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Ketogenic Diet

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Q&A #41 with Dr. Rhonda Patrick (11/12/2022)

Posted on November 12th 2022 (over 2 years)

Dr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.

ketogenic diet

Exogenous ketones can support a ketogenic diet | Dominic D'Agostino

Posted on May 23rd 2022 (about 3 years)

In this clip, Dr. Dominic D'Agostino explains the rationale behind the development and use of exogenous ketones.

ketogenic diet

Why "second generation" epigenetic clocks are better at detecting biological age | Dr. Morgan Levine

Posted on May 21st 2022 (about 3 years)

Dr. Morgan Levine, describes the importance of this step in making her epigenetic clock PhenoAge and that of her postdoctoral mentor GrimAge more accurate in their ability to detect biological age and epigenetic age acceleration.

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News & Publications

  • Ketogenic diet raises brain blood flow by 22% and increases brain-derived neurotrophic factor by 47%, highlighting its potential to support cognitive function even in people without cognitive impairment. pubmed.ncbi.nlm.nih.gov
    Brain Diet Ketosis Memory BDNF Ketogenic Diet

    Glucose has long been considered the brain’s primary fuel, but ketone bodies may offer critical support, especially during periods of low carbohydrate availability. A recent study found that a ketogenic diet boosted levels of brain-derived neurotrophic factor (BDNF)—a key protein that supports brain health—by 47%, highlighting the diet’s potential to support brain health even in people without cognitive impairment.

    Researchers recruited 11 healthy but overweight adults to participate in a randomized, crossover study. Each participant followed two different diets: a ketogenic diet high in fat and low in carbohydrates, and a standard balanced diet. Each diet lasted three weeks and ended with brain imaging scans (using MRI and PET) and blood tests to measure brain blood flow and BDNF levels.

    They found that the ketogenic diet markedly increased ketone levels in the blood compared to the standard diet. Brain blood flow rose by 22% after eating the ketogenic diet, and BDNF levels increased by 47%. Researchers also found a strong link between ketone levels in the blood and higher brain blood flow.

    This was a small study, but the findings suggest that a ketogenic diet enhances brain blood flow and boosts vital brain-supporting proteins, even in people without memory loss. This opens up new possibilities for using ketogenic nutrition as a strategy to preserve cognitive function and support long-term brain health. Learn how to plan the optimal ketogenic diet in this clip featuring Dr. Dominic D'Agostino.

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  • A modified Mediterranean ketogenic diet boosts healthy brain fats and reduces Alzheimer's-associated markers, suggesting potential neuroprotective effects. pmc.ncbi.nlm.nih.gov
    Nutrition Brain Alzheimer's Diet Ketogenic Diet

    Roughly 60% of the human brain is made up of fat, which plays a crucial role in the structure and function of brain cells. In Alzheimer’s, fat metabolism in the brain becomes altered, influencing disease progression. A recent study found that a modified Mediterranean ketogenic diet boosted healthy fats in the brain and lowered Alzheimer’s-associated markers.

    The study included 20 adults with prediabetes who were at risk for developing Alzheimer’s. Participants followed the modified Mediterranean ketogenic diet or the American Heart Association diet for six weeks. After a six-week break, they switched to the opposite diet for another six weeks. Before and after each diet intervention, participants underwent cognitive testing, and the researchers evaluated their blood lipids and Alzheimer’s markers, including amyloid-beta and tau.

    They found that the modified Mediterranean ketogenic diet caused notable changes in blood lipids, increasing molecules linked to fat breakdown and energy use (such as free fatty acids and acylcarnitines) while lowering triglycerides. It also boosted healthy lipid types (plasmalogens) and reduced harmful ones (deoxyceramides). These alterations in blood lipids correlated with improved Alzheimer’s biomarkers and cognitive measures. The American Heart Association diet had little or no effect on blood lipids or cognitive function.

    The traditional ketogenic diet is high in fat and low in carbohydrates. The modified Mediterranean-ketogenic diet is rich in fish, lean meats, and fiber-rich green leafy vegetables, nuts, and berries. About 5% to 10% of its calories come from carbohydrates, 60% to 65% from fat, and 30% from protein. In the American Heart Association diet, about 55% to 65% of calories come from carbohydrates, 15% to 20% from fat, and 20% to 30% from protein.

    The findings from this small intervention study suggest that a modified Mediterranean ketogenic diet protects against Alzheimer’s disease. Learn more about the ketogenic diet and Alzheimer’s disease in this clip featuring Dr. Dale Bredesen.

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  • Beta-hydroxybutyrate, a ketone used by the brain during fasting or exercise, may help counteract toxic protein buildup in aging and Alzheimer's disease. pmc.ncbi.nlm.nih.gov
    Brain Alzheimer's Diet Ketosis Dementia Protein Ketogenic Diet

    Protein misfolding in the brain is a central player in both aging and Alzheimer’s disease, driving toxic protein buildup and brain cell dysfunction. However, evidence indicates that ketones—a critical brain fuel produced during fasting or exercise—may help reduce or prevent this damage. A recent cell study found that beta-hydroxybutyrate, a type of ketone, helps protect the brain by targeting toxic proteins for disposal.

    Researchers delivered beta-hydroxybutyrate to brain cells collected from mice and monkeys via an exogenous ketone ester. They examined the cells for changes in protein solubility and pathways involved in protein breakdown. They also studied beta-hydroxybutyrate’s effects on pathological proteins, such as amyloid-beta, in a nematode model of Alzheimer’s disease.

    They found that beta-hydroxybutyrate made pathological proteins insoluble, preventing their toxic spread while promoting their clearance through autophagy, the cell’s natural recycling process. This effect was specific to pathological proteins and wasn’t the result of changes in acidity or random chemical interactions. Beta-hydroxybutyrate also reduced amyloid-beta toxicity in nematodes.

    These findings suggest that a ketone ester of beta-hydroxybutyrate counteracts the toxic buildup of proteins in aging and Alzheimer’s disease. Further research is needed to translate these results to humans. Learn more about how ketone ester supplementation may improve brain health in this episode featuring Dr. Mark Mattson.

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  • Ketones may protect against cognitive decline by mitigating insulin resistance-induced neuronal damage. www.futurity.org
    Brain Aging Insulin Resistance Memory Insulin Ketogenic Diet

    Insulin regulates many processes involved in memory and cognitive function. However, age-related insulin resistance in the brain disrupts neuronal synaptic activity and contributes to cognitive decline. A recent study found that ketones may protect the brain from age-related insulin resistance in the brain.

    Researchers induced acute insulin resistance in mouse hippocampal tissue and determined its effects on neuronal function. Then, they administered beta-hydroxybutyrate, a type of ketone, to the tissues and evaluated the outcomes.

