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Prescribing a ketone-based diet to prevent or reduce the progression of age-related disease

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Brett M.
Brett M. Dec 02, 2020

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[4]McNally MA, Hartman AL. Ketone bodies in epilepsy. J Neurochem. 2012;121(1):28–35.

[5]Cervenka MC, Kossoff EH. Dietary treatment of intractable epilepsy. Continuum (Minneap Minn) [Internet]. 2013;19(June): 756–66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 23739109

[6]McDonald, T., & Cervenka, M. C. (2018). Ketogenic Diets for Adult Neurological Disorders. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 15(4), 1018–1031. https://doi.org/10.1007/s13311-018-0666-8

[7]Rieger J, Bähr O, Maurer GD, Hattingen E, Franz K, Brucker D, et al. ERGO: A pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol. 2014;45(6):1843–52.

[8]Nebeling, L.C., Miraldi, F., Shurin, S.B., Lerner, E., 1995. Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. Journal of the American College of Nutrition 14: 202e208.

[9]Weber, D. D., Aminzadeh-Gohari, S., Tulipan, J., Catalano, L., Feichtinger, R. G., & Kofler, B. (2020). Ketogenic diet in the treatment of cancer - Where do we stand?. Molecular metabolism, 33, 102–121. https://doi.org/10.1016/j.molmet.2019.06.026

[10]Kudryavtseva, A. V., Krasnov, G. S., Dmitriev, A. A., Alekseev, B. Y., Kardymon, O. L., Sadritdinova, A. F., Fedorova, M. S., Pokrovsky, A. V., Melnikova, N. V., Kaprin, A. D., Moskalev, A. A., & Snezhkina, A. V. (2016). Mitochondrial dysfunction and oxidative stress in aging and cancer. Oncotarget, 7(29), 44879–44905. https://doi.org/10.18632/oncotarget.9821

[11]Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev [Internet]. Elsevier B.V.; 2009;59(2):293–315. https:// doi.org/10.1016/j.brainresrev.2008.09.002

[12]Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv. Elsevier Inc.; 2018;4:28–36.

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[14]Ota M, Matsuo J, Ishida I, Hattori K, Teraishi T, Tonouchi H, et al. Effect of a ketogenic meal on cognitive function in elderly adults: potential for cognitive enhancement. Psychopharmacology (Berl)

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General comments

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Martina Pesce
Martina Pesce2 months ago
I really like the idea of prescribing a diet as a prevention factor, expetially for a population that is as vast as the elderly one.
It will have also a brilliant side effect which is acknowledging the importance and relevance of nutrition for the health condition.
Shubhankar Kulkarni has already presented the controversial sides of the ketogenesis diet, though.
Maybe finding a diet which is less problematic and risky could be an option.
For example, since the responsible of many benefits of the diet are the ketonic bodies, another diet which produces the same is the so called "longevity diet". It is characterized by some fasting-like periods. Their length and frequency depends on the patients health conditions, weight and other factors.

I know it is a quite radical change on your idea, but maybe it will make it less questionable, what do you think?
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Brett M.
Brett M.2 months ago
Martina Pesce interesting points. I am wondering--do you have a link to the effects of this "longevity diet"? I cannot find anything on PubMed, but I found an overview article about this diet (https://www.verywellhealth.com/the-longevity-diet-plan-overview-2223476) and it looks to be similar in approach as the plant-based diet that Shubhankar Kulkarni mentioned in his comment. This definitely sheds light on the importance of plant-based diets, especially in the later years. I'm wondering about the caloric restriction--this may have to be tailored to individual lifestyles. 800-1100 calories a day for an active 65-70-year-old may not be the best, but I'm sure as long as they stick to the ratios provided in the linked article, this form of fasting will provide benefit. Seems quite reasonable since the fasting periods are not very long either.

As I mentioned in my response to Shubhankar's comment, there is the potential of adding exogenous ketone esters and medium-chain triglycerides to a ketogenic diet to mitigate the negative side effects of low-carb and long-term increases in cholesterol and blood lipids. I think what you provide here is an interesting perspective on the idea of a nutrition-based approach to promoting longevity, which I also find is necessary for the discussion about the impact of diet on health.

