Ketogenic Diet - Powerful Dietary Strategy for Certain Conditions


FOTCM Member
Macias was actually highly critical of the research done by D'Agostino. He very convincingly discussed the shortcomings of the research, and he brought up the fact that treating cancer with diets is not so clear cut. There are cancers that apparently can use ketones/ fatty acids as their fuel.]

True. Fatty acids seem to be a major source of energy for many cancers. It seems that cancer cells will burn whatever is available.

When you consider Gerson therapy (which supposedly had great results), it limited most fats and animal products from the diet and focused primarily on nutrients and juices. So many factors appear to be at play.

Here's a paper I read some months ago on fatty acid oxidation in cancer cells:

Cancer metabolism: fatty acid oxidation in the limelight

Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the ‘metabolic switch’ in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function.

The process of cellular transformation and cancer progression involves genetic mutations and epigenetic alterations, as well as the rewiring of cellular signalling and the reprogramming of metabolic pathways1. We now perceive these processes as intimately interconnected and interdependent2. Emanating from the initial hypothesis of Warburg3 (now known as Warburg's hypothesis), the latest research has revealed that metabolic reprogramming occurs as a consequence of mutations in cancer genes and alterations in cellular signalling. Much of the hype in cancer metabolism comes from the genuine observation that most cancer cells are programmed to increase glucose uptake, but to reduce the proportion of glucose oxidized in the Krebs cycle. Rather than oxidizing glucose for ATP production, glucose in cancer cells tends to be used for anabolic processes, such as ribose production, protein glycosylation and serine synthesis4–7. Cancer cells use additional nutritional inputs for anabolism besides glucose. From its metabolism to pyruvate, glutamine is key for providing reduced NADPH, which is needed for lipid synthesis, and to refill the Krebs cycle (anaplerosis)8,9. The control of this pathway by key oncogenes, such as MYC and mutant RAS, has further enforced the importance of this route in cancer. This view of cancer metabolism takes the focus away from ATP as the key product of glucose and glutamine catabolism. The fact is that in most biological contexts (but not all, as we discuss below), ATP production is sufficient for cancer cell function.

In addition to glucose and glutamine, fatty acids are an extremely relevant energy source. They can be incorporated from the extracellular media, or can be potentially obtained from hydrolysed triglycerides (in cells accumulating lipid droplets) by neutral (N) hydrolases in the cytoplasm or acid (A) hydrolases through a novel autophagic pathway: lipophagy10. De novo synthesis of fatty acids is required for membrane synthesis and therefore for cell growth and proliferation. Fatty acid synthesis is an anabolic process that starts from the conversion of acetyl CoA to malonyl CoA by acetyl CoA carboxylase. Malonyl CoA is then committed to fatty acid synthesis (FAS) and is involved in the elongation of fatty acids through fatty acid synthase (FASN). Additional modifications of fatty acids can be carried out by elongases and desaturases. Fatty acids are catabolized by the fatty acid oxidation (FAO; also known as β-oxidation) pathway.

With most cancer researchers focusing on glycolysis, glutaminolysis and fatty acid synthesis, the relevance of FAO for cancer cell function has not been carefully examined, and its relevance has remained obscure. However, studies in the past 4 years have started to bring to light a relevant role for this metabolic pathway in cancer, and this is accompanied by new and exciting therapeutic implications. The focus of this Progress article is to enumerate, highlight and integrate these recent findings into our current understanding of metabolic reprogramming in cancer cells.

Extra ATP when needed
Relative to their dry mass, fatty acids provide twice as much ATP as carbohydrates (six times more when comparing stored fatty acids to stored glycogen), and in turn they are the preferred nutrient for storage (in the form of triglycerides in adipose tissue) under conditions of nutrient abundance. FAO is composed of a cyclical series of reactions that result in the shortening of fatty acids (two carbons per cycle) and that generate in each round NADH, FADH2 and acetyl CoA, until the last cycle when two acetyl CoA molecules are originated from the catabolism of a four-carbon fatty acid (FIG. 1). NADH and FADH2 that are generated by FAO enter the electron transport chain (ETC) to produce ATP (FIG. 2). FAO is carried out in energy-demanding tissues (such as the heart and skeletal muscle) and in the liver as a central organ for nutrient supply and conversion.