    They found that insulin resistance adversely affected aspects of neuronal communication, including synaptic activity, axonal conduction, network synchronization, synaptic plasticity, and action potential properties. However, ketones restored these functions.

    These findings suggest that ketones rescue the brain from the deleterious effects of acute insulin resistance. The high blood glucose levels associated with insulin resistance induce glucotoxicity, which causes structural damage and functional impairments of neuronal cells. Learn more about the effects of insulin resistance in the brain in this clip featuring Dr. Dale Bredesen.

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  • A ketogenic diet restores long-term potentiation, a crucial mechanism for learning and memory, to healthy levels in mice prone to Alzheimer's-like symptoms, implicating ketone bodies as potential therapeutic agents. www.ucdavis.edu
    Alzheimer's Diet Aging Ketosis Memory Dementia Ketogenic Diet

    A ketogenic diet – a high-fat, low-carbohydrate dietary pattern – offers potential benefits in various health contexts, including weight management and seizure control. Some evidence suggests that the ketogenic diet is beneficial in preventing or treating neurodegenerative diseases, such as Alzheimer’s and dementia. A recent study in older mice found that a ketogenic diet improves memory functions and increases lifespan.

    Researchers compared the effects of a seven-month ketogenic diet to a standard diet in mice prone to developing Alzheimer’s-like symptoms. They examined the hippocampal region of the animals' brains, a crucial area for memory and learning, to gauge the diet’s effects on synaptic plasticity – the brain’s ability to form and reorganize synaptic connections, especially in response to learning or new experiences.

    They found that mice on the ketogenic diet experienced restoration of their long-term potentiation – a measure of synaptic strength and a fundamental mechanism for learning and memory – to levels comparable to healthy mice. They attributed this restoration to the marked elevation of beta-hydroxybutyrate (BHB), a ketone body produced during the ketogenic diet. They also found that the diet triggered enhancements in several key pathways and molecules associated with synaptic plasticity, including notable increases in specific enzymes and brain-derived neurotrophic factor (BDNF), particularly in female mice.

    BDNF is crucial for cognitive functions, providing support for neuronal survival, growth, and differentiation and enhancing learning and memory by strengthening and creating synaptic pathways. Elevated BDNF levels correlate with better cognitive performance, whereas its deficiency is linked to various mental and neurodegenerative disorders, highlighting its significance in brain health. Learn more about BDNF in our overview article.

    These findings suggest that a ketogenic diet ameliorates memory impairments and bolsters neuronal health in an Alzheimer’s mouse model, primarily through the action of BHB and its enhancement of synaptic plasticity. Learn more about beta-hydroxybutyrate in our overview article.

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  • A ketogenic diet decreases alcohol cravings in people with alcohol use disorder, offering an alternative to the brain's energy needs. www.frontiersin.org
    Brain Alcohol Addiction Ketogenic Diet

    Alcohol use disorder accounts for approximately 2.8 million deaths worldwide. It’s a chronic condition marked by a strong desire to drink and persistent alcohol use despite its harmful effects. A recent study found that a ketogenic diet reduces alcohol cravings in people with alcohol use disorder.

    The study involved 33 adults with an alcohol use disorder enrolled in a three-week inpatient alcohol detoxification program. Slightly more than half of the patients received a ketogenic diet, while the remainder received a standard American diet. Once a week, using functional magnetic resonance imaging, researchers assessed the participants' brain function and craving responses during exposure to alcohol-related triggers. In addition, the participants reported their perceived alcohol cravings when exposed to the triggers.

    The imaging revealed that participants who ate a ketogenic diet showed reduced neural activity related to alcohol cravings than those who ate the standard American diet across the entire three weeks of treatment. Those who ate a ketogenic diet also reported fewer perceived cravings.

    Following alcohol consumption, the brain uses acetate, a metabolic byproduct of alcohol, for energy instead of glucose. As a result, glucose levels in the brain drop, and acetate levels increase – even after the effects of alcohol wear off. These alterations in fuel can contribute to withdrawal symptoms, cravings for alcohol, and a higher risk of relapse, especially when acetate levels drop. Ketones are structurally similar to acetate and can serve as an alternative energy source for the brain, providing energy in place of glucose.

    This was a small study, but its findings suggest that a ketogenic diet reduces alcohol cravings among people with alcohol use disorders. Other evidence suggests vigorous exercise reduces alcohol cravings, likely due to exercise’s effects on FGF21 – a hormone produced during vigorous activity. Learn more in this short video featuring Dr. Rhonda Patrick.

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  • Long-term nutritional ketosis improves metabolism and reduces inflammatory markers in women. www.mdpi.com
    Diet Metabolism Ketosis Inflammation Insulin Ketogenic Diet

    Nutritional ketosis is a powerful tool for managing weight and moderating inflammation. However, most studies on ketosis have been conducted in men and have only assessed short-term effects. A recent study found that nutritional ketosis reduces blood glucose, insulin, and inflammatory markers in healthy women practicing long-term ketosis.

    Researchers asked ten healthy young women who had been maintaining nutritional ketosis for more than a year to alter their dietary habits to suppress ketosis. The study involved three one-week phases: nutritional ketosis, suppressed ketosis, and return to nutritional ketosis. The researchers measured the women’s ketone levels daily; at the end of each phase, they took their women’s body measurements and assessed their metabolic and inflammatory biomarkers.

    They found that when the women suppressed ketosis, their insulin, IGF-1, glucose, and pro-inflammatory markers increased. However, when they returned to ketosis, those markers returned to baseline levels.

    These findings suggest that nutritional ketosis maintains healthy metabolism and suppresses inflammation without altering metabolic flexibility. Other evidence demonstrates that a ketogenic diet promotes weight loss and reduces cancer risk. Learn how to design the optimal ketogenic diet in this episode featuring Dr. Dominic D'Agostino

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  • Dietary AGEs linked to overeating and 30 percent shorter lifespan in worms. www.sciencedaily.com
    Nutrition Diet Aging Diabetes Ketogenic Diet

    Advanced glycation end-products (AGEs) form when the sugars, amino acids, and fats in food encounter heat. The molecules in the foods rearrange, forming brown polymers (a process known as the Maillard reaction) and creating the deep flavors of browned barley in beer, roasted coffee, seared meats, and French fries. A recent study in worms shows that dietary AGEs promote overeating and reduce lifespan by as much as 30 percent in those genetically susceptible.

    Researchers investigated the health effects of AGEs in Caenorhabditis elegans, a type of roundworm often used to model human aging. Specifically, they looked at the effects of dietary AGEs derived from methylglyoxal, a byproduct of glycolysis and lipid peroxidation.

