Background

"Because BHB is involved in such foundational cellular functions as gene regulation, increasing BHB concentrations may be protective against a wide range of diseases." Click To Tweet

Beta-hydroxybutyrate (BHB) is an endogenous (i.e., produced by the body) ketone produced via the breakdown 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 convert to other energy carriers such as acetyl-CoA, succinyl-CoA, and nicotinamide adenine dinucleotide (NAD+).^[1] BHB is also a signaling molecule involved in basic metabolic processes in various cell types.

Evidence suggests BHB benefits human health via the promotion of:

• Longer lifespan: BHB is a histone deacetylase (HDAC) inhibitor that improves gene transcription and extends lifespan in C. elegans, a type of worm used to model fundamental cellular processes.^[2]
• Reduced inflammation: BHB reduces inflammation due to chronic stress by inhibiting activation of the NLRP3 inflammasome, a potent proinflammatory pathway necessary for immunity to infection but implicated in autoimmunity.^[3]
• Cancer suppression: BHB activates tumor suppressor p53, a protein that regulates DNA repair, cell growth, apoptosis, and senescence.^[1]

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:

• Ketogenic diets, defined as a carbohydrate intake low enough (typically 5 to 10 percent of caloric intake) to induce ketone (BHB, acetone, acetoacetate) production by the liver. ^[4]
• Intermittent fasting, a dietary pattern that may deplete glycogen (carbohydrate stores) in the liver, increasing ketone production.^[5]
• Prolonged fasting, defined as fasting long enough to deplete carbohydrate stores, causing the body to switch from carbohydrate-based energy production to ketone metabolism, typically taking two to four days or more.^[6]
• Exercise, which depletes carbohydrate stores in the muscle and liver, causing an increase in ketone production that acts not only as a source of fuel for carbohydrate-starved muscles but also as a signaling molecule that modulates exercise recovery and adaptation.^[7]
• Fasted exercise, particularly at the beginning of a fast, which accelerates the transition from carbohydrate metabolism to ketosis (a phenomenon called fuel switching) while also reducing feelings of hunger, thirst, stomach discomfort, and poor mood that may occur during fuel switching.^[8]
• SGLT2 inhibitors, a class of drugs used to treat type 2 diabetes that reduce the reuptake of glucose in the kidney, increasing the amount of glucose in the urine, decreasing blood sugar levels, and increasing the production of ketones by the liver.^[9]

Effects on cellular senescence

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.^[1] 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.

• Learn more about cellular senescence in our overview article.

Anticancer effects

Evidence suggests that BHB exerts anticancer effects in the colon. Although the liver produces most of the body's ketones, cells that line the colon, called colonocytes, are also capable of ketone production. Researchers have postulated that colonocytes synthesize BHB using butyrate as a substrate, exposing antigen-presenting cells and dendrites (immune cells in the gut) to high concentrations of the ketone and protecting against carcinogenesis while suppressing induction of proinflammatory T cells.^[10] The principal mediator of these effects is the GPR109A receptor, a known tumor suppressor.^[11]

Paradoxical effects on NLRP3 inflammasome

Inflammasomes are large, intracellular complexes that detect and respond to internal and external threats. Activation of inflammasomes drives 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 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 boosted the production of beta-hydroxybutyrate, which in turn protected the animals against uric acid-induced elevations in proinflammatory 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 regular 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.^[12]

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 proinflammatory effects.^[13]

What about BHB supplementation? While previous research has demonstrated that BHB supplementation is safe in adults^[14] and adolescents,^[15] few trials have been conducted. Among these trials, the effects of BHB on health markers were variable, indicating a need for further research.^[16]

Research summaries

Below is a selection of summaries from current research investigating the role of beta-hydroxybutyrate in health and disease.

Fasting or beta-hydroxybutyrate administration reduces the production of senescent cells.

