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Could Diet Help Fight Brain Cancer?
A British man who rejected the standard of care to treat his brain cancer has lived with the typically fatal glioblastoma tumor growing very slowly after adopting a ketogenic diet, providing a case study that researchers say reflects the benefits of using the body's own metabolism to fight this particularly aggressive cancer instead of chemo and radiation therapy.
Published recently in the journal Frontiers in Nutrition, the report is the first evaluation of the use of ketogenic metabolic therapy (KMT) without chemo or radiation interventions, on a patient diagnosed with IDH1-mutant glioblastoma (GBM), said Boston College Professor of Biology Thomas Seyfried, a co-author of the report. Ketogenic therapy is a non-toxic nutritional approach, viewed as complementary or alternative, that uses a low-carbohydrate, high-fat diet to manage a range of cancers, including glioblastoma.
In this particular case, the patient's tumor contained a mutation, known as the IDH1. This mutation is acquired by chance and is known to improve overall survival. So the findings are particularly relevant to other patients whose tumors contain this mutation, said Seyfried, a leading researcher who has long advocated the benefits of KMT to treat disease.
"As GBM, like most malignant cancers, is dependent on fermentation for energy synthesis and survival, the simultaneous restriction of fermentable fuels, such as glucose and glutamine, while elevating non-fermentable ketone bodies, offers a non-toxic therapeutic strategy for managing GBM," said Seyfried. "Further studies will be needed to test this hypothesis in other patients diagnosed with GBM."
Glioblastoma kills about 15,000 people each year and remains largely unmanageable. While the standard of care has shifted to new immuno-therapies, the median survival time of 11 to 15 months for GBM has not improved significantly for more than 100 years, according to the co-authors.
A number of high-profile cases have illustrated the deadly progression of GBM. The late U.S. Sen. John McCain was diagnosed at age 80 with glioblastoma in July 2017, and died in August 2018. U.S. Sen. Edward M. Kennedy lived for a year after his diagnosis with GBM, dying at age 77. Beau Biden, son of U.S. President Joe Biden, was diagnosed at age 44 with GBM in August 2013, and died in May 2015.
The current standard of care for GBM involves surgical resection, radiation, and chemotherapy, which have been shown in studies to result in significant toxicity. However, large-scale clinical trials for alternative therapies are difficult to initiate, leading researchers to carefully examine individual cases.
The patient in this case was diagnosed with glioblastoma in 2014 and eschewed the traditional standard of care and instead embarked on a self-directed ketogenic diet—low in carbohydrates and high in fat—in an effort to manage his cancer.
The researchers found "the patient's tumor continued to grow very slowly over a three-year period without expected vasogenic edema until 2017," according to Seyfried and his co-authors, Boston College researcher Purna Mukherjee, Aditya Shivane, MD, of University Hospital Plymouth NHS Trust, in the United Kingdom, U.S.-based nutritionist Miriam Kalamian, Joseph Maroon, MD, of the University of Pittsburgh, and Giulio Zuccoli, MD, of the Drexel University School of Medicine.
At that point, the patient underwent "surgical debulking" of his tumor. The pathology specimen confirmed the diagnosis of GBM and that the patient's tumor also contained the IDH1 mutation.
"Following surgery, the patient continued with a self-administered ketogenic diet to maintain low Glucose Ketone Index (GKI) values, indicative of therapeutic ketosis," the researchers report. "In light of continued slow progression of the residual tumour, the patient intensified his KMT starting in October, 2018 with inclusion of mindfulness techniques to reduce stress. While Magnetic Resonance Imaging (MRI) shows slow interval tumor progression, the patient remains alive with a good quality of life at the time of this report." He is now at 82 months from original diagnosis.
"We were surprised to discover that KMT could work synergistically with the IDH1 mutation to simultaneously target the two major metabolic pathways needed to drive the growth of GBM," said Seyfried. "Glucose drives the glycolysis pathway, while glutamine drives the glutaminolysis pathway."
He added: "No tumor, including GBM, can survive without glucose and glutamine. Our study has identified a novel mechanism by which an acquired somatic mutation acts synergistically with a low carbohydrate, high fat diet to provide long-term management of a deadly brain tumor."
Despite the compelling interest in such individual case studies, the co-authors note: "We cannot predict if the therapeutic response to KMT seen in our GBM patient will also be seen in other similarly treated GBM patients. For those GBM patients not fortunate enough to have acquired the spontaneous IDH1 mutation in their tumour, glutamine targeting drugs used with KMT will be necessary to reduce tumour growth."
The researchers noted that additional studies they've conducted have shown that the simultaneous targeting of glucose and glutamine availability, using KMT and the a pan-glutaminase inhibitor—known as 6-diazo-5-oxo-L-norleucine (DON)—can significantly prolong survival in preclinical syngeneic glioblastomas in mice. Earlier research has shown that ketogenic diets can facilitate delivery of small-molecule therapeutic drugs through the blood brain barrier without toxicity.
