Journal Review #4: Detrimental Effects of a Long-Term Ketogenic Diet
August 11, 2022
Background - The ketogenic diet has gained much notoriety over the years, with promises of significant weight loss, better brain health, and improved mood. All of the benefits of the ketogenic diet have been plastered all over social media without any mention of the possible negative impacts on health. While much misinformation is splattered over the internet about dieting, weight loss, and nutrition, to tackle all of those subjects would require several textbooks. The aim of this journal review is to shed light on the possible negative impacts that result from a long-term ketogenic diet.
"Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis"
Authors: Sha Xu, Hui Tao, Wei Cao, Li Cao, Yan Lin, Shi-Min Zhao, Wei Xu, Jing Cao, & Jian-Yuan Zhao
Journal: Signal Transduction and Targeted Therapy; Volume 6
Published: Febraury 9th 2021
"Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis"
Authors: Sha Xu, Hui Tao, Wei Cao, Li Cao, Yan Lin, Shi-Min Zhao, Wei Xu, Jing Cao, & Jian-Yuan Zhao
Journal: Signal Transduction and Targeted Therapy; Volume 6
Published: Febraury 9th 2021
Journal Review - This journal article focuses on the long-term consequences that arise from a ketogenic diet. A ketogenic diet is any diet in which carbohydrate intake is below 50 grams/day and fat intake is above 80 grams/day. This low-carbohydrate, high-fat diet results in the body creating an alternate fuel source since all of the carbohydrates are being used to maintain circulating blood glucose levels. This alternate fuel source comes from the breakdown of lipids, which eventually form ketone bodies. There are three main ketone bodies: acetoacetate, beta-hydroxybutyrate (OHB), and acetone. Interestingly, acetone is used as a cleaning agent in the laboratory due to its ability to break down molecules and evaporate very quickly. As stated in the article, OHB constitutes 70% of circulating ketone bodies during deep ketosis. Since OHB is not usually circulating at high concentrations during a carbohydrate-rich diet, OHB’s effects on the body require further exploration.
To explore the effects of OHB on the cardiovascular system, rats were fed either a ketogenic diet or a standard carbohydrate diet. After 16 weeks, several measurements were taken, including heart rate, blood pressure, weight, fat mass, and several measurements of the heart. Mice fed a ketogenic diet demonstrated significantly reduced body weight, fat mass, and blood pressure, suggesting on the surface that the ketogenic diet is beneficial. Heart dissection and measurement of anatomical structures revealed that rats fed a ketogenic diet had significantly increased left and right ventricular wall thickness and increased left ventricular dimension in diastole and systole. This data suggests that rats fed a ketogenic diet experienced impaired cardiac function.
The authors then state that a ketogenic diet usually provides fewer calories than a carbohydrate-rich diet, so a third group of rats fed a calorically restricted diet ensued. While caloric restriction increased both acetoacetate and OHB, it was not as significant of an elevation as seen in rats fed a ketogenic diet. This result led the researchers to conclude that a ketogenic diet impacts cardiovascular health negatively.
To determine which ketone body and mechanism were responsible for the impairment of the cardiovascular system, rats fed a standard carbohydrate-rich diet were injected with OHB or acetoacetate for 16 weeks. After the injection period, similar measurements were taken as previously described. It was found that OHB injections resulted in impaired cardiovascular health and, furthermore, atrial staining for fibrosis markers was performed. A western blot, a test used to identify if a protein is present, was used to test if certain proteins associated with cardiac fibrosis were present in the rats injected with OHB. It was shown that these proteins were expressed in rat atrial tissue, thus suggesting that high levels of circulating OHB promotes cardiac fibrosis and impaired function.
To explore the mechanism explaining OHB’s significant impact on cardiomyocytes (heart muscle cells), the researchers aimed to test OHB treatment on a multitude of pathways. The first pathway is cellular apoptosis or programmed cell death. It was demonstrated that OHB induced an increase in apoptosis. Since apoptosis is a process in which cells program themselves to terminate, more cell growth is needed to compensate. This can cause fibrosis and scarring. Along with promoting apoptosis, OHB also led to a significant decrease in cellular mitochondrial levels. The mitochondria, or the powerhouse of the cell, are especially important for cellular survival, and a decrease in mitochondria can have diminishing effects on cellular processes. The researchers then investigated the mechanism by which OHB decreases mitochondrial levels in cardiomyocytes. A western blot was performed to determine which proteins were expressed in cells treated with either control saline or OHB. It was found that OHB treatment inhibited histone deacetylase 2, or HDAC2, and led to an increase in SIRT7 transcription. HDAC2 is responsible for deacetyating histones in chromatin. Chromatin is essentially DNA wrapped around histone proteins, which allows the cell to compact DNA for safekeeping and regulation. The negatively charged DNA electrostatically interacts with the positively charged lysine residues of the histone proteins. Thus, proteins that add an acetyl group to the histone proteins blunt the positive charge of the lysine residues on the histone protein. This causes the DNA to loosely interact more than with the histone, thus slightly unpacking the DNA and making it more accessible to be transcribed. In this case, a molecule that removes acetyl groups causes the DNA to become more tightly packed. This molecule is known as an HDAC. Therefore, a molecule that inhibits the function of an HDAC inhibits the formation of tightly packed chromatin (heterochromatin), thus allowing the chromatin to be loosely packed (euchromatin) and more accessible to the transcription machinery.