"Fasting or beta-hydroxybutyrate administration may activate youth-associated DNA factors that reduce senescence in mice and cell culture." Click To Tweet

Ketogenic diets,^[17] fasting,^[18] and exercise^[19] have all demonstrated the ability to extend healthspan and lifespan, possibly through mechanisms mediated by beta-hydroxybutyrate (BHB). However, scientists don't fully understand the precise effects of BHB on the cellular mechanisms of aging. 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 growth and reproduction cycles to prevent the accumulation of damaged DNA or mitochondria. While senescence plays a vital role in human development and wound healing, the proliferation of senescent cells is associated with diseases of aging such as Alzheimer's disease, Parkinson's disease,^[20] cardiovascular disease, type 2 diabetes, and glaucoma.^[1] 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 regular diet. They then randomly assigned the mice to receive an injection of BHB or a placebo after fasting 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. The researchers measured changes in gene expression and metabolic activity in the cell culture and mice experiments.

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, activating senescence-associated markers such as mTOR inhibition and AMPK activation, two pathways that modulate lifespan.

Before this study, whether Oct4 was active in adult cells was unknown; however, these results demonstrate that fasting or BHB administration activates youth-associated DNA factors that reduce senescence in mice and cell cultures. 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.

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Beta-hydroxybutyrate blocks activity of the NLRP3 inflammasome: gout study

Gout is a painful, debilitating disease affecting more than 8 million people 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 drives 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,^[1] a form of cell death triggered by proinflammatory signals and closely linked with inflammation. Because BHB inhibits NLRP3 activation^[1], 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 rats a regular diet and another a ketogenic diet. After one week, they measured the ketones in the animals' urine. They found that the ketogenic diet boosted beta-hydroxybutyrate production, protecting 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 regular 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.

• Link to full publication.

Ketogenic diet and beta-hydroxybutyrate improve gene transcription and reduce intellectual disability in inherited epigenetic machinery disorder.

Kabuki syndrome is a debilitating inherited disorder caused by mutations in two genes that regulate chromatin remodeling, an early step in DNA transcription. Ketones such as beta-hydroxybutyrate 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. Scientists attribute this wide range of severe health issues to impaired chromatin remodeling.

Chromatin is the name for the coiled structure DNA forms within the cells of plants and animals that resembles a tangled telephone cord. This unique structure prevents DNA's random opening and transcription (the first step in gene expression and replication). Chromatin encircles histone proteins, which can modulate chromatin accessibility through the presence or absence of chemical tags known as acetyl groups. As DNA undergoes cumulative epigenetic modifications throughout an organism's life, histones can develop resistance to acetylation. Consequently, chromatin becomes less amenable to unwinding, leading to a decrease in the rate of gene expression. 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.^[1]

The researchers used a strain of mice with the same DNA mutations that cause Kabuki syndrome in humans and fed them either a normal or a ketogenic diet for two weeks. The researchers provided a third group of mice with a regular diet and three daily BHB injections for two weeks. To assess memory and cognitive performance, mice completed a water maze, a sensitive measure of hippocampal function. The researchers measured changes in gene expression, HDAC activity, and neurogenesis.

Compared to a regular chow diet, a ketogenic diet increased the concentration of serum BHB, normalized acetylated histone levels, and increased the expression of several genes 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 regular 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 genetic disorder. Future research is needed to translate these insights into clinically useful information.

• Link to full publication.

Frequently asked questions

Q: Which foods increase BHB production on a ketogenic diet? A: Medium chain triglycerides (MCTs) increase BHB production in some people.^[21] Dietary sources of MCTs include coconut oil, palm kernel oil, butter, milk, yogurt, cheese, and supplements. However, it is unknown how these foods affect human ketosis, which can vary widely with the intake 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, likely due to faster exhaustion of glycogen stores, which increases the ketogenesis.

Related resources

• Butyrate overview page
• Dr. Eric Verdin on Ketogenic Diet, Longevity, Beta-Hydroxybutyrate, HDAC Inhibitors, & NAD+
• Lactate and beta-hydroxybutyrate in the treatment of traumatic brain injury | Peter Attia