We have summarized the metabolic switch as a programme in which the utilization of metabolic intermediates for anabolism prevails beyond ATP production. But there are situations in which cancer cells seem to require increased ATP production. This is exemplified by loss of attachment (LOA) to the extracellular matrix. Cells derived from solid tumours that undergo LOA display inhibition of glucose uptake and catabolism, which results in the loss of ATP, NADPH (as a result of decreased flux through the pentose phosphate pathway (PPP)) and increased production of reactive oxygen species (ROS) (FIG. 3). Schafer and co-workers11 showed that in these settings ROS inhibit FAO, and that antioxidants counteract ROS accumulation and can reactivate FAO, increase ATP levels and prevent LOA-induced anoikis, although the exact mechanism by which an increase in ATP rescues anoikis remains unclear.

Cancer metabolism can be perceived as a network of pathways with plasticity, feedback loops and crosstalk that ensure the fitness of tumour cells. Plasticity is key, and FAO might provide some of this plasticity by enabling the production of ATP and NADPH when required, eliminating potentially toxic lipids, inhibiting pro-apoptotic pathways and providing metabolic intermediates for cell growth. However, FAO cannot be perceived as a metabolic pathway that is active independently of the microenvironment of the cancer cell. Indeed, in ovarian cancers, which have a predilection to metastasize to the omentum (an adipocyte-rich tissue), the interaction with adipocytes is necessary for the transfer of lipids to the cancer cell, the activation of FAO and the establishment of metastasis38.

A big challenge is to unify the idea of FAO as an essential pathway in cancer cells with the fact that cancer cells also require active FAS in order to grow and divide. Dogma states that FAO and FAS are incompatible. In principle, ACC determines which pathway is active, on the basis of acetyl CoA and malonyl CoA levels. Therefore, as ACC is a ‘one-way street’, both metabolic activities cannot coexist. However, we might need to rethink such a rigid regulatory framework. The group of Nissim Hay32 showed that genetic manipulation of ACC1 or ACC2 in cancer cells yielded different outcomes in terms of FAS and FAO. In addition, FAO metabolism can contribute to the accumulation of acetyl CoA in the cytoplasm that is needed to initiate FAS, so that FAS and FAO can support each other23. On the basis of this idea, we can speculate that, rather than a total pool of acetyl CoA and malonyl CoA, there might be ACC1 and ACC2 localization-dependent compartmentalization39 of these metabolites that allows both metabolic pathways to be active simultaneously and independently from each other.

The data suggesting a greater requirement of FAO in undifferentiated cells also raise an interesting possibility. It is plausible that in quiescent and undifferentiated cells the competition between FAS and FAO may be less prominent (as these cells display a lower membrane synthesis rate), thus indicating that these cells might derive a full survival benefit from FAO activation and its biological output. In turn, their dependence on FAO could make them vulnerable, providing a unique therapeutic opportunity from the pharmacological manipulation of this metabolic pathway.

For all the reasons stated above, there is an exciting therapeutic potential for the pharmacological blockade of FAO in cancer. Two key enzymes in the FAO pathway are particularly interesting as potential targets for pharmacological intervention. CPT1 is considered the rate-limiting enzyme in FAO and can be pharmacologically targeted. Drugs that target 3-ketoacylthiolase (3-KAT), which catalyses the final step in FAO, are also available (TABLE 1).


Jedi Master
FOTCM Member
Regarding the podcast with Chad Macias, below are some of the points highligted by him, with links to the pertinent studies.

D'Agostino does not recommend ketogenic diets in e.g. breast and prostate cancers, but caution appears to be needed with brains cancers as well:

But Schwarz et al. using a ketogenic diet as a mono therapy in patients with Glioblastoma observed
the expression of two critical mitochondrial ketolytic enzymes, advancement in tumor growth and
creation of new lesions during a 12 week intervention. "It has been proposed that energy-restricted
ketogenic diets (ERKD) might serve as a metabolic treatment to improve survival of primary brain
cancer patients. Subjects were trained by an experienced registered dietitian (RD) to assure
competency for adherence to the ERKD protocol. The energy-restricted ketogenic diets protocol was
to be administered for 12 weeks as medically appropriate. The patients who enrolled in our ERKD
pilot study were monitored with twice daily measurements of blood glucose and ketones and daily
weights. However, both patients showed tumor progression while on the energy-restricted
ketogenic diet therapy.
Immunohistochemistry reactions showed that their tumors had tissue
expression of at least one of the two critical mitochondrial ketolytic enzymes succinyl CoA: 3-oxoacid
CoA transferase, beta-3-hydroxybutyrate dehydrogenase 1. These data suggest that some of the
malignant cells in these patients’ cancers could metabolize ketones and derive energy for
subsequent growth.