In this case, OHB inhibits HDAC2c, thus causing an increase in SIRT7 transcription. Increased SIRT7 transcription is associated with a decrease in mitochondrial biogenesis or the formation of mitochondria in the cell. Altogether, the researchers tell a story displaying the negative impact on cardiovascular health from long-term exposure to the ketogenic diet. This article is important for reminding the public that a ketogenic diet is not perfect and that cycling between different diets may be optimal for longevity and performance.
Lastly, it should be noted that there are very few studies that analyze the detrimental effects of a long-term ketogenic diet. With this in mind, any changes in your diet should be performed as a self-experimentation trial, as described in a previous blog post. As well as following this protocol, your primary care physician should also be aware of your diet intervention and should help guide you along the way.
To explore the effects of OHB on the cardiovascular system, rats were fed either a ketogenic diet or a standard carbohydrate diet. After 16 weeks, several measurements were taken, including heart rate, blood pressure, weight, fat mass, and several measurements of the heart. Mice fed a ketogenic diet demonstrated significantly reduced body weight, fat mass, and blood pressure, suggesting on the surface that the ketogenic diet is beneficial. Heart dissection and measurement of anatomical structures revealed that rats fed a ketogenic diet had significantly increased left and right ventricular wall thickness and increased left ventricular dimension in diastole and systole. This data suggests that rats fed a ketogenic diet experienced impaired cardiac function.
The authors then state that a ketogenic diet usually provides fewer calories than a carbohydrate-rich diet, so a third group of rats fed a calorically restricted diet ensued. While caloric restriction increased both acetoacetate and OHB, it was not as significant of an elevation as seen in rats fed a ketogenic diet. This result led the researchers to conclude that a ketogenic diet impacts cardiovascular health negatively.
To determine which ketone body and mechanism were responsible for the impairment of the cardiovascular system, rats fed a standard carbohydrate-rich diet were injected with OHB or acetoacetate for 16 weeks. After the injection period, similar measurements were taken as previously described. It was found that OHB injections resulted in impaired cardiovascular health and, furthermore, atrial staining for fibrosis markers was performed. A western blot, a test used to identify if a protein is present, was used to test if certain proteins associated with cardiac fibrosis were present in the rats injected with OHB. It was shown that these proteins were expressed in rat atrial tissue, thus suggesting that high levels of circulating OHB promotes cardiac fibrosis and impaired function.
To explore the mechanism explaining OHB’s significant impact on cardiomyocytes (heart muscle cells), the researchers aimed to test OHB treatment on a multitude of pathways. The first pathway is cellular apoptosis or programmed cell death. It was demonstrated that OHB induced an increase in apoptosis. Since apoptosis is a process in which cells program themselves to terminate, more cell growth is needed to compensate. This can cause fibrosis and scarring. Along with promoting apoptosis, OHB also led to a significant decrease in cellular mitochondrial levels. The mitochondria, or the powerhouse of the cell, are especially important for cellular survival, and a decrease in mitochondria can have diminishing effects on cellular processes. The researchers then investigated the mechanism by which OHB decreases mitochondrial levels in cardiomyocytes. A western blot was performed to determine which proteins were expressed in cells treated with either control saline or OHB. It was found that OHB treatment inhibited histone deacetylase 2, or HDAC2, and led to an increase in SIRT7 transcription. HDAC2 is responsible for deacetyating histones in chromatin. Chromatin is essentially DNA wrapped around histone proteins, which allows the cell to compact DNA for safekeeping and regulation. The negatively charged DNA electrostatically interacts with the positively charged lysine residues of the histone proteins. Thus, proteins that add an acetyl group to the histone proteins blunt the positive charge of the lysine residues on the histone protein. This causes the DNA to loosely interact more than with the histone, thus slightly unpacking the DNA and making it more accessible to be transcribed. In this case, a molecule that removes acetyl groups causes the DNA to become more tightly packed. This molecule is known as an HDAC. Therefore, a molecule that inhibits the function of an HDAC inhibits the formation of tightly packed chromatin (heterochromatin), thus allowing the chromatin to be loosely packed (euchromatin) and more accessible to the transcription machinery.
In this case, OHB inhibits HDAC2c, thus causing an increase in SIRT7 transcription. Increased SIRT7 transcription is associated with a decrease in mitochondrial biogenesis or the formation of mitochondria in the cell. Altogether, the researchers tell a story displaying the negative impact on cardiovascular health from long-term exposure to the ketogenic diet. This article is important for reminding the public that a ketogenic diet is not perfect and that cycling between different diets may be optimal for longevity and performance.
Lastly, it should be noted that there are very few studies that analyze the detrimental effects of a long-term ketogenic diet. With this in mind, any changes in your diet should be performed as a self-experimentation trial, as described in a previous blog post. As well as following this protocol, your primary care physician should also be aware of your diet intervention and should help guide you along the way.
Meet The Author
Hello everyone,
My name is Joshua Giblin. I am a post-bachelor researcher/research technician at USC. My interests range from nutrition to nanomedicine and also practical science to improve everyday life. Through this blog, I aim to communicate practical scientific research and present it to curious individuals so that an educated decision can be made. Thank you for reading the blog and showing your support.
Editors
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