    They found that worms lacking the gene for glyoxalase, an enzyme that protects the body from methylglyoxal-derived AGEs, showed increased appetite when exposed to AGEs. They also found that the methylglyoxal-derived AGE known as MG-H1 influences the production of the neurotransmitter tyramine, ultimately contributing to the harmful effects of AGEs, including increased feeding, decreased lifespan, and neuronal damage.

    These findings suggest that dietary AGEs promote overeating and reduce lifespan by as much as 30 percent in genetically susceptible organisms. Although AGEs are present in the diet, they also form in the body during normal glucose metabolism. However, if high AGE levels accumulate in the tissues and blood, they can become pathogenic, driving many chronic diseases, including diabetes, atherosclerosis, Alzheimer’s disease, macular degeneration, and kidney failure. The body clears excess AGEs via the liver (and possibly the kidney)00462-3/fulltext), but the clearance rate declines with age.

    Evidence suggests that a low carbohydrate diet inhibits AGE formation. The ketogenic diet typically restricts carbohydrate intake to roughly 10 percent or less of one’s calories. Learn more about the ketogenic diet and its health effects in this episode featuring Dr. Dominic D'Agostino.

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  • Ketogenic diet may alleviate ADHD symptoms by altering gut microbiota and boosting neurotransmitter expression. journals.plos.org
    Microbiome ADHD Neurotransmitter Ketogenic Diet

    Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral condition observed in children and adults. A recent study in mice suggests that a ketogenic diet reduces symptoms of ADHD via alterations in the gut microbiota.

    Researchers conducted experiments using two groups of rats: one with ADHD-like symptoms and another without. They further divided each group into three subgroups: those fed a standard diet, those treated with methylphenidate (an ADHD drug commonly sold as Ritalin, Concerta, or others), and those fed a ketogenic diet.

    They found that both the methylphenidate and ketogenic diet interventions reduced ADHD-like behaviors, such as increased activity and hypermobility. In addition, both groups demonstrated elevated levels of various neurotransmitters, including serotonin, norepinephrine and others, in brain tissue, along with changes in the expression of key proteins related to neural signaling. Interestingly, the ketogenic diet also altered the gut microbial composition in ADHD-like rats, especially microbes involved in amino acid and sugar metabolism.

    These findings suggest that the ketogenic diet may hold promise as a novel approach for mitigating ADHD-related behavioral challenges, possibly by influencing the gut microbiota. It also underscores the robust effects the ketogenic diet has on the brain. Learn more in this clip featuring Dr. Dominic D'Agostino.

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  • Ketogenic diet helps mouse muscle stem cells survive stress apple.news
    Stem Cells Stress Ketogenic Diet

    Ketones produced during fasting or a ketogenic diet promote muscle stem cell survival.

    Fasting – the voluntary abstention from food and drink – is widely appreciated for its beneficial effects on human metabolism and healthspan. Evidence suggests that fasting flips a metabolic “switch,” liberating fat stores via fatty acid oxidation and ketone production. Findings from a recent study suggest that ketones induce a deep resting state in muscle stem cells, protecting them from future stressors.

    Ketones are molecules produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), ketogenic diets, starvation, or prolonged intense exercise. There are three types of ketones produced in the body: acetoacetate, beta-hydroxybutyrate, and acetone. Ketones are readily used as energy by a diverse array of cell types, including neurons.

    Next, they examined muscle stem cells from both groups and found that the fasted animals' cells were smaller; had less mitochondrial content, RNA content, and basal oxygen consumption; and exhibited delayed cell division, compared to cells of non-fasting animals. Interestingly, the fasted animals' cells exhibited greater resilience to environmental stressors, such as oxidative stress and low nutrient availability.

    Then the investigators treated muscle stem cells from the non-fasting mice with beta-hydroxybutyrate, a type of ketone. The cells exhibited similar resistance, likely due to beta-hydroxybutyrate’s actions as a histone deacetylase (HDAC) inhibitor. HDAC inhibition is associated with improved cellular resilience and longevity.

    These findings suggest that ketones, particularly beta-hydroxybutyrate, induce a deep resting state in muscle stem cells, protecting them from future stressors. Learn more about beta-hydroxybutyrate in our overview article.

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  • Strict 12-week keto without calorie counting: participants lost >5% percent body fat, 44% of their visceral fat, and 48% better insulin sensitivity www.sciencedaily.com
    Diet Obesity Ketosis Insulin Resistance Metabolic Syndrome Visceral Fat Ketogenic Diet

    This is a Jeff Volek study and used hard biomarkers, checking ketones daily.

    From the article:

    In the study, which appears in the journal Military Medicine, participants on the keto diet lost an average of almost 17 pounds and were able, with support of counselors, to maintain ketosis for 12 weeks. As a group, they lost more than 5 percent of their body fat, almost 44 percent of their belly, or visceral, fat and had a 48 percent improvement in insulin sensitivity – a marker that predicts risk of diabetes.

    […]

    The ketogenic diets in the study included no caloric restrictions, just guidance about what to eat and what to avoid. Carbs were restricted to about 30 to 50 grams daily, with an emphasis on nuts and non-starchy vegetables.

    […]

    Keto diet participants had near-daily check-ins during which they reported blood ketone measurements from a self-administered finger-prick test and received feedback, usually through text messages, from the research team. Ketosis was defined as a blood concentration of ketones, chemicals made in the liver, between 0.5 and 5.0 mM (millimolar).

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  • Restoring integrity of blood-brain barrier critical for epilepsy: blood-brain barrier disruption was a key driver of seizure activity www.sciencedaily.com
    Brain Blood-Brain Barrier Ketogenic Diet

    Probably one of the better known and highly effective non-pharmacological approaches to changing seizure threshold is achieving nutritional ketosis via a ketogenic diet. Which begs the question… what effect does nutritional ketosis have on maintenance of the blood-brain barrier?

    From the article:

    Scientists have announced a significant advance in our understanding of epilepsy, as they have identified a potential method of preventing damaging seizure activity. Brain cells are nourished by an intricate network of capillaries that forms the so-called blood-brain barrier (BBB). Fundamentally, it is disruption to the integrity of these capillaries and the BBB that a group of scientists believe is a key driver of seizure activity in humans. Promisingly though, their new research shows that restoring that integrity can prevent seizures.

    Animal and human evidence:

    Importantly, the work was translational in nature and included both basic and clinical research arms involving patients diagnosed with epilepsy. Using similar techniques in humans and in pre-clinical models, the scientists were able to show that BBB disruption was a key driver of seizure activity.

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  • How precision nutrition may lower the risk of Alzheimer's disease in people with an APOE4 allele www.mdpi.com
    Nutrition Brain Alzheimer's Neurodegeneration Ketogenic Diet

    Abstract

    “The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.”

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  • Restricting dietary fat can slow the growth of tumors in mice www.sciencedaily.com
    Cancer Diet Fat Ketogenic Diet

    Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.