Gliomas have been thought to rely upon glycolysis for energy production, yet recent results from
human NMR spectroscopy studies suggest that glucose contributes to <50% of acetyl-CoA
production in gliomas
. We observed the presence of enzymes required for fatty acid oxidation within
human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major
contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown
under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity
in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant
. Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this
metabolic pathway reduces energy production and cellular proliferation in glioma cells"

In fact, neuroblastoma and glioblastoma cells are only able to utilize ketone bodies as substrates for lipid synthesis"

Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis. We show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by∼2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue"

Neuron, astrocyte, and oligodendrocyte cultures were examined for their utilization of glucose,
ketone bodies, and free fatty acids by oxidative processes. All three cell populations readily utilized
the ketone bodies for oxidative metabolism at rates 7-9 times greater than they utilized glucose"

Apparently, biomarkers could be used to check if a cancer responds to ketogenic diet:

"Results suggest that many of these tumors have alterations in mitochondrial metabolism. On the
other hand, the positive expression of ACAT1, also a mitochondrial enzyme, in most tumors suggests
that the observed decreases of OXCT1 and BDH1 do not necessarily reflect a complete loss or
absence of mitochondria enzymes in these tumors. Nevertheless, our results showing that GBMs
from different patients have different expression of these enzymes are consistent with previous
molecular genetic studies showing that these are genetically heterogeneous tumors. Our results are
also consistent with a recent study showing variable but positive expression of the ketone body
metabolizing enzymes in several human glioma cell lines. Our results suggest that the differential
expression of these enzymes could serve as potentially useful biomarkers to select human glioma patients who may or may not respond optimally to KD"

Ketone bodies serve as sources for energy and as precursors for lipid synthesis in developing brain.
Using purified populations of neurons and astrocytes and purified oligodendroglia from bovine brain,
the activities for the three enzymes involved in ketone body metabolism were evaluated.
Surprisingly, astrocytes had the highest levels of activity for both 3-ketoacid-CoA transferase and acetoacetyl-CoA thiolase; these activites showed dramatic changes during development.
Nonetheless, neurons, astrocytes and oligodendroglia are all quite capable of using ketone bodies as metabolic fuels"

Metformin seems to work as a cancer drug as well:

We showed here that both ketones and lactate promote the growth of embryonic stem (ES) cells.
Consistent with these findings, a recent study showed that ES cells preferentially use mitochondrial
oxidative metabolism, and that their dependence on mitochondria decreases as they undergo
differentiation. This fits well with the idea that ES cells use lactate and ketones as fuel for the TCA
cycle and oxidative mitochondrial metabolism, thereby stimulating stem cell growth. In
accordance with our assertion that cancer cells use mitochondrial oxidative phosphorylation for energy
production, metformin treatment prevents and/or inhibits tumor formation both in diabetic patients
and in mouse animal models. Moreover, metformin also kills “cancer stem cells”. We see that these
high-energy metabolites induce a “stem-like” transcriptional profile that is specifically associated
with tumor recurrence, metastasis and poor clinical outcome. Finally, it is quite ironic that such a
promising anti-cancer drug (metformin) exerts its therapeutic effects by inducing a type of
metabolism (aerobic glycolysis) that has been proposed to be the “root-cause” of cancer for the last 85 years. Thus, induction of aerobic glycolysis in cancer cells may not be the “cause of cancer,” but rather it may be the “cure for cancer

Well, looks like treating brain cancer with diets isn't so simple and clear cut after all!


FOTCM Member
Re: Ketogenic Diet - Path To Transformation?

hiker said:
I listened to sigma nutrition's podcast, where they interviewed Chad Macias.

I listened to this today. First some background on Chad Macias:

Chad is currently pursuing post-graduate research in Molecular Oncology. He is in the process of writing a review paper on ketogenic diets and cancer, along with Brad Dieter and Tim Sharpe. Chad has spent over 19 years conducting research and developing protocols in cellular and molecular physiology. He is an adjunct faculty member at the University of San Diego, and has developed some of the most advanced blood lactate testing and intermittent hypoxia protocols in the world.

