Beta-hydroxybutyrate (BHB) is an endogenous (i.e., produced by the body) ketone produced via the break down of fats during times of carbohydrate scarcity (e.g., during fasting, exercise, or carbohydrate restricted/ketogenic diets). BHB is produced from butyrate, a short-chain fatty acid produced by the gut microbiota via the fermentation of dietary fiber. Along with the ketones acetone and acetoacetate, BHB serves as a source of cellular energy.
BHB is a small energy-carrying molecule that can be converted to other energy carriers such as acetyl-CoA, succinyl-CoA, and nicotinamide adenine dinucleotide (NAD+). BHB is also a signaling molecule involved in basic metabolic processes in a variety of cell types.
Evidence suggests BHB benefits human health via promotion of:
Because BHB is involved in such foundational cellular functions as gene regulation, increasing BHB concentrations may be protective against a wide range of diseases. Strategies for enhancing BHB concentrations include:
Research in rodents and cell cultures suggests that fasting (which induces endogenous ketone production) and BHB administration reduce cellular senescence via increased expression of the transcription factor Oct4, a protein that binds to DNA and regulates cell regeneration and stem cell differentiation. Activation of Oct4 led to activation of senescence-associated markers such as mTOR inhibition and AMPK activation, two pathways that modulate lifespan. Future studies are needed to translate these results into relevant use for humans because humans have very different nutritional needs than mice and cells in culture.
Evidence suggests that BHB exerts anticancer effects in the colon. Although most ketones are produced in the liver, cells that line the colon, called colonocytes, are also capable of ketone production. Researchers have postulated that, using butyrate as a substrate, colonocytes synthesize BHB, exposing antigen-presenting cells and dendrites (immune cells in the gut) to high concentrations of the ketone and providing protection against carcinogenesis while suppressing induction of pro-inflammatory T cells. The principal mediator of these effects is the GPR109A receptor, a known tumor suppressor.
Inflammasomes are large, intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes has been implicated in a host of inflammatory disorders. The NLRP3 inflammasome, in particular, triggers the release of the proinflammatory proteins interleukin (IL)-1 beta and IL-18 and drives pyroptosis, a form of cell death that is triggered by proinflammatory signals and closely linked with inflammation. Because BHB inhibits NLRP3 activation, it may be an effective treatment for chronic inflammatory issues.
A study in rats investigated the effects of BHB on the NLRP3 inflammasome in gout, an inflammatory disorder of the joints, and found that a ketogenic diet induced production of beta-hydroxybutyrate, which in turn protected the animals against uric acid-induced elevations in pro-inflammatory interleukin-1 beta. Examination of the animals' joints revealed that the rats that ate the ketogenic diet had less joint inflammation than those fed a normal diet. (See "Research summaries" below for more information about this study.) Another study investigated the effects of BHB administration or a ketogenic diet in mouse models of various NLRP3-mediated diseases and found that both scenarios suppressed NLRP3 and reduced inflammation.
However, two small, randomized double-blind placebo-controlled experiments in which participants received BHB supplements (as ketone salt or ketone monoester) found that various markers of NLRP3 inflammasome activation, including caspase-1 and interleukin 1-beta, increased, suggesting that the ketones may have unintended pro-inflammatory effects.
What about BHB supplementation? While previous research has demonstrated that BHB supplementation is safe in adults and adolescents, few trials have been conducted. Among these trials, the effects of BHB on health markers were variable, indicating a need for further research.
Below is a selection of summaries from current research investigating the role of beta-hydroxybutyrate in health and disease.
Ketogenic diets, fasting, and exercise have all demonstrated the ability to extend healthspan and lifespan, possibly through mechanisms mediated by beta-hydroxybutyrate (BHB). However, the precise effects of BHB on the cellular mechanisms of aging are not well understood. Findings of a 2018 study suggest that BHB administration and fasting both reduce senescence in mice.
Senescence occurs when a damaged cell terminates its normal cycles of growth and reproduction for the purpose of preventing the accumulation of damaged DNA or mitochondria. While senescence plays a vital role in human development and wound healing, the accumulation of senescent cells is associated with diseases of aging such as Alzheimer's disease, Parkinson's disease, cardiovascular disease, type 2 diabetes, and glaucoma.[10.1016/j.cell.2017.05.015] Lifestyle habits or drugs that increase beta-hydroxybutyrate may extend healthspan and reduce disease risk by slowing the rate of senescence.
The researchers conducted an experiment that involved culturing human vascular endothelial (i.e., blood vessel cells) from the umbilical cord and aorta, followed by an experiment with mice. To compare the effects of BHB supplementation and fasting, the researchers fed one group of mice a normal diet, then randomly assigned the mice to receive an injection of BHB or a placebo after they had fasted for just five hours. Using a second group of mice, the researchers randomly assigned half of the group to fast for 72 hours and the other half to eat normally. In both the cell culture and mice experiments, the researchers measured changes in gene expression and metabolic activity.
The researchers found that BHB reduced senescence in vascular cells due to increased expression of the transcription factor Oct4, a protein that binds to DNA and regulates cell regeneration and stem cell differentiation. Compared to mice that received a placebo injection, mice that received BHB had reduced senescence in vascular cells through the same Oct4 pathway as in cell culture. Mice that fasted also robustly activated Oct4, leading to activation of senescence-associated markers such as mTOR inhibition and AMPK activation, two pathways that modulate lifespan.