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  • Ketogenic diet and β-Hydroxybutyrate may improve disorders of epigenetic machinery via HDAC inhibition, reducing intellectual disability www.sciencedaily.com
    Brain Epigenetics Ketosis Intelligence HDAC Inhibitor Ketogenic Diet

    Ketogenic diet and beta-hydroxybutyrate improve gene transcription and reduce intellectual disability in Kabuki syndrome.

    Kabuki syndrome is a debilitating inherited disorder caused by mutations in two genes involved in the regulation of chromatin remodeling, one of the first steps in DNA transcription. Ketones such as beta-hydroxybutyrate have been shown to enhance DNA transcription and gene expression. Findings from one group of researchers show 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 those with Kabuki syndrome.

    Chromatin is the name for the coiled structure DNA forms within the cells of plants and animals, which looks a bit like 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 in order to translate these insights into clinically useful information for humans.

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  • Beta-hydroxybutyrate produced from a ketogenic diet may improve gout symptoms (animal study) www.sciencedaily.com
    Nutrition Diet Ketosis Inflammation Arthritis NLRP3 Ketogenic Diet

    Beta-hydroxybutyrate 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.

    Beta-hydroxybutyrate is a type of ketone body. It forms in the liver via the breakdown of fatty acids and can be used to produce energy in the mitochondria. Beta-hydroxybutyrate also acts as a signaling molecule that alters gene expression via a wide range of molecular pathways. Ketogenic diets induce beta-hydroxybutyrate production.

    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.

    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.

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  • Compounds produced during ketosis may slow prostate cancer growth. www.biorxiv.org
    Cancer Metabolism Ketosis Prostate Carbohydrates Ketogenic Diet

    Prostate cancer is a leading cause of cancer death among men in the United States. While some prostate cancers respond well to local treatment, many cases require systemic treatments, such as chemotherapy or hormone therapies, which can have many side effects. Because having overweight or obesity increases the risk of death from prostate cancer](https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.22443), newer and alternative therapies that slow cancer growth and help patients lose weight are needed. Findings of a new report show that a low carb diet generates ketones and other metabolic compounds associated with slower prostate cancer growth.

    Low carbohydrate and ketogenic diets are popular with adults looking to lose weight, but they also have therapeutic power for a growing list of diseases such as epilepsy, [diabetes](​​https://www.magonlinelibrary.com/doi/full/10.12968/pnur.2020.31.4.176), Parkinson’s disease, and some cancers. In addition to the metabolic benefits of weight loss, many anticancer compounds are produced during ketosis such as beta-hydroxybutyrate, a short-chain fatty acid with documented antioxidant and anti-inflammatory effects. Additional research is needed to characterize the wide range of molecules generated on a low carb diet and explore their relationship to prostate cancer growth.

    The investigators recruited participants who had recurrent prostate cancer and a BMI in the overweight or obese range (greater than 24). They assigned participants to consume a low carbohydrate diet (less than 20 grams of carbohydrates per day) for six months or continue their habitual diet. Participants provided a blood sample to measure metabolic and cancer biomarkers at multiple time points.

    The investigators found increased concentrations of multiple ketone bodies in the blood and increased expression of genes for ketone production, indicating participants succeeded in maintaining ketosis. A low carbohydrate diet altered serum concentrations of multiple amino acids, such as glycine, alanine, and asymmetric dimethylarginine, and increased the expression of genes involved in the synthesis of malate, citrate, and branched-chain amino acids. The researchers found a relationship between increased concentrations of ketosis-related compounds and prostate specific antigen (PSA) double time (a marker of prostate cancer growth rate), indicating that cancer growth was reduced as ketosis intensified.

    These results show that metabolites produced in response to a ketogenic diet may contribute to the beneficial effects of a low carb diet for patients with prostate cancer.

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  • Redefining the causes of obesity. www.sciencedaily.com
    Diet Obesity Ketogenic Diet

    Obesity is a complex, multifactorial disease influenced by genetic, molecular, environmental, and behavioral factors. Characterized as having excessive body fat, obesity affects more than 650 million people worldwide and markedly increases a person’s risk for many chronic diseases, including cardiovascular disease, type 2 diabetes, cancer, and depression, among others. The authors of a recent report challenge the prevailing theory regarding the root causes of obesity.

    A widely espoused concept in bodyweight management is the “eat less, exercise more” model, based on the principle that the number of calories consumed must be equivalent to (or less than) the number of calories expended. This model is supported by evidence suggesting that consuming high-fat foods drives overconsumption of calories due the foods' high caloric levels, poor ability to provide satisfaction and fullness, and high “pleasure factor.” However, this concept, which forms the basis for national dietary guidelines, public health messaging, and dietary counseling, is inherently flawed, because it fails to take into consideration the biological mechanisms that promote weight gain. Ultimately it places blame on people with obesity and promotes stigmatization.

    In recent decades, scientists have proposed a new model for explaining the root causes of obesity. In this model, body fat accumulation arises from hormonal responses to the consumption of high-glycemic load carbohydrates, ultimately driving a vicious cycle of body fat accumulation, hunger, and food intake. Commonly referred to as the “carbohydrate-insulin” model of obesity, this new paradigm reverses causation and provides a starting point for developing testable hypotheses.

    The concepts presented in this report suggest that what a person eats, rather than how much, plays key roles in body weight management. The authors of the report posited that if the carbohydrate-insulin model is accurate, dietary modifications that limit carbohydrate intake, such as a ketogenic diet, may alter hormonal responses and promote fat oxidation and weight loss. Learn more about the health benefits of the ketogenic diet in this clip featuring Dr. Dominic D'Agostino.

    Link to full publication.

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  • Excess sugar intake induces mitochondrial dysfunction. www.sciencedaily.com
    Sugar Ketogenic Diet

    Hyperglycemia, which occurs when glucose levels in the blood rise to dangerous levels, is a hallmark of diseases such as metabolic syndrome and type 2 diabetes. The effects of hyperglycemia are well documented and include cellular damage, inflammation, and pro-cancer effects; however, few studies have elucidated the cellular mechanisms of hyperglycemia. Findings of a new report suggest mitochondrial damage explains the connection between hyperglycemia and disease.

    Glucose is consumed in the diet from simple sugars and starches. Glucose transport proteins, which move glucose from the bloodstream into cells, are expressed in the heart, skeletal muscle, adipose tissue, and brain among others. TXNIP is a protein that binds to glucose transporters, preventing the movement of glucose into cells. Mice who do not produce the TXNIP protein, called knockouts, experience uncontrolled glucose transport into cells. Glucose metabolism produces damaging compounds called reactive oxygen species, which attack the delicate lipid membranes in mitochondria, the cell structures that produce energy.

