Keto (low-carb) diet causes heart fibrosis, blocks mitochondrial biogenesis

haidut

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The bad news for the low-carb / keto community keep piling on. There are a number of posts on this blog about studies demonstrating insulin resistance, diabetes, obesity and even sarcopenia as a result of low-carb diets or their close mimetic known as intermittent fasting. Now, the study below provides the first direct evidence that a keto / low-carb diet directly leads to cardiac fibrosis combined with reduced mitochondrial biogenesis, as a result of increased serum fatty acids (FFA), ketone bodies, fatty acid oxidation (FAO), and reduced glucose metabolism. While the study claims that the fibrosis is likely to be localized only to the heart due to its unique vulnerability to elevated FFA, I am far from convinced this is true. For example, chronic kidney and liver diseases commonly seen in patients with type II diabetes are now known to also be caused by elevated FFA. Several neurodegenerative conditions are also strongly linked to elevated FFA. Finally, cancer (arguably the ultimate killer disease) is now slowly becoming exposed as a disease of elevated FFA and fatty acid oxidation (FAO), and it is common knowledge that fibrosis always precedes (solid) tumor formation. So, if elevated FFA, ketone bodies, and FAO leads to fibrosis then in my opinion the findings of the study below are relevant for virtually ALL chronic diseases. Perhaps the most corroborating evidence for this hypothesis is the reduced mitochondrial biogenesis as a result of the fatty acid overload. Finally, the study demonstrates that the elevation of FFA and ketone bodies as a result of low-carb / keto diet leads to activation of the sirtuin gene SIRT7, and this activation was crucial for the inhibition of mitochondrial biogenesis. Multiple other studies have already demonstrated that sirtuin activation leads to increased FAO and accelerated cancer growth. These combined findings should give a pause not only to the low-carb dieters, but also to people who consider using stilbenoid substances such as resveratrol, which are known to be potent sirtuin activators (and are heavily marketed for that purpose). Conversely, these findings once again corroborate the benefits of niacinamide, which is the most potent sirtuin inhibitor used clinically. Even if none of what I wrote so far seems convincing, perhaps the opinions of the study authors would receive greater consideration. Namely, the study concludes with the warning that unless an intervention is discovered that can mitigate/block these fibrotic and antimetabolic effects of low-carb / keto diets, it may not be wise for the general population to embark on such dietary "adventures" at all.

https://www.jacc.org/doi/full/10.1016/j.jacc.2007.09.055
Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

"...n addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary."

"...Third, increased levels of SIRT7 were observed in cardiac tissues from patients with AF compared with those in patients with SR, according to both western blotting (Fig. 6b and Supplementary Fig. 11a) and IHC (Fig. 6c and Supplementary Fig. 11b). Fourth, markers of fibrosis, including type I collagen, type III collagen, and α-SMA, were higher in patients with AF (Fig. 6b and Supplementary Fig. 11a). Lastly, the number of mitochondria was significantly lower in cardiac tissues from patients with AF than in those from patients with SR, as indicated by the ratio of mtDNA to nucleic DNA (Fig. 6d). These findings, together with the observation that the cardiac β-OHB concentration was negatively correlated with the number of mitochondria (Fig. 6e), confirmed that elevations in β-OHB were associated with cardiac fibrosis and an increased risk of AF."

"...Some studies have indicated that β-OHB exhibits beneficial effects in the cardiac system under pathological conditions and can, for example, be used as an alternative fuel in the human failing heart.43 Moreover, this compound improves cardiac cell excitation–contraction coupling during hypoxia44 and prevents myocardial damage after coronary occlusion in animal model.45 In this study, we provided evidence and mechanistic explanations from cultured cells, animal models, and clinical samples to show that long-term KD-induced β-OHB accumulation was detrimental to heart health by promoting cardiac fibrosis (Fig. 6f)."