The work was supported with funding from several foundations, including the Foundation for Metabolic Cancer Therapies, Children with Cancer UK, the John & Kathy Garcia Foundation, the Kenneth Rainin Foundation, and Mr. Edward Miller.
Ed HaywardUniversity CommunicationsJune 2021
Sports Researchers Say Ketogenic Diets Don't Boost Performance
A position paper from a prominent sports nutrition research group has concluded ketogenic diets are generally not helpful for achieving the best performance, though such diets might have other benefits.
The International Society of Sports Nutrition (ISSN) published a position paper on ketogenic diets in its captive journal yesterday. Listed as authors were many of the most prominent members of the organization who comprise a who's who of sports nutrition research in North America.
The paper summarizes what recent research has to say about ketogenic diets as they relate to sports nutrition. It includes 149 citations.
Ketogenic diets are generally low in carbohydrates and high in fats. The goal of such diets is to induce ketosis, or the process by which the body burns stored fat instead of glucose for energy.
Most people adopt a ketogenic diet to lose weight, and these diets appear to achieve this by inducing satiety and consequently restricting caloric intake. Health authorities have noted, however, that many people find the most restrictive of these diets to be very difficult to follow for an extended period.
Secondary reasons for following a keto diet include a perception that it could be healthier for many reasons. Some promoters claim, for example, that humans were not "made" to digest large quantities of carbohydrates and that our progenitors ate mostly meat proteins and fats combined with crude, low-carbohydrate plantstuffs.
What is ketosis?During ketogenesis, the body produces three kinds of ketone bodies in the liver: acetoacetate, beta-hydroxybutyrate (βHB) and acetone (ketones). These compounds, being water soluble, can easily disperse throughout the body to provide an alternative form of energy for the body's cells.
Ketosis generally occurs when the body's glucose stores are low, such as during fasting. It can also occur when ready stores of glucose and glycogen have been depleted during long-duration aerobic exercise.
The ISSN authors noted that interest in keto diets to boost endurance exercise outcomes began in the 1980s. Interest was further aroused by a 2015 paper that postulated "keto adapted" athletes — those who had trained their bodies to preferentially use ketone bodies as fuel — could have an advantage in endurance events.
At the time, many athletes were experimenting with the diets, the ISSN authors said, but there was little clinical data to substantiate whatever effects they claimed to be experiencing.
Ketogenic diets do appear to help users lose weight, the authors noted, but it seems to come at the expense of lean body mass. In other words, people lose weight, but they lose muscle tissue, too.
Including the 2015 paper, the ISSN authors evaluated 16 studies done on human athletes. They cited a significant lack of data pertaining to female athletes.
ISSN position pointsAfter evaluating the data contained in those studies, the authors came to the following conclusions that athletes and trainers should consider when thinking about whether to adopt a ketogenic diet:
Ketogenic diets can induce a state of nutritional ketosis.
Nutritional ketosis achieved through carbohydrate restriction and a high dietary fat intake is not intrinsically harmful.
A ketogenic diet has largely neutral or detrimental effects on athletic performance compared to a diet higher in carbohydrates and lower in fat.
The endurance effects of a ketogenic diet may be influenced by both training status and duration of the dietary intervention, but further research is necessary to elucidate these possibilities.
A ketogenic diet does not help an athlete gain strength better than a more standard diet.
When compared to a diet higher in carbohydrates and lower in fat, a ketogenic diet may cause greater losses in body weight, fat mass and fat-free mass, but may also heighten losses of lean tissue.
There is insufficient evidence to determine if a ketogenic diet affects males and females differently.
Susan Kleiner, Ph.D., a clinical nutritionist and founding member of the ISSN, was not involved with the ketogenic position paper effort. But she said it will help direct future research to fill in gaps in the field.
"The paper walks the reader through the basics of energy metabolism and the process (of both diet and metabolism) of achieving ketogenesis," she said. "Along with reviewing the current body of evidence, it is a guide to missing data that could generate new studies, as well as what methods are required to deliver reliable and reproducible data of the quality to be included in a position stand review."
Kleiner said she has three key questions regarding the ketogenic diet, and the position paper addresses some of these issues. While 16 papers are not a lot of data to draw upon, there are good answers for the first two of her questions below, and less data pertaining to the third.
She asks:
1. How does a keto diet affect both endurance and strength training performance?
2. How does a keto diet affect body composition and body weight?
3. Do we know the difference in effects of the keto diet on males versus females?
Conclusion: Using a keto diet not a winning strategyThe ISSN authors concluded by saying the evidence argues against using a ketogenic diet for an active athlete.