    Brown adipose tissue is particularly vulnerable to the effects of hyperglycemia. This fatty tissue produces heat in response to cold temperatures, while white adipose tissue is mainly for energy storage. Brown adipose tissue appears brown because it has a higher density of mitochondria, which may make these cells more susceptible to damage from hyperglycemia, especially in cold temperatures.

    The investigators compared normal mice with those that did not express the TXNIP protein in their brown adipose tissue. After exposing both groups of animals to cold temperatures (40°F, 4°C) for four hours, the researchers measured their body temperatures using a thermal camera and performed an in vitro study to examine the cellular integrity of mitochondria and their ability to produce energy from multiple common fuel sources.

    These experiments revealed that TXNIP knockout mice had lower body temperatures after cold exposure than normal mice, suggesting that their brown adipose tissue was less effective at producing heat under stress conditions. Their mitochondria also showed signs of membrane damage and reduced concentration of polyunsaturated fats, which indicated that they were significantly more stressed due to reactive oxygen species produced during cold exposure compared to mitochondria in normal mice. TXNIP knockout mice had lower expression of genes related to energy metabolism and heat production.

    Interestingly, the researchers found that severely restricting the TXNIP-deficient animals’ glucose intake by feeding them a ketogenic diet for five weeks mitigated the stress-induced deficit in mitochondrial function and reversed the detrimental changes to the polyunsaturated fat content of their mitochondrial membranes.

    These findings indicate that excess sugar intake creates mitochondrial dysfunction, which contributes to poor health. A ketogenic diet reversed the effects of hyperglycemia on mitochondrial function.

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  • A ketogenic diet may be beneficial for people with brain tumors. www.sciencedaily.com
    Cancer Ketosis Ketogenic Diet

    Glioma is a collective term for tumors that arise from the glial cells in the brain. Astrocytoma, the most common form of glioma, arises from star-shaped cells in the brain called astrocytes. The the survival rate for glioma, including astrocytoma, is low. Findings from a recent study suggest that a ketogenic diet is beneficial for people with astrocytoma.

    Ketogenic diets are low in carbohydrates and high in proteins and fats. They cause the body to oxidize fats to produce ketones for energy. For many years, ketogenic diets have been used in the clinical setting to reduce seizures in children. They are currently being investigated for the treatment of cancer because evidence suggests that cancer cells cannot use ketones for energy.

    The eight-week intervention study involved 25 people with astrocytoma whose disease was stable following chemotherapy. Participants followed a weekly dietary protocol consisting of five days of a ketogenic diet (consuming 20 grams or less of carbohydrates per day) and two non-consecutive days of fasting (consuming less than 20 percent of their estimated caloric needs). Participants kept food diaries and provided weekly blood and urine for measuring ketones, insulin, glucose, hemoglobin A1c (a measure of long-term blood glucose control), and IGF-1. They underwent brain scans at the beginning and end of the intervention.

    About half of the participants adhered to the dietary intervention, which was well-tolerated and elicited few adverse events. Despite the relatively low compliance, all the participants had ketones in their urine, with 80 percent achieving moderate levels. Participants' hemoglobin A1c, insulin, and fat body mass decreased, but their lean body mass increased. No changes were noted in glucose or IGF-1 levels. The brain scans showed that ketone concentrations increased in the brain (including the tumor tissue) and correlated with ketone levels in the urine.

    These findings demonstrate that a ketogenic diet is safe for people with astrocytoma and may be beneficial as adjunctive therapy. Learn more about how a ketogenic diet, combined with fasting and the standard of care treatment, may help treat aggressive cancers in this clip featuring Dr. Valter Longo.

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  • A ketogenic diet improves immunity and reduces excessive inflammation. elifesciences.org
    Ketosis COVID-19 Ketogenic Diet

    A Western dietary pattern, characterized by a low intake of fruits and vegetables and a high intake of red and processed meats and added sugars, promotes chronic diseases, including obesity. It also increases low-grade inflammation by directly reprogramming immune cells to become pro-inflammatory. Authors of a recent report investigated the impact of a ketogenic diet on immunity.

    Glucose is the primary energy source for most cells in the body. However, when a person fasts or restricts carbohydrate intake, the body produces ketones from dietary and body fat for energy. One such ketone is beta-hydroxybutyrate, which has been shown to ameliorate low-grade inflammation and related diseases in mice. Whether consuming a very low carbohydrate diet alters immunity in humans is unclear.

    The investigators recruited 44 healthy adults to complete a three-week ketogenic diet that provided less than 30 grams of carbohydrates per day (the amount in about two slices of sandwich bread). Participants gave blood samples before and after the diet period for measurement of immune cells, including antibody-producing T cells. The researchers exposed white blood cells from the pre-diet and post-diet timepoints to varying concentrations of beta-hydroxybutyrate for 48 hours, stimulated them to produce an immune response, and measured the effect.

    When exposed to beta-hydroxybutyrate, pre-diet white blood cells associated with the innate immune system (the driver of chronic low-grade inflammation) did not alter their behavior; however, antibody-producing white blood cells associated with the adaptive immune system became more active. CD4+ and CD8+ T cells exposed to the highest concentration of beta-hydroxybutyrate (10 millimolar), comparable to the maximum circulating level in humans, produced more cytokines used to fight infection. Regulatory T cells, which prevent autoimmunity and excessive inflammation, also increased their activity, including the mitochondrial metabolism of ketones. Participants lost a significant amount of weight over the three-week ketogenic diet period, and their post-diet T cells showed the same metabolic and immunological responses as those in the in vitro experiment.

    The authors concluded that a very low carbohydrate diet or ketogenic diet is a clinical tool for improving T cell-mediated immunity. They suggested that nutrition and dietary interventions should be used more in modern medicine.

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  • A ketogenic diet may reduce COVID-19 severity. www.embopress.org
    Diet Immune System Ketogenic Diet

    Aging impairs the body’s ability to fight infection due to chronic low-grade inflammation and a decrease in antibody-producing T cells. Consequently, 80 percent of deaths due to COVID-19 in the United States have been among adults 65 years of age and older. Researchers investigated the use of a ketogenic diet in mice as a strategy for treating COVID-19.

    A ketogenic diet is a high fat, low carbohydrate diet. Adherence to a ketogenic diet reduces blood glucose levels, which are associated with increased inflammation. Adopting a ketogenic diet may be an effective strategy for limiting excessive inflammation, especially in older adults, who are more likely to have poor blood glucose control.

    The SARS-CoV-2 virus, the cause of COVID-19 illness, induces lung inflammation. In severe cases, patients may need mechanical ventilation to breathe and may have long-lasting respiratory problems after recovery. Previous COVID-19 research has shown that white blood cells such as neutrophils and monocytes accumulate in the lungs. There they become more reliant on glucose, accelerate their mitochondrial metabolism, and produce more damaging oxidative compounds, contributing to unchecked inflammation and disease severity.