I think the consensus from what I'm reading so far is that intermittent fasting on a plant-based diet seems quite feasible to promote longevity. It would be interesting to see how this diet would fare with exogenous ketone esters or MCTs since ketone bodies are more energy-efficient and may provide protection against mitochondrial-related neurological diseases (https://pubmed.ncbi.nlm.nih.gov/25101284/). Nevertheless, thanks for your comment--the longevity diet seems quite interesting. I'd like to see some more sources about the diet's efficacy in the experimental setting if you have any on hand!
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Martina Pesce
Martina Pesce4 days ago
Brett M.
Here you can get some papers on the research Valter Longo did behind the longevity diet:
-A Periodic Diet that Mimics Fasting Promotes MultiSystem Regeneration, Enhanced Cognitive
Performance, and Healthspan (https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00224-7.pdf)
-Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease (https://valterlongo.com/wp-content/uploads/2017/10/2017-02-Wei-Fasting-mimicking-diet-markers.pdf)

I would say these are the most relevant for longevity, but on Valter Longo's site you will find a proper list of all the papers related tot he diet (https://www.valterlongo.com/scientific-articles/)

It is actually not an exclusively plant-based diet. There is fish involved (for my joy, I would add ;) ).
The initial idea for the diet was not to have it plant-based but to observe what people who live very long eat and base it on that.

There are guidelines but ideally, the diet needs to be personalized per every single person. Age, health status, weight and lifestyle have a big impact on the diet setting. I remember checking for an average weighted person of my age (23) it was suggesting fasting of 5 days every 6 months. Very doable.

This diet, in the fasting periods, want exactly to focus on the production of ketone bodies, but in a way that avoids the negative effects of them. You can maybe call it a extremely light ketonic diet ;).
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Shubhankar Kulkarni
Shubhankar Kulkarni2 months ago
Since the keto diet mimics starvation (caloric restriction), which is one of the strategies to promote lifespan and healthspan, it can be a lifestyle choice during old age to reduce the impact of age-related diseases.

However, the keto diet comes with its own problems. Here, I will avoid the ones associated with the keto "flu", which is only observed during the switch from the regular diet to the keto diet, in most people. I will talk about the problems associated with long-term keto diet: (https://www.health.com/weight-loss/keto-diet-side-effects)
Consuming more fat may put more pressure on the gall bladder. Several keto-dieters, therefore, experience diarrhea.
Ketoacidosis: It is not advisable to have a keto diet if the person has type and diabetes or related metabolic disorders due to the risk of ketoacidosis. Diabetics are already at risk of ketoacidosis and the keto diet increases the risk further.

Studies that do not report beficial results regarding the keto diet:
A study comprising 25,000 participants suggested that people on the lowest-carb diets had the highest risk of all-cause mortality, including that related to cancer and cardiovascular (https://academic.oup.com/eurheartj/article/40/34/2870/5475490).
Another study found that people who followed diets that were low in carbs and high in animal proteins had a higher risk of early death compared to those who consumed carbs in moderation. On the other hand, low-carb dieters who consumed plant-based proteins lived longer (https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(18)30135-X/fulltext).
Keto diet led to insulin resistance in the liver in one experiment (https://www.eurekalert.org/pub_releases/2018-08/tps-kdm080718.php).
Keto diet increases the risk of cardiovascular diseases by increasing cardiovascular risk factors like low-density lipoproteins (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452247/).

There are mixed reports regarding the effect of the keto diet on health. It might probably depend on the person's regular diet. If a person might be consuming a low-carb diet for generations, a keto-diet may not be a bad idea for them. However, for a person who has consumed mostly a plant-based diet, might present negative effects.