He founded the Institute for Human Kinetics in 2011, where he works with many of the world’s top athletes. In addition, he was a two sport Olympic athlete. He also serves as the Human Performance Specialist at Navy Special Warfare developing programs to prepare Navy Seals for combat deployment though their Tactical Athlete Program. Chad also heads OPI’s Research Team and has the knowledge base to conduct medical and exercise physiology research in both humans and rodents.

In a sense, he is also sponsored by the Department of Defense, just like Dominic D'Agostino. The above is his bio from early 2017. He has since then finished the papers promised and he is also associate professor in other universities.

His main arguments against the ketogenic diet as a therapeutic approach for cancer are explained in his research papers. However, people can get the down to earth version by listening to the podcast or by subscribing to get the transcript of the podcast:

Chad Macias is pretty worked up about the keto diet gaining so much popularity in social media and the internet as a cancer treatment without so little questioning. He does have the scientific background (molecular cancer researcher) to raise some serious red flags and I think his arguments are convincing in that he has read textually some of the papers written by Dominic D'Agostino (or his research group) and explained how the papers don't stand the test of the scientific method. D'Agostino et al. used a mouse model of metastatic glioblastoma multiforme which doesn't apply to human beings because in clinical practice, glioblastoma multiforme rarely if ever metastasizes.

As I understood it, Chad Macias is at a loss explaining the incompetence in D'Agostino's research. From what I can see, D'Agostino got sponsored to research the ketogenic diet and was pressed for results. That creates confirmation bias, blind spots and so forth. He genuinely thinks it is helpful in certain cases, but when you have a conflict of interest or a bias, it is much harder to see anything that contradicts your preconceived views. We'll have to see what D'Agostino's future research shows and I suspect that it will not include only the ketogenic diet, but several things that addresses multiple factors. In a sense, he is already doing that with the metformin, DCA, hyperbaric oxygen chamber, etc.

Perhaps I would add that Chad Macias, just as D'Agostino, don't have a clinical practice nor do they focus on the bigger picture. Just to put an example, environmental toxicity coupled with a mutagenic diet (that creates mutations on DNA) rich in toxic vegetable oils can have a detrimental effect on people's health. It can predispose them to cancer, neurodegeneration, etc. But if they detox and eat healthy fats that are non-mutagenic and anti-inflammatory, that can have a healing outcome and that could be more important than getting down to the nitty-gritty molecular mechanisms. Ultimately, perhaps doing that which is more healing to your body, mind and soul might matter more than any specific molecular detail.

Chad Macias formation in molecular cancer comes from a background that typically gets sponsored for the development of cancer drugs. He admits studying in Spain, a system that I'm familiarized with. I found the master program he followed:

And yes, they do have a specific program related with the pharmaceutical industry, though his research was a different one of molecular oncology. To his merit, he does have a track record in nutrition for athletes. Due to his research background, Chad Macias might be in a better position to see how it all ties together, and hence his strong opposition of the ketogenic diet as the only therapeutic approach to cancer. His voice of caution is valid, or so it seems to me.

Here are some of his papers which explains in a scientific way what he talked in the podcast in an informal way:

Assessing the Role of the Ketogenic Diet as a Metabolic Therapy in Cancer. Is it Evidence Based?

Several studies have shown potential therapeutic benefit in certain rodent models of cancer, particularly in glioblastoma multiforme [2, 3]. Additionally, in a model of pancreatic cancer, mechanistic studies have demonstrated that ketone bodies can diminish cancer growth and increase cancer cell death [4]. However, there are other data demonstrating that ketone bodies may fuel growth in other models of cancer [5, 6], including the potential for aggressive adaptations [7, 8]. Thus it appears that the use of KD or ketone bodies as a therapeutic intervention in human cancers requires precision in identifying patients who will benefit from these therapies. [...]

Mechanistic Concerns

In contrast to the Warburg effect, aerobic glycolysis can take place in tumor-associated fibroblasts rather than in cancer cells. Cancer biologists refer to this as the “reverse Warburg effect” [14]. In the stromal environment, tumor-associated fibroblasts stimulate both autophagy and mitochondrial biogenesis, as well as increase radiotherapy resistance [15]. The stromal environment also provides lactate and ketones, using monocarboxylate transporters to shuttle those substrates into cancer cells (Figure 1) [16]. This method of obtaining fuel from stromal fibroblasts is facilitated by oxidation and can be viewed as weaponized autophagy [17].