    The researchers used mice that express the human angiotensin-converting enzyme (ACE) 2 receptor, which is the point of entry for the SARS-CoV-2 virus in the lungs and other organs. They fed young adult mice and older adult mice either a standard diet or a ketogenic diet for five days before exposing them to a hepatitis virus that closely mimics the SARS-CoV-2 infection in humans. The mice continued their assigned diet for an additional seven days following infection. The investigators measured markers of inflammation and metabolic function.

    Older mice had significantly higher levels of inflammation and metabolic dysfunction at the beginning of the study. Upon infection, they had greater inflammation in the heart, adipose tissue, and hypothalamus; worse pneumonia symptoms and increased blood clot formation; and were more likely to die due to infection, compared to younger mice. The increased inflammation was due to an increase in neutrophil accumulation and a decrease in tissue-protective T cells in the lungs. A ketogenic diet reprogrammed metabolism and the immune system to a greater extent in older mice by increasing the number of beneficial T cells and reducing the number of harmful monocytes in the lungs, leading to less inflammation overall and reduced disease severity.

    Although this study was conducted in mice, the authors concluded that a ketogenic diet may be a potential treatment for SARS-CoV-2 infection in older adults due to its ability to modulate immune function and dampen excessive inflammation.

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  • Omega-6 and omega-3 fats kill cancer cells. www.eurekalert.org
    Cancer Omega-3 Ketogenic Diet

    Cancer is a leading cause of death in the United States, but new therapies targeting diet and lifestyle may aid in fighting the disease. Emerging research suggests that modulating the kind of nutrients available to cancer cells may encourage or inhibit their growth. Findings of a recent study detail the effects of polyunsaturated fats on cancer growth in mice.

    Polyunsaturated fats are fatty acids that have more than one unsaturated carbon bond in the molecule, such as omega-3 and omega-6 fatty acids. They are present in fish, nuts, and seeds and are more prone to oxidation than other fatty acids. Polyunsaturated fats play critical roles in cardiovascular and neurological health.

    While cancer is often viewed as a genetic disease, metabolic changes occur in cancer cells that contribute to their growth and spread. Cancer cells tend to produce energy by fermenting glucose to produce lactic acid, which acidifies the tumor environment, a phenomenon known as “cancer acidosis.” The acidity of the tumor environment alters the way cancer cells metabolize fats, increasing both the storage and the breakdown of fats.

    Previous research demonstrated that targeting fatty acid metabolism may promote cancer cell death and prevent cancer spread by increasing lipid peroxidation (the breakdown of fats in the presence of iron) resulting in oxidative stress. Peroxidized lipids signal cellular damage, inducing a type of programmed cell death called ferroptosis (apoptosis occurring due to iron). However, it is unclear how different types of dietary fats affect cancer metabolism.

    First, the authors of the present study exposed cervical, colorectal, and pharyngeal (throat) cancer cells to a variety of fats and measured the effects on metabolism. These fats included saturated fats, like those found in butter and palm oil; monounsaturated fats, like those found in olive oil; and polyunsaturated fats, including omega-6 fats, like those found in corn oil, and omega-3 fats, like those found in fish (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]). Next, they fed mice a diet supplemented with either olive oil or fish oil for four weeks. Two weeks into the diet, the mice developed cancer and the researchers measured the effects of the two diets on cancer progression. Finally, the researchers administered compounds to mice with cancer that induce or inhibit ferroptosis to further explore the mechanisms of cancer cell metabolism.

    In cancer cells, exposure to both omega-6 and omega-3 polyunsaturated fats enhanced fat uptake and storage, which increased lipid peroxidation and induced ferroptosis to a greater extent than saturated or monounsaturated fats. Fats with the least saturation (meaning the most double bonds) were most effective, with the omega-3 fat DHA demonstrating the most cancer-fighting ability. However, this result only occurred in cancer cells with an acidic pH compared to a neutral pH. Mice that received the fish oil supplementation lost harmful white adipose tissue but gained metabolically beneficial brown adipose tissue, improving whole-body metabolism. The fish oil diet delayed cancer growth and increased survival, and this effect was magnified by the addition of a ferroptosis-inducing drug.

    The authors of this important work concluded that polyunsaturated fats may be an effective add-on treatment to complement pharmacological therapies for cancer.

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  • Intermittent fasting improves long term memory retention in mice. www.sciencedaily.com
    Fasting Memory Ketogenic Diet

    Intermittent fasting is a broad term that describes periods of fasting between meals, lasting several hours to days. Intermittent fasting increases ketone production because it uses stored fat as an energy source. It also activates genetic pathways associated with enhanced healthspan and longevity. Caloric restriction, which typically involves a 10 to 40 percent reduction in total caloric intake, activates similar pathways. Findings from a new study suggest that intermittent fasting is more effective than caloric restriction in activating klotho, a longevity gene, to improve long-term memory retention in mice.

    The klotho gene provides the instructions for making the klotho protein in mammals, including mice and humans. Klotho is produced primarily in the kidneys, but some is produced in the brain, where it appears to play a role in cognition and in neurogenesis, the process of forming new neurons. Neurogenesis is the basis for memory, but it declines with age, leading to cognitive decline.

    The authors of the study assigned mice to one of three feeding regimens: intermittent feeding every other day (approximately 10 percent fewer calories over a one-week period); 10 percent calorie restriction; or eating freely. After the mice had followed their respective feeding regimens for three months, the authors of the study subjected them to behavioral studies (to assess spatial learning and memory, conducted at 24 hours and ten days post regimen) or gene expression studies.

    The memory assessment conducted at 10 days post regimen revealed that the mice in the intermittent feeding group performed 25 percent better than those in the caloric restriction group and 30 percent better than those that ate freely. The mice in the intermittent feeding group also exhibited more signs of hippocampal neurogenesis and upregulation of the klotho gene. Further analysis revealed that adult hippocampal neurogenesis is dependent upon klotho activity.

    These findings demonstrate that the longevity gene klotho is necessary for neurogenesis and that intermittent feeding may be beneficial in promoting memory retention in humans. A ketogenic diet also improves memory in mice. Learn more in this episode featuring aging expert Dr. Eric Verdin.

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  • Benefits of low-fat versus low-carbohydrate diets. www.sciencedaily.com
    Nutrition Ketogenic Diet

    Obesity affects more than 650 million people worldwide. Although low-carbohydrate and low-fat diets are effective at helping people lose weight, the health benefits and sustainability of the two dietary approaches are matters of controversy. A recent trial weighed the benefits of low-fat versus low-carbohydrate diets.