"The research to date indicates that a ketogenic diet has largely neutral or detrimental effects on athletic performance," they wrote. "For endurance events, a ketogenic diet interferes with the body's ability to generate energy from glucose, a necessity when performing at high intensities observed in real-world competitions. Even when one is 'keto-adapted,' performance under real-world race conditions is impaired in endurance athletes. Special consideration is needed for female athletes, as sex differences in metabolic pathways, mitochondrial function, and the effects of ovarian hormones may nullify many desirable adaptations from ketogenic diets that are observed in male participants."
However, if the goal is simple weight loss, the keto diet might make sense. But even here, it's problematic for athletes, who are seeking to maintain or increase muscle mass while shedding pounds of fat.
"For body composition, ketogenic diets appear to be superior to higher carbohydrate diets for reducing body weight and fat mass, but they are suboptimal for increasing fat-free mass," the authors concluded.
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Keto Diet Proven To Boost Brain Health
The ketogenic diet, more commonly referred to as the keto diet, has been around for over a century now. This may surprise many, as it only really gained traction in popular culture in the mid-1990s. The term 'ketogenic' was first coined by Dr Russell Wilder of the Mayo Clinic in the United States in 1921 in his works to find a nutritional treatment for epilepsy. Since then, scientists and health professionals have been looking at the potential benefits of the ketogenic diet on other health issues and on general health.
FoodNavigator previously reported on a study by the University of California, Davis, which looked at the potential for the ketogenic diet to combat the early signs of Alzheimer's. Now, researchers are looking at the ketogenic diet as a way to improve brain health.
What is a ketogenic diet?The ketogenic diet, better known as the keto diet, is a low-carbohydrate, high fat and moderate protein diet, which shifts the body's metabolism from using glucose as the main fuel source to burning fat and producing ketones for energy.
What are ketones?Ketones are a type of chemical that the liver produces when it breaks down fats. The body uses ketones for energy during fasting, long periods of exercise or when it does not have access to carbohydrates.
How can the keto diet boost brain health?A new study, conducted by scientists at the Buck Institute and the University of Chile, has found that the high-fat, low-carbohydrate content of the ketogenic diet enhances memory in older mice. The team identified a novel molecular signalling pathway that improves synapse function, when consuming the ketogenic diet, shedding light on the diet's benefits for brain health and aging.
"Our work indicates that the effects of the ketogenic diet benefit brain function broadly, and we provide a mechanism of action that offers a strategy for the maintenance and improvement of this function during aging," says Dr Christian González-Billault, Professor at the University of Chile.
The study follows on from previous research carried out by the team, looking at the impact of the ketogenic diet on memory.
"Building off our previous work showing that a ketogenic diet improves healthspan and memory in aging mice, this new work indicates that we can start with older animals and still improve the health of the aging brain, and that the changes begin to happen relatively quickly," said Dr John Newman, at the Buck Institute. "It is the most detailed study to date of the ketogenic diet and aging brain in mice.
The current study aimed to understand what part of the ketogenic diet was having the memory-saving effect and how it was affecting the brain on a molecular level to improve memory.
How was the study conducted?The study involved one group of mice fed a ketogenic diet of 90% calories from fat and 10% from protein, and another group of mice on a control diet fed the same amount of protein but only 13% fat.
The team explained that the benefits of the ketogenic diet were demonstrated through neurophysiological and behavioural experiments. The mice were tested on memory generation, storage, and retrieval function. The test results showed that the ketogenic diet appeared to benefit how well the synapses, responsible for memory, worked.
"Surprisingly, we saw that the ketogenic diet caused dramatic changes in the proteins of the synapse," explains Dr Birgit Schilling, Professor at the Buck Institute.
Dr Birgit Schilling further explained that the changes started after a relatively brief exposure to the diet, with the mice showing positive results after only one week on the diet. The effects were also shown to become more pronounced over time.
Further testing indicated that in synapses, a particular signalling pathway (protein kinase A, which is critical to synapse activity) was activated by the ketogenic diet. In isolated cells, the team then showed that it appears that BHB, the main ketone body produced in a ketogenic diet, is activating this pathway.
"BHB is almost certainly not the only molecule in play, but we think this is an important part of understanding how the ketogenic diet and ketone bodies work," said Newman "This is the first study to really connect deep molecular mechanisms of ketone bodies all the way through to improving the aging brain."
Health concerns linked to a ketogenic dietThe ketogenic diet has received some criticism in recent years following links to a range of health concerns including an increased risk of kidney stones, liver disease and micronutrient deficiencies. There are further long-term concerns relating to the impact of the high-fat levels, maintained in the ketogenic diet, on cardiovascular health.
Source: Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signalling pathway in aging micePublished online: 5 June 2024DOI: https://doi.Org/10.1016/j.Xcrm.2024.101593Authors: Diego Acuña-Catalán, Samah Shah, Cameron Wehrfritz, Mitsunori Nomura et al.
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