Since the old already suffer from one or more of these ailments, how advisable is keto diet to this population, is questionable. If there was a way to administer the diet without its downsides, that would be beneficial.
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Brett M.
Brett M.2 months ago
Shubhankar Kulkarni Great points. I see where you are coming from, definitely. I absolutely agree with your suggestion that this diet is not for those with impairments in glucose metabolism (e.g., diabetes), due to ketoacidosis.

Interesting that diarrhea is pointed out, I'll have to dig into this further as the source you provide there says it could be due to pressure on the gallbladder, though I can only seem to find one article that suggests such a relationship--albeit each adverse event was observed in 3 of 52 study participants; https://pubmed.ncbi.nlm.nih.gov/10465141/. This makes me question whether this is actually an issue of the gallbladder or if these individuals are simply experiencing a transition from carbohydrate-based (fibrous) to ketone-based (low fiber) diets, which makes more sense to me. What do you think?

As well, they suggest this could also be due to artificial sweeteners and dairy products that are more regularly consumed in the ketone-based diets. Perhaps, this warrants an area of the keto-diet that may not be for everyone and further increases support for the idea of individualized treatment plans when dealing with health-related circumstances (which includes dieting; https://pubmed.ncbi.nlm.nih.gov/29935653/).

It is a great point about the extremely low-carb ketogenic diets, which I agree, do not seem that beneficial. Regarding your Lancet reference, this indicates that plant-based pseudo-ketone-based diets may be most beneficial--balancing plant-based protein with 50-55% carbohydrate intake in the diet. Another interesting approach to the low-carb problem that can arise in some individuals who wish to transition to ketone-based diets is the use of exogenous medium-chain triglyceride (MCT) supplementation (pubmed.ncbi.nlm.nih.gov/19049583/), which allows one to consume more carbohydrates in their diet while preserving ketosis. It was also found that supplementing with MCTs can actually produce similar results as the ketogenic diet in children with epilepsy and with "minimal side effects," the authors claim. Additionally, supplementing with exogenous ketones, in the form of ketone esters, can help mitigate the long-term effects of ketogenesis, such as increased cholesterol and lipidemia (https://pubmed.ncbi.nlm.nih.gov/27528626/).

The finding you highlight in Eurekalert is interesting... I have an issue with their methodology, however. It would be expected that an animal transitioning from carb- to ketone-based diets would have a lower tolerance for glucose since their physiological dependence begins to shift towards fatty acid metabolism. The indication that fasting insulin levels in KD-fed rats remain unchanged tells me that they are not experiencing glucose intolerance to the same extent as observed in conditions with impaired glucose metabolism (e.g., diabetes). It seems as though KD-fed rats do experience glucose intolerance, but this may not be pathological, as is glucose intolerance observed in diabetes if this makes sense? I would expect a large insulin spike if someone on the ketogenic diet just downed a bowl of candy, which is essentially what the glucose tolerance test is. Also, an important characteristic of diabetes and other metabolic disorders is the presence of insulin resistance in skeletal muscle and adipose tissue (https://pubmed.ncbi.nlm.nih.gov/30311716/), whereas this study only observed insulin resistance in hepatic tissue. It would certainly be interesting to see a follow-up of this study to examine insulin sensitivity in these other tissues in rats fed a KD. Though, I reckon since the liver is responsible for gluconeogenesis, insulin insensitivity here could be due to the tissue's increased dependence on fatty acids to breakdown their glycerol backbone as a means to provide glucose in a state of ketosis, thereby maintaining normoglycemia (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945587/). Just a hypothesis--this would need to be followed up experimentally.

I do see significant merit in this last finding though, which highlights the importance of weaning oneself off of a ketogenic diet by slowly transitioning the ratio of lipid to carbohydrate intake to bias the latter as one progresses off of the ketone-dependence. It is clear from the summary of data that both you and I have provided that there still remains a lot of work to be completed in order to have a well-rounded idea as to whether this diet is truly beneficial in this population. Though, as I mentioned, the MCT-supplementation provides ketogenic diet-like effects with minimal side effects, so perhaps this is an alternative to switching to full-keto in the later years? Interesting points - thanks for commenting!