    The causes of obesity and overweight are not fully known. Some scientists have suggested that consuming high-glycemic carbohydrates increases insulin levels, ultimately driving a vicious cycle of body fat accumulation, hunger, and food intake, commonly referred to as the “carbohydrate-insulin” model of obesity. Others have suggested that consuming high-fat foods drives overconsumption of calories due the foods' high caloric levels, poor ability to provide satisfaction and fullness, and high “pleasure factor.”

    The four-week crossover trial involved 20 healthy men and women (average age, 30 years). Half of the participants ate an animal-based, ketogenic, low-carbohydrate diet that provided about 10 percent of its calories from carbohydrates and about 75 percent from fat and high calorie foods. The other half ate a plant-based, low-fat diet that provided about 10 percent of its calories from fat and about 75 percent from carbohydrates and low-calorie foods. After two weeks on their respective diets, participants switched diets and adhered to the new diet for another two weeks. All meals were prepared and served in an in-patient metabolic ward to ensure compliance. The study investigators monitored the participants' weight, vital signs, blood ketones, energy expenditure, activity, and other measures throughout the study.

    Although both diets promoted weight loss, participants on the low-carbohydrate diet lost more weight (1.5 pounds) and faster, but the difference was not statistically or clinically significant. The participants who ate the low-fat diet had higher glucose and insulin levels compared to those who ate the low-carbohydrate diet. They didn’t report any differences in hunger, fullness, or satisfaction with their meals. When eating the low-fat diet, participants ate about 690 fewer calories per day than when eating the low-carbohydrate diet over the two-week period.

    These findings suggest that whereas eating a low-carbohydrate diet is beneficial in reducing glucose and insulin levels, the low-fat diet reduces appetite, a finding that contradicts the carbohydrate-insulin model of obesity.

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  • Brain aging emerges in the late 40's but dietary ketosis increases overall brain activity and stabilizes functional networks. news.stonybrook.edu
    Brain Aging Ketosis Insulin Time-Restricted Eating Carbohydrates Ketogenic Diet

    Insulin resistance and poor blood glucose control – defining characteristics of type 2 diabetes – drive changes associated with brain aging and cognitive decline. A growing body of evidence suggests that dementia is the manifestation of insulin resistance and altered metabolism in the brain. A recent study suggests that dietary patterns that promote ketosis improve brain metabolism and function.

    Ketosis is a metabolic state that results in the body’s production and use of ketones (byproducts of fatty acid metabolism). It occurs under conditions of fasting, starvation, and low carbohydrate intake. Ketones induce physiological and metabolic responses to promote brain health.

    The study had multiple components. First, the authors of the study investigated the time course of human brain aging. Using functional MRI (fMRI) data from more than 900 people between the ages of 18 and 88 years, they determined that neural network stability is a biomarker of brain aging, and the loss of network stability manifests as early as the fifth decade of life (average age, 47 years). They found that the greatest changes in the brain occur around the age of 60 years.

    Then they performed fMRI scans on 12 young adults (average age, 28 years) to assess how different energy sources – glucose versus ketones – alter brain function. Each participant underwent three scans under different dietary conditions: a normal diet without fasting, a normal diet with overnight fasting, or a ketogenic diet for one week. They performed fMRI scans on 30 young adults (average age 29 years) 30 minutes after they took an oral bolus of either glucose or ketones or after following their normal diet with overnight fasting. The authors of the study measured the participants' blood glucose and ketone levels before and after each of the scans.

    The fMRI scans revealed that ketones increased overall brain activity and stabilized functional networks, but glucose had the opposite effect, regardless of whether the ketones were produced endogenously or supplied from exogenous sources. These findings suggest that dietary interventions that increase ketone production may be useful in mitigating the harmful effects of glucose on the brain.

    Certain dietary patterns promote ketosis. For example, the Ketoflex 12/3 diet, a form of time-restrictive eating that limits the period during which a person eats to a 12-hour window at least three hours before bedtime, promotes the production of ketones. Watch this clip in which Dr. Dale Bredesen describes this novel dietary protocol and how it improves cognitive function.

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  • Mice fed a high-fat, low-carbohydrate diet were better able to combat the flu virus and had better survival rates than mice fed a normal diet. www.sciencedaily.com
    Ketosis Immune System Protein Carbohydrates Weight Loss Ketogenic Diet

    More than 20,000 people die every year in the United States from influenza-related complications. Findings from a new study demonstrate that a ketogenic diet confers protection against the influenza virus and improves survival rates in mice.

    A ketogenic diet is a high fat, moderate protein, low carbohydrate eating pattern that causes the body to oxidize fat to produce ketones for energy. The ketogenic diet has been used in the clinical setting to reduce seizures in children and is being investigated for the treatment of traumatic brain injury, Alzheimer’s disease, weight loss, and cancer.

    The authors of the study fed a ketogenic diet or regular chow to mice for seven days and then infected them with influenza virus. The mice that ate the ketogenic diet lost less weight, maintained better blood oxygen levels, and had improved survival rates compared to the mice that ate the regular chow. In addition, the mice on the ketogenic diet had higher levels of specialized T-cells in their lungs that enhanced airway cell mucus production to improve lung barrier function.

    Interestingly, the beneficial effects of a high fat diet were only observed with the ketogenic diet. Feeding the mice a high-fat, high-carbohydrate diet or providing exogenous ketones in the diet had no beneficial effects against influenza virus.

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  • Time-restricted eating, a ketogenic diet, and exercise improved cognitive function and markers of metabolism in a woman with ApoE4 and Alzheimer's . www.sciencedirect.com
    Alzheimer's Ketosis Fasting Insulin Triglycerides Time-Restricted Eating Metabolic Syndrome Ketogenic Diet

    Time-restricted eating (TRE), a ketogenic diet, and exercise improved cognitive function and markers of metabolism including triglycerides, VLDL, and HbA1c in a 71-year-old woman with ApoE4 that has mild Alzheimer’s disease and metabolic syndrome (case study).

    This is an interesting proof of principle study showing that implementing a nutrition protocol purposed at raising plasma ketones through fasting (TRE) a ketogenic diet and physical exercises can compensate for insulin resistance and the ApoE4 gene in a mild Alzheimer’s patient experiencing cognitive impairment.

    The APOE4 gene is the largest risk factor for Alzheimer’s disease besides age itself.

    To learn more check out this episode highlight of Dr. Dale Bredesen talking about time-restricted eating and a ketogenic diet in the context of Alzheimer’s disease in people with and without ApoE4.

