YW, Gräff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH. 2010. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466(7310):1105-9.
- Heyward FD, Gilliam D, Coleman MA, Gavin CF, Wang J, Kaas G, Trieu R, Lewis J, Moulden J, Sweatt JD. 2016. Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1. J. Neurosci. 36(4):1324-35.
- Kriaucionis S. 2017. The Role of DNA Base Modifications. The Scientist September 2017.
- Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, Ulja D, Karuppagounder SS, Holson EB, Ratan RR, Ninan I, Chao MV. 2016. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife 5:e15092.
- Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ. 2012. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging. 33(2):e19-e27.
- Ginieis R, Franz EA, Oey I, Peng M. 2018. The “sweet” effect: Comparative assessments of dietary sugars on cognitive performance. Physiol. Behav. 184:242-247.