In today’s post, I’ll review a recent study proposing a possible mechanism for the benefits of a ketogenic diet. This post builds on my previous post about epigenetics.
In the research paper “Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor,” researchers investigate the role of β-Hydroxybutyrate (βOHB) in preventing damage by oxidative stress. βOHB is a product of fat oxidation and serves as the major source of energy during prolonged exercise, under fasting conditions, or when following a ketogenic diet.
The researchers first sought to determine if βOHB inhibits histone deacetylases (HDACs). HDACs are proteins involved in epigenetics. HDACs perform a function that results in the tightening of DNA, thereby reducing the expression of genes in the affected region. Through a series of experiments, the researchers were able to confirm the βOHB did inhibit the action of HDACs.
Next, the researchers wanted to know which genes were up-regulated as a result of βOHB inhibiting HDACs. They found that five genes involved in the FOXO3A pathway were up-regulated. The FOXO3A pathway is relevant in cancer because its up-regulation results in a cell-cycle arrest (cells do not divide as quickly) and reduced oxidative stress (less oxidative stress= less damage to DNA). Also, expression of the metallothionein-2 (Mt2) gene was increased. Like FOXO3A, Mt2 protects against oxidative stress.
The researchers wanted to determine whether increased levels of βOHB actually reduced oxidative stress in vivo. To do this, they implanted mice with a subcutaneous βOHB pump, which supplied a steady release of βOHB. Researchers then injected a chemical, paraquat, which induces build up of reactive oxygen species. Compared to control mice (with no βOHB pump), βOHB mice had an impressive 54% reduction in reactive oxygen species.
Researchers also evaluated a maker of oxidative stress in these mice, 4-hydroxynonenal (4-HNE). 4-NHE is a product of polyunsaturated lipid degradation and accumulates in response to oxidative stress. The control mice had a three-fold increase in 4-NHE, indicating high levels of oxidative stress. This increase was completely suppressed in βOHB mice, indicating that high levels of βOHB protect against oxidative stress.
Ketogenic diets have been shown to be neuroprotective[i]. The authors propose that this neuroprotective effect could be due to a reduction in oxidative damage.
Additionally, oxidative damage can cause DNA damage and mutations. Ketogenic diets may protect against DNA damage and could even reduce the incidence of cancer. This is one area that I am researching for my PhD dissertation, so stay tuned!
[i] Y Kim et al. (2007) Ketone bodies are protective against oxidative stress in neocortical neurons. J. Neurochem. 101: 1316.