"...However, although theoretically all cells in the body are exposed to elevated levels of ketone bodies, cardiomyocytes are among those most vulnerable to high ketone body exposure, as high levels of ketone bodies reduce the mitochondrial content significantly, as demonstrated in our study."

"...In the current study, we aimed to confirm that the β-OHB/HDAC2/SIRT7 pathway was important to mitochondrial biogenesis. Therefore, we did not measure other cardiac fetal genes that may be regulated by HDAC2. Further studies are required to reveal regulatory effects of HDAC2 on mitochondrial genes. Last, we validated that SIRT7 inhibited mitochondrial biogenesis in cardiomyocytes, consistent with previous findings showing that increased expression or activity of SIRT7 inhibited mitochondrial biogenesis in hematopoietic stem cells and human embryonic kidney cells.40,50 "

"...The findings of our current study defined the mechanism underlying the negative health effects of KDs, which are adopted worldwide for therapeutic purposes and have been increasingly preferred by healthy individuals in order to prevent obesity. Our results strongly suggest that unless the adverse effects of a KD on the cardiac system can be effectively avoided, healthy individuals should reconsider the use of a KD for weight loss."

Keto Diets Cause Scarring Of Heart Tissue And Inhibit Mitochondria Production In Rats

"...Ketogenic diets, which forgo carbohydrates to replace them with fats, have become extremely popular in recent years, rising to the top as the most-searched-for diet of 2020. Whilst these diets are effective in treating epilepsy and have applications in various other diseases, the evidence for use as a tool for weight loss in healthy individuals remains disputed. In a recent study performed on rats, researchers have suggested that keto diets are having a dramatic impact on people’s hearts. The results showed the high-fat-diet-induced changes within the rats’ hearts, reducing the production of mitochondria and creating scar tissue. Their work was published in the journal Signal Transduction and Targeted Therapy. "
 

Dolomite

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I used to read Seth Roberts blog. He was interesting and had written a book describing his Shangri la diet. A dieter was to hold their nose while drinking 1/2 cup of oil. He also ate large amounts of butter. I was surprised when he died of a heart condition at age 60 or so. But not after reading this.
 

OccamzRazer

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Good stuff, thanks!!

Dumb question: I understand that ketosis is harmful, but does this study contradict the idea that increasing ketone production by taking coconut oil/MCT oil/caprylic acid would be beneficial?

I'm thinking of the Ray Peat quote: "Glucose is often thought as the most direct source of energy, but other substances are perhaps used even more easily. 'Ketones' for example...are used more easily... Short and medium chain fatty acids are used more easily, and it is apparently this fact that accounts for their presence in milk."
 

OccamzRazer

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My nephew's been obese nearly his whole life. He went keto and lost over 100 lbs.
That's great!

Perhaps the ketogenic diet is less stressful than being hugely obese...but more stressful than normal metabolism?
 

rei

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here are a number of posts on this blog about studies demonstrating insulin resistance, diabetes, obesity and even sarcopenia as a result of low-carb diets or their close mimetic known as intermittent fasting.
I don't know how you arrive at this conclusion, intermittent fasting only leads to same result as low carb/keto in this regard if your glycogen storage capacity is so small you spend long times in ketosis during your fasting window. Even RP himself has said it is not bad to miss a meal or two if you have intact glycogen storage capacity, and that is equal to IF.

IF at a duration that barely makes you start producing ketones before the next meal is probably optimal, it gives a good rest to your intestines between meals, and holds up metabolic flexibility ensuring you keep burning fat effortlessly, yet you mainly use glucose as your energy source without excess release of fatty acids.
 
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Perry Staltic

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That's great!

Perhaps the ketogenic diet is less stressful than being hugely obese...but more stressful than normal metabolism?

Possibly so. I asked him if he was going to keep doing it. He said yes, for the time being. Which made me think that he has a good head and is weighing everything out, and possibly will adapt his diet when he gets to his target weight.
 

