When was the last time you exercised? Was it yesterday, a few weeks ago… or maybe a few months ago? Well, you may want to tack on “epigenetics” to the long list of reasons why you should exercise more often. We all know exercise is beneficial, but the difficulty usually lies in trying to be motivated enough to actually do it.

The CDC states that frequent physical activity is one of the most important things for your health. It can help control your weight, reduce risk of an abundance of diseases such as cardiovascular disease, type 2 diabetes, and cancer, improve your mood and mental health, and even increase your chances of living a longer life. A new study by researchers at NYU Langone Medical Center shows that running could have a positive effect on your brain due to key epigenetic players such as histone deacetylases (HDACs) and epigenetic mechanisms, perhaps even helping to ward off neurological disease.

In a rodent study published in eLife, researchers measured the buildup of various chemicals in the brain while mice ran on their “exercise” wheels. These substances are known to lead to the production of a protein called brain-derived neurotrophic factor, BDNF. This well-known protein enhances memory and growth of nerve cells, lending to its nickname “Miracle-Gro.”

Cell biologist Moses Chao, PhD, the study’s senior investigator, explained: “We believe that our study shows a precise biological mechanism behind increased BDNF production in mammals due to exercise. Unraveling the mysteries of BDNF is important as we seek more ways to naturally keep mammalian brains healthy, including those of people.” Chao is a professor at NYU Langone and the Skirball Institute of Biomolecular Medicine.

Chao said the evidence suggests ways to boost production of BDNF, which other studies have shown protects the brain. Not only rodent studies, but research with humans has confirmed a link between exercising, increased levels of BDNF, and reduced dementia rates. Other experiments have also shown that, on average, BDNF levels of those suffering from Alzheimer’s or Huntington’s disease are half that of those without either disease.

They found that a chemical called beta-hydroxybutyrate (DBHB), a ketone produced naturally in the liver, triggers reactions in the body that increase the expression of the BDNF gene, which, in turn, increases the production of its protein. DBHB is known to build up in the brain and body as a result of exercise and ketones are by-products that form when fat is broken down as an alternative source of energy. This metabolite has also been shown to act as a class I HDAC inhibitor in non-neuronal tissues, according to the research study.

Chao said that this ketone prevents histone deacetylases, or HDACs, from suppressing the production of BDNF. HDACs are epigenetic enzymes involved in histone deacetylation, which is defined as the removal of an acetyl group from a histone protein. HDACs control gene expression by adjusting chromatin structure so that the DNA is more tightly wound around the histones, thereby reducing the expression of certain genes.

They found that exercise was linked to a reduction in HDAC2 and HDAC3 mRNA levels, but not HDAC1 levels. “These results suggest that exercise may modulate BDNF gene expression in the hippocampus by inducing changes to the epigenetic landscape of its promoter,” the researchers wrote. In order to test this, they performed a common technique for investigating protein-DNA interactions known as chromatin immunoprecipitation (ChIP). They found a decreased in HDAC2 and HDAC3 bound to the BDNF promoter in mice that exercised compared to those that were sedentary. Their results suggest that exercise could significantly reduce the binding of HDAC3 to the BDNF promoter.

The researchers also discovered that, after they treated the mice with DBHB, BDNF expression was increased via HDAC2 and HDAC3 inhibition and histone H3 acetylation. By inhibiting HDACs, the chromatin structure can become less densely packed, making the BDNF gene more accessible and increasing BDNF production by as much as 50 percent.

Although this research is preliminary, the study provides us with clues about the interplay between exercise, epigenetics, and key molecules – DBHB and BDNF – that help promote good health. For future studies, the researchers aim to investigate the impact ketone buildup might have on different regions of the brain and what factors might discourage or enhance HDAC activity.

Source: Sleiman, S.F. et al. (2016). Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife.

Reference: NYU Langone Medical Center. Mice on wheels show scientists how exercise benefits their brains. EurekAlert. 2 Jun 2016. Web.