Introduction

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 be converted 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 a variety of cell types.

Health benefits associated with BHB

Evidence suggests BHB benefits human health via the promotion of:

  • Longer lifespan: BHB is a histone deacetylase (HDAC) inhibitor that improves gene transcription and has been shown to extend 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 pro-inflammatory 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.[4]

Strategies that promote BHB production

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 blood concentrations of BHB 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. [5]
  • Intermittent fasting, a dietary pattern that may deplete glycogen (carbohydrate stores) in the liver, leading to an increase in ketone production.[6]
  • Prolonged fasting, defined as fasting for a period long enough to deplete carbohydrate stores in the body, causing the body to switch from carbohydrate-based energy production to ketone metabolism, typically taking two to four days or more.[7]
  • A fasting-mimicking meal replacement bar that was high in fat and low in carbs extended the ketogenic benefits of a 15-hour overnight fast and increased serum concentrations of BHB.[8]
  • 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.[ref doi='10.14814/phy2.14497'
  • Fasted exercise, particularly at the beginning of a fast, 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 can occur during fuel switching.[9]
  • Endurance exercise, but not strength training, increased the concentration of BHB in the muscles of aged mice. BHB levels improved skeletal muscle growth and cognitive function.[10]
  • 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.[11]

Effects of BHB 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.[12] 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.

Anticancer effects of BHB

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. Integral to this process is butyrate, a short-chain fatty acid produced during the microbial fermentation of dietary fiber. 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 BHB concentrations and protecting against carcinogenesis while suppressing induction of pro-inflammatory T cells.[13]

The principal mediator of these effects is GPR109A, a G-protein coupled receptor found in tissues of the colon.[14] GPR109A plays important roles in maintaining gut barrier integrity, promotes apoptosis of cancer cells, and suppresses the activity of nuclear factor-κB, a transcription factor that drives inflammation and tumor growth.[15] [14] Evidence indicates that BHB is the natural ligand of GPR109A. As such, its binding may activate the receptor, facilitating its anticancer effects.

Paradoxical effects of BHB on NLRP3 inflammasome

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 pro-inflammatory proteins interleukin (IL)-1 beta and IL-18 and drives pyroptosis, a form of cell death that is triggered by pro-inflammatory 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.[16]

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.[17]

What about BHB supplementation? While previous research has demonstrated that BHB supplementation is safe in adults[18] and adolescents[19], few trials have been conducted. Among these trials, the effects of BHB on health markers were variable, indicating a need for further research.[20]

Research summaries

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

Fasting or BHB administration reduces the production of senescent cells.

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. 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.

BHB reduces symptoms of gout.

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 pro-inflammatory proteins interleukin (IL)-1 beta and IL-18 and drives pyroptosis, a form of cell death that is triggered by pro-inflammatory 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.

Ketogenic diet and BHB 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 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.

Frequently asked questions

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 ketogenesis.

Pages

  • [Butyrate, a precusor of BHB, is a short-chain fatty acid (SCFA) that occurs naturally in butter and other foods and is also produced by microbes in the gut.]https://foundmyfitness.com/topics/butyrate)

Clips and Episodes - In this clip, ketogenic diet researcher Dr. Eric Verdin discusses how BHB protects against oxidative stress as a nutrient and as a transcription regulator. - Lactate and beta-hydroxybutyrate in the treatment of traumatic brain injury | Peter Attia - To learn more about BHB supplementation and ketosis, watch this interview with Dr. Dom D'Agostino.

  1. ^ DOI: j.diabres.2014.08.009
  2. ^ D-beta-hydroxybutyrate extends lifespan in C. elegans Aging 6, no. 8 (August 2014): 621–44. https://doi.org/10.18632/aging.100683.
  3. ^ Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses Scientific Reports 7, no. 1 (August 2017). https://doi.org/10.1038/s41598-017-08055-1.
  4. ^ -hydroxybutyrate and its metabolic effects on age-associated pathology Experimental & Molecular Medicine 52, no. 4 (April 2020): 548–55. https://doi.org/10.1038/s12276-020-0415-z.
  5. ^ How does the ketogenic diet induce anti-seizure effects? Neuroscience Letters 637 (January 2017): 4–10. https://doi.org/10.1016/j.neulet.2015.07.034.
  6. ^ Impact of intermittent fasting (5:2) on ketone body production in healthy female subjects Ernahrungs Umschau , no. 66(1) (January 2019): 2–9. https://doi.org/10.4455/eu.2019.002.
  7. ^ Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men PLOS ONE Edited by Andrew Philp. 13, no. 9 (September 2018): e0200817. https://doi.org/10.1371/journal.pone.0200817.
  8. ^ An Intermittent Fasting Mimicking Nutrition Bar Extends Physiologic Ketosis in Time Restricted Eating: A Randomized, Controlled, Parallel-Arm Study Nutrients 13, no. 5 (April 2021): 1523. https://doi.org/10.3390/nu13051523.
  9. ^ The Effects of Exercise on -Hydroxybutyrate Concentrations over a 36-h Fast: A Randomized Crossover Study Medicine & Science in Sports & Exercise 53, no. 9 (March 2021): 1987–98. https://doi.org/10.1249/mss.0000000000002655.
  10. ^ Effects of exercise-induced beta-hydroxybutyrate on muscle function and cognitive function Physiological Reports 9, no. 3 (February 2021). https://doi.org/10.14814/phy2.14497.
  11. ^ Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low-grade inflammation the neglected component? Diabetes, Obesity and Metabolism 20, no. 11 (September 2018): 2515–22. https://doi.org/10.1111/dom.13488.
  12. ^ DOI: 0.1016/j.molcel.2018.07.036
  13. ^ Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Biochimica Et Biophysica Acta (BBA) - Reviews on Cancer 1868, no. 1 (August 2017): 246–57. https://doi.org/10.1016/j.bbcan.2017.05.003.
  14. ^ a   b GPR109A Is a G-protein Coupled Receptor for the Bacterial Fermentation Product Butyrate and Functions as a Tumor Suppressor in Colon Cancer Research 69, no. 7 (March 2009): 2826–32. https://doi.org/10.1158/0008-5472.can-08-4466.
  15. ^ G Protein-Coupled Receptor 109A Maintains the Intestinal Integrity and Protects Against ETEC Mucosal Infection by Promoting IgA Secretion Frontiers in Immunology 11 (January 2021). https://doi.org/10.3389/fimmu.2020.583652.
  16. ^ The ketone metabolite -hydroxybutyrate blocks NLRP3 inflammasome mediated inflammatory disease Nature Medicine 21, no. 3 (February 2015): 263–69. https://doi.org/10.1038/nm.3804.
  17. ^ Oral Ketone Supplementation Acutely Increases Markers of NLRP3 Inflammasome Activation in Human Monocytes Molecular Nutrition &thsemicolon Food Research 63, no. 11 (April 2019): 1801171. https://doi.org/10.1002/mnfr.201801171.
  18. ^ The Effects of Exogenous Beta-Hydroxybutyrate Supplementation on Metrics of Safety and Health International Journal of Nutrition and Food Sciences 9, no. 6 (2020): 154. https://doi.org/10.11648/j.ijnfs.20200906.13.
  19. ^ The Effect of Exogenous Beta-Hydroxybutyrate Salt Supplementation on Metrics of Safety and Health in Adolescents Nutrients 13, no. 3 (March 2021): 854. https://doi.org/10.3390/nu13030854.
  20. ^ Utility of Ketone Supplementation to Enhance Physical Performance: A Systematic Review Advances in Nutrition , October 2019. https://doi.org/10.1093/advances/nmz104.

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