OccamzRazer

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IF at a duration that barely makes you start producing ketones before the next meal is probably optimal, it gives a good rest to your intestines between meals, and holds up metabolic flexibility ensuring you keep burning fat effortlessly, yet you mainly use glucose as your energy source without excess release of fatty acids.
Interesting approach...what type of duration/meal frequency is that?

Would the standard 8-hour feeding window allow one to ramp up ketone production a little bit prior to meal 1, or is something more limited needed?
 

David PS

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Interesting approach...what type of duration/meal frequency is that?

Would the standard 8-hour feeding window allow one to ramp up ketone production a little bit prior to meal 1, or is something more limited needed?

An 8-hour window would seem do be sufficient to get into ketosis. Dr. Dale Bredesen of the Buck Institute for Research on Aging has a protocol for treating alzheimer's. He recommends getting into mild ketosis. His protocol includes a 12-hour nightly fast + a 3-hour fast before bedtime. The eating window is only one component of his protocol. What one eats during the 8 hours is also important. A quick summary of his updated protocol (from his latest book).
 

Jam

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IF at a duration that barely makes you start producing ketones before the next meal is probably optimal, it gives a good rest to your intestines between meals, and holds up metabolic flexibility ensuring you keep burning fat effortlessly, yet you mainly use glucose as your energy source without excess release of fatty acids.
Exactly. Even on a low-carb (for this forum) 20-25p/15-20c/60-65f (as saturated as possible) diet I never hit ketosis. That's with 100g or so of daily carbs, an amount I consider optimal. An athlete would probably require a bit more, though. I also normally fast 12 hours between dinner and breakfast. Despite this, I continue to maintain optimal glucose metabolism, considering that I can switch over to carb-heavy days with absolutely zero issues (besides more hunger between meals, the downside of high-carb diets). I'm not a fan of being in ketosis for lung durations, but a bit of "intermittent ketosis" doesn't hurt.
 

rei

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Interesting approach...what type of duration/meal frequency is that?

Would the standard 8-hour feeding window allow one to ramp up ketone production a little bit prior to meal 1, or is something more limited needed?
as i wrote, and as RP has said, it depends very much on your glycogen storage capacity (and metabolic flexibility). Of course also what (and how) you eat matters; if it is able to reload glycogen or not. Get keto strips and find out what works for you!

With IF and especially OMAD it is important to not gorge the food no matter how hungry you are and how satisfying it would be. With OMAD you should probably spend close to an hour eating your portion.
 
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Nomane Euger

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Hi jam,did you measure your ketones with a ketones reader?
Exactly. Even on a low-carb (for this forum) 20-25p/15-20c/60-65f (as saturated as possible) diet I never hit ketosis. That's with 100g or so of daily carbs, an amount I consider optimal. An athlete would probably require a bit more, though. I also normally fast 12 hours between dinner and breakfast. Despite this, I continue to maintain optimal glucose metabolism, considering that I can switch over to carb-heavy days with absolutely zero issues (besides more hunger between meals, the downside of high-carb diets). I'm not a fan of being in ketosis for lung durations, but a bit of "intermittent ketosis" doesn't hurt
 

Jam

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Hi jam,did you measure your ketones with a ketones reader?
Yes, I have a Ketonix. Not super accurate but I only use it to make sure that I stay out of ketosis.
 

Nomane Euger

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Yes, I have a Ketonix. Not super accurate but I only use it to make sure that I stay out of ketosis.
Thanks,excellent.btw how much fat can you eat in one meal with out getting floating stools and greenish stools?how do you eat suet when you eat it?raw or cool it has 0 taste
 

Jam

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Thanks,excellent.btw how much fat can you eat in one meal with out getting floating stools and greenish stools?how do you eat suet when you eat it?raw or cool it has 0 taste
I have never suffered from such issues, and have been known to eat 80g or more of SFA-heavy fats in one sitting.
 

Jam

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how do you eat suet when you eat it?raw or cool it has 0 taste
I don't eat suet, raw or cooked, as they don't sell it here. I only have grass-fed beef tallow which I use to cook with.
 
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