Prior to this study, it was not known whether Oct4 was active in adult cells; however, these results demonstrate that fasting or BHB administration activates youth-associated DNA factors that reduce senescence in mice and cell culture. Future studies are needed to translate these results into relevant use for humans because humans have very different nutritional needs than mice and cells in culture.
Gout is a painful, debilitating disease that affects more than 8 million people living in the United States. The condition arises when uric acid crystals form in and around the joints, causing inflammation, pain, and impaired mobility. Evidence from a 2017 study suggests that beta-hydroxybutyrate inhibits the activity of the NLRP3 inflammasome, reducing symptoms of gout.
Inflammasomes are large, intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes has been implicated in a host of inflammatory disorders. The NLRP3 inflammasome, in particular, triggers the release of the proinflammatory proteins interleukin (IL)-1 beta and IL-18 and drives pyroptosis,ref pmid='PMC5123939'] a form of cell death that is triggered by proinflammatory signals and closely linked with inflammation. Because BHB inhibits NLRP3 activation, it may be an effective treatment for gout or other chronic inflammatory issues.
The study involved rats that are prone to developing gout. The investigators fed one group of the rats a normal diet and fed another group a ketogenic diet. After one week, they measured ketones present in the animals' urine. They found that the ketogenic diet induced production of beta-hydroxybutyrate, which in turn protected the animals against uric acid-induced elevations in IL-1 beta. Examination of the animals' joints revealed that the rats that ate the ketogenic diet had less joint inflammation than those fed a normal diet.
Next, the investigators assessed the effects of beta-hydroxybutyrate on neutrophils, a type of immune cell, from both young and old humans. They found that the compound inhibited the NLRP3 inflammasome-induced IL-1 beta secretion in both young and old neutrophils, suggesting that the ketone plays a role in activating the inflammasome in neutrophils, regardless of age.
These findings suggest that beta-hydroxybutyrate inhibits the activity of the NLRP3 inflammasome, reducing the symptoms of gout. Researchers do not know if these results translate to humans, however. Learn more about the health effects of beta-hydroxybutyrate in our overview article.
Kabuki syndrome is a debilitating inherited disorder caused by mutations in two genes involved in the regulation of chromatin remodeling, an early step in DNA transcription. Ketones such as beta-hydroxybutyrate have been shown to enhance DNA transcription and gene expression. Findings from one group of researchers demonstrate that a ketogenic diet can alleviate some of the neurological deficits of Kabuki syndrome and improve memory.
Kabuki syndrome is named for the facial features common to people with the disorder, which looked similar to Kabuki theatre makeup to the Japanese scientists who first researched the disease. In addition to distinctive facial features, the syndrome causes a wide range of health problems such as heart defects, difficulty eating, weak muscle tone, immune deficiency, and intellectual disability. This wide range of severe health issues is explained by the fundamental importance of chromatin remodeling to the body's functioning, which is impaired in people with Kabuki syndrome.
Chromatin is the name for the coiled structure DNA forms within the cells of plants and animals that resembles a tangled telephone cord. This coiled structure prevents DNA from being opened and transcribed (the first step in gene expression and DNA replication) randomly. Chromatin is wrapped around histone proteins that open or close the chromatin based on whether the histone has a chemical tag called an acetyl group attached or not. As DNA accumulates epigenetic changes over the lifespan, histones become resistant to acetylation, chromatin is harder to open, and gene expression slows. Histone deacetylase (HDAC) inhibitors, such as the ketone beta-hydroxybutyrate (BHB), are compounds that help release histones, open chromatin, prevent loss of gene expression with aging, and may even lengthen lifespan.
The researchers used a strain of mice that have the same DNA mutations that cause Kabuki syndrome in humans and fed them either a normal diet or a ketogenic diet for two weeks. The researchers fed a third group of mice a normal diet and gave them three daily injections of BHB for two weeks. To assess memory and cognitive performance, mice completed a water maze, a sensitive measure of hippocampal function, which is closely related to memory. The researchers measured changes in gene expression, HDAC activity, and neurogenesis.
Compared to a normal chow diet, a ketogenic diet increased the concentration of serum BHB, normalized acetylated histone levels, and increased the expression of several genes that are downregulated in Kabuki syndrome. These changes in gene expression enhanced multiple markers of neurogenesis and improved performance during the water maze test. Mice eating a normal diet that received daily BHB injections achieved similar serum BHB levels as mice eating a ketogenic diet and experienced the same gains in neurogenesis.
This comprehensive study provides insight into the potential of ketogenic diets and supplemental BHB to improve deficits in gene expression in mice with a debilitating genetic disorder. Future research is needed to translate these insights into clinically useful information for humans.
Q: Which foods increase BHB production on a ketogenic diet? A: Medium chain triglycerides (MCTs) have been shown to increase BHB production in some people. Dietary sources of MCTs include coconut oil, palm kernel oil, butter, milk, yogurt, cheese, and supplements. However, it is unknown how these foods affect ketosis in humans in general and individuals particularly, who can vary widely in their metabolism of different foods.
Q: Which types of exercise are best for BHB production? A: Some research suggests that endurance exercise may be better for enhancing BHB production compared to resistance training. This is likely due to faster exhaustion of glycogen stores, which increases the ketogenesis.