    Episode: https://youtu.be/PWZbeq6MCKU

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  • PPAR-Alpha Agonists
    Diet Ketosis Fat Saturated Fat Dairy Ketogenic Diet

    For the last year and a half, I have been on a ketogenic diet. Admittedly, it was heavy on saturated fat from dairy. Recently discovered that I have hypofunctioning PPAR-alpha genetics. Which now makes perfect sense because I could never get my ketones above 1 mmol, and my LDL skyrocketed (~190 on NMR, 86 when not in ketosis). Obviously, there were negatives to that dietary approach for me, but there were also a lot of positives. Not to mention, I would like to take advantage of the potential for longevity, decreasing cancer risk, etc that the ketogenic diet holds. Since learning this info (on top of the not so stellar labs), I have transitioned to a more Mediterranean diet with an emphasis on PUFA and MUFA. I’ve thought about doing periods of ketosis and fasting every now and then, while using PPAR-alpha agonists (like sesamin) to offset the genetic hypofunctioning. Would really like to get some insight on the safety, efficacy, etc of doing this.

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  • Beta-hydroxybutyrate production from fasting or a ketogenic diet may reduce the production of senescent cells associated with vascular aging www.sciencedaily.com
    Aging Ketosis Heart Disease DNA Damage Fasting Ketogenic Diet

    Fasting or beta-hydroxybutyrate administration reduces cellular senescence.

    Beta-hydroxybutyrate (BHB) is a ketone produced by the body during times of carbohydrate scarcity such as those encountered while practicing a ketogenic diet, fasting, or exercise, which have all demonstrated the ability to extend healthspan and lifespan. However, the precise effects of beta-hydroxybutyrate on the cellular mechanisms of aging are not well understood. Findings of one report show 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 them 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, which is a protein that binds to DNA and regulates cell regeneration and stem cell differentiation. Compared to mice who received a placebo injection, mice who received BHB had reduced senescence in vascular cells through the same Oct4 pathway as in cell culture. Mice who 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 show 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 to cells in culture.

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  • Insulin Sensitivity and Glucose Tolerance Are Altered by Maintenance on a Ketogenic Diet (2010) academic.oup.com
    Ketosis Insulin Carbohydrates Ketogenic Diet

    Low-carbohydrate, ketogenic diets (KD) are frequently implemented in efforts to reduce or maintain body weight, although the metabolic effects of long-term exposure to this type of diet remain controversial. This study assessed the responsivity to peripheral and central insulin, glucose tolerance, and meal-induced effects of consuming a KD in the rat. After 8 wk of consuming chow or KD, caloric intake after peripheral or central insulin and insulin and glucose levels after a glucose challenge were assessed. In a separate group of rats, glucose and insulin responses to either a low- or high-carbohydrate test meal were measured. Finally, rats maintained on KD were switched back to a chow diet, and insulin sensitivity and glucose tolerance were evaluated to determine whether the effects of KD were reversible. Maintenance on KD resulted in decreased sensitivity to peripheral insulin and impaired glucose tolerance. Furthermore, consumption of a high-carbohydrate meal in rats that habitually consumed KD induced significantly greater insulin and glucose levels for an extended period of time, as compared with chow-fed controls. Responsivity to central insulin was heightened in KD rats and associated with increased expression levels of insulin receptor mRNA. Finally, returning to a chow diet rapidly reversed the effects of KD on insulin sensitivity and glucose tolerance. These data suggest that maintenance on KD negatively affects glucose homeostasis, an effect that is rapidly reversed upon cessation of the diet.

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  • Suppression of insulin with a ketogenic diet improves the efficacy of cancer drugs known as PI3K inhibitors and shrinks tumors in mice. www.nature.com
    Cancer Ketosis Insulin Ketogenic Diet

    Suppression of insulin with a ketogenic diet improves the efficacy of cancer drugs known as PI3K inhibitors and shrinks tumors in several different animal models of cancer.

    Insulin activates the PI3K pathway is usually which then leads to cell proliferation and tumor growth. Drugs inhibiting the PI3K pathway have not been very effective due to an insulin feedback response. A ketogenic diet lowered the insulin response and made the drugs more effective.

    The researchers point out that this study doesn’t suggest a ketogenic diet alone would treat cancer. Their data showed in a leukemia model, the ketogenic diet seemed to make cancer more aggressive in mice who were not also given a PI3K inhibiting drug. However, the combination of a PI3K inhibitor and ketogenic diet showed efficacy in many different cancer types (in mice).

    Talk of a pilot clinical study in humans is underway.

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  • Fasting-like diet kills autoimmune cells & replaced them with healthy cells & improved symptoms in MS patients. www.sciencedaily.com
    Brain Fasting Immune System Multiple Sclerosis Autophagy Dairy Autoimmunity Ketogenic Diet

    This fasting-like diet also promotes regeneration of the myelin in mice with multiple sclerosis. In human patients with multiple sclerosis, the fasting-like diet led to improvements in symptoms if followed by a Mediterranean diet or a ketogenic diet.

    Here is the fasting-like diet that humans were given: Day 1 – pre-fasting followed by Day 2-8 – very low calorie diet. Day 1-prefasting consists of an 800 kcal (about 40% of normal caloric intake similar to mouse Day1 FMD) monodiet (fruit, rice, or potatoes) by preference of individuals. On the following day patients were recommended to use an oral laxative, Natrium Sulfuricum (20-40 g). FMD consisted of 100 ml vegetable broth or vegetable juice with 1tablespoon of linseed oil 3 times daily, plus additional calorie-free liquids. The daily calorie intake was predefined with 200 – 350 kcal (10-18% of normal caloric intake similar to mouse Day 2-3 FMD). Patients were advised to drink 2-3 L of unsweetened fluids each day (water, and herbal teas) and to use an enema if tolerated. After the 7-day fasting period solid foods were stepwise reintroduced for three days, starting with a steamed apple at day 8. After the fasting and refeeding period a normocaloric, plant-based Mediterranean diet was maintained until study end.

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  • Beta-hydroxybutyrate produced from a ketogenic diet, fasting, or high-intensity exercise dampens inflammation via blocking of the NLRP3 inflammasome www.sciencedaily.com
    Exercise Diet Ketosis Inflammation Fasting Immune System NLRP3 Ketogenic Diet

    From the article:

    BHB is a metabolite produced by the body in response to fasting, high-intensity exercise, caloric restriction, or consumption of the low-carbohydrate ketogenic diet. Dixit said it is well known that fasting and calorie restriction reduces inflammation in the body, but it was unclear how immune cells adapt to reduced availability of glucose and if they can respond to metabolites produced from fat oxidation.

    Working with mice and human immune cells, Dixit and colleagues focused on how macrophages – specialized immune cells that produce inflammation – respond when exposed to ketone bodies and whether that impacts the inflammasone complex.

    The team introduced BHB to mouse models of inflammatory diseases caused by NLP3. They found that this reduced inflammation, and that inflammation was also reduced when the mice were given a ketogenic diet, which elevates the levels of BHB in the bloodstream.

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