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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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The population around the world is steadily increasing . However, the aged population is increasing at an alarming rate which raises concerns about the potential, significant increase in age-related diseases including cancer, Alzheimer's, and inflammatory disorders. It is evident that aging is associated with higher rates of cancer, but evidence suggests this, along with other age-related ailments, do not have to be inevitable . One approach that may provide benefit in the prevention of these ailments is the utilization of ketogenic diets. Ketogenic diets are characterized by a diet that is 4:1, fats to carbohydrates and is typically used to simulate a state of physiological starvation in the body . It is common for these diets to involve a maximum of about 20 g of carbohydrates per day, which steadily shifts the body from relying on carbohydrate-based energy to ketone-based energy, which can be generated from the ketones acetoacetate and beta-hydroxybutryate . These ketones have been found to play a significant role in protecting against age-related processes.

Ketogenesis in tumor malignancy

There is evidence that ketogenesis can significantly improve the prognosis of patients with malignant gliomas. Specifically, it was found that tumor patients had an increase in survival rate while tumor progression was slowed when they were maintained in a steady-state of ketosis . In another study, it was found that glucose uptake by astrocytoma tumor cells was significantly reduced and the patients experienced an increase in quality of life. Furthermore, the continuation of a ketogenic diet for 12 months results in a cessation of disease progression and elevated mood . Several other cases have been reported where ketogenesis is beneficial to slowing the progress of cancer and malignant cells . One process by which the incidence of cancer increases with age is through an increase in reactive oxygen species (ROS) generated by mitochondrial dysfunction over time . Interestingly, it was found that ketogenesis can enhance the efficiency of mitochondrial respiration and reduce ROS produced by this process , suggesting a possible link between the utility of ketogenic diets in the prevention of tumor malignancy.

Ketogenesis in neurological disease

Studies have shown that ketone-based diets can improve symptoms of Alzheimer's disease (AD). Specifically, patients with mild-moderate AD were placed on a ketogenic diet for 3 months and were found to have improved scores on an AD assessment scale . Importantly, this study involved the addition of medium-chain triglycerides to their diet to facilitate the ketogenic process. Interestingly, a series of studies have shown that the ketogenic diet may be selectively beneficial to individuals who have the "apolipoprotein E (APOE) ε4" allele . Since APOE has been identified as a significant risk factor for dementia , and the utility of ketogenesis in protecting against memory-related disease such as dementia, perhaps APOE may provide as an early biomarker for those who should consider transitioning to ketogenic diets in their later years to ward off symptoms of diseases such as Alzheimer's, dementia, and so on.

Ketogenesis as an anti-inflammatory

There is this concept that inflammatory activity increases as we age, otherwise referred to as inflammaging , and this is considered to contribute to a variety of age-related diseases
and is accumulated through various sources . Interestingly, ketogenesis has been found to produce significant anti-inflammatory effects , and this may result from the ability of fatty acids to stimulate peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Stimulation of PPAR-alpha initiates an inhibitory intracellular cascade that suppresses nuclear factor kappa B (NF-κB), which ultimately downregulates the expression of COX-2and inducible nitric oxide synthase (iNOS)—genes involved in regulating the inflammatory response . Moreover, it was found that beta-hydroxybutyrate can directly suppress the release of pro-inflammatory cytokines IL-1-beta and IL-18 from the NLRP3 inflammasome , suggesting a process by which ketogenesis can provide anti-inflammatory effects.

So, what does all of this mean?

Taken together, it seems as though ketogenesis can play a significant role especially in our later years given its substantial protective effects in all three domains discussed here. "Prescribing" this kind of diet, albeit to the right populations and depending on health status, would provide an interesting approach that healthcare workers could take to promote longevity and improve quality of life in the aged population.

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[2]https://www.un.org/en/sections/issues-depth/ageing/#:~:text=According%20to%20data%20from%20World,be%20aged%2065%20or%20over.

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[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

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[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.

[13]Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, et al. Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 2004;25(3):311–4.

[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)

[15]Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) [Internet]. 2009;6(1):31. Available from: http://nutritionandmetabolism. biomedcentral.com/articles/10.1186/1743-7075-6-31

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inflammagingketogenesisketonesfatty acidsinflammationlongevity
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Martina Pesce
Martina Pesce2 years 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 years 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 Pesce2 years 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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Brett M.
Brett M.2 years ago
Martina Pesce Great! Thank you for the referral links. Interesting reads...

I like the idea of a personalized diet, which is really where I think medicine is transitioning to. It's a necessity. The blanket approach for health does not work and it is clear that individuals require their own, personalized treatment. So, extending this to personalized diet plans would be a great idea as well. The following paper highlights the "person-centered" approach to measuring longevity as it relates to diet and health [1]. They also mention the measurement of biomarkers as they relate to dietary and lifestyle changes. It would be interesting to be able to take a blood sample to measure levels of biomarkers known to promote and/or impede healthy aging and prescribe a diet that specifically aims to modulate these biomarkers and thereby promote healthy aging.

As for fasting, 5 days every 6 months is definitely doable. There are other ways to fast as well, such as 12 hour fasting, which is very easy to do if you are able to get 8 hours of sleep and restrict eating between say 8PM and 8AM. Another fasting strategy that has been shown to improve overall health is the 5:2 intermittent diet [2].

The thing about ketone- based diets is that they take time to generate a state of ketosis that is generally desired to produce results -- 2-4 days for initial ketosis in some people but several weeks to adapt to the ketogenic state completely in others [3].

So, is it that the fasting periods are meant to "enhance" the production of ketones that is already occurring to optimize the ketogenic state?

References

1. Wickramasinghe K, Mathers JC, Wopereis S, Marsman DS, Griffiths JC. From lifespan to healthspan: the role of nutrition in healthy ageing. J Nutr Sci. 2020 Aug 24;9:e33. doi: 10.1017/jns.2020.26. PMID: 33101660; PMCID: PMC7550962.

2. Bjarnadottir, A. (May 31, 2018). The Beginner's Guide to the 5:2 Diet. Healthline.

3. Raman, R. (April 16, 2019). How Long Does It Take to Enter Ketosis?. Healthline.
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Shubhankar Kulkarni
Shubhankar Kulkarni2 years 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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