Experimentally, some types of cancers have shown a preference for fatty acids or ketones as a metabolic substrate to contribute to tumorigenesis [18-23]. In a study conducted at the University of Bordeaux, researchers documented “oxidative phenotype" cancer cells in lymphomas, melanomas, glioblastomas, and breast cancer [24]. Lastly, contrary to reports that cancer is primarily a metabolic disease [25], there are hundreds of oncogenes that regulate metabolism, tumorigenesis, and angiogenesis [26]. Focusing on metabolism by manipulating dietary
substrates does not adequately account for the gene-controlled compensatory mechanisms inherent in cancer
. The tumor environment appears to bridge the substrate gap in a manner which we do not yet fully comprehend, e.g. the reverse Warburg effect. There may at some point be an application for KD in certain cancers (likely as an adjunctive therapy), but widespread application of KD as a cancer treatment appears premature based on existing evidence.

Tumor Metabolism, the Ketogenic Diet and Hyperbaric Oxygen Therapy In Systemic Metastatic Cancer: Is the evidence lacking?

Poff and colleagues write “a ketogenic diet (KD) and hyperbaric oxygen therapy (HBO2T) produce significant anti-cancer effects when combined in a natural model of systemic metastatic cancer” [1]. The authors suggest these therapies may be potential non-toxic treatments or adjuvant therapies to standard care for patients with systemic metastatic disease. However, the VM-M3 model of metastasis, as well as the authors’ explanation of human Glioblastoma Multiform (GBM) are at odds with an extensive body of oncology literature.

The study reports that “the VM-M3 model of metastatic cancer is a novel murine model that closely mimics the natural progression of invasion and metastasis”. However, for a model to have validity, it must first be externally validated. There are several established methods of demonstrating external validity of in vivo efficacy studies. Both replication by an independent research group, and the establishment of effect in one or more additional models is required [2]. Neither of these are referenced in the current paper, nor can we find evidence in the existing literature of external validation.

They further write that systemic metastasis has repeatedly been documented in human GBM. These claims are exaggerated and misleading as it is well established that human Glioblastoma Multiform rarely metastasizes. There are an estimated 20,000 new cases of human GBM in the U.S. each year, and it’s been reported that only ~0.44% of all cases metastasize [3, 4].

Regarding methodology, their choice of using syngenic ectopic transplantation is problematic. Ectopic transplantation of inoculated cancer cells lacks the appropriate microenvironment of the primary tumor and the corresponding metastatic dissemination to the relevant organs [5]. The inoculation of these ectopically transplanted cell lines requires continuous passaging in cell culture which leads to well-documented changes that may significantly alter their properties, including but not limited to an augmentation of their proliferative ability [5]. Rather than using a syngenic ectopic transplantation, primary tumor tissue taken from human patient-derived explants (xenografts) would be a more accurate representation of human GBM. Xenografts are not grown in vitro or propagated as cell cultures, therefore may maintain the original tumor heterogeneous histology, clinical biomolecular signature, malignant phenotypes and genotypes, tumor architecture, and tumor vasculature [6].

Syngenic models, in contrast, are based on inbred mouse strains and lack the genetic heterogeneity of human patients [5]. Observations in these models may be specific to the strain thus limiting generalizability to other mouse or human models [2].

Finally, the authors suggest many cancers do not express the Succinyl-CoA: 3-ketoacid CoA-Transferase (SCOT) enzyme which is required for ketone body metabolism. They write, the “literature as a whole strongly suggests that cancer cells cannot effectively use ketones for fuel”. However, this does not reflect what has been observed extensively in cell culture [7, 8], multiple rodent models [9], human studies [10, 11] and a meta-analysis of cancer metabolites [12]. GBM studies in humans have identified ketone oxidation, the presence of one or more mitochondrial ketolytic enzymes, subsequent tumor growth, and development of a new lesion while utilizing a ketogenic diet as an adjunct or monotherapy [7, 10, 11]. It should also be noted many other types of cancers have shown a preference for fatty acids or ketones as a metabolic substrate to contribute to tumorigenesis [13-18]. In a study conducted at the University of Bordeaux, researchers documented “oxidative phenotype" cancer cells in lymphomas, melanomas, glioblastoma and breast cancer [19].

In breast and prostate cancer, enzymes necessary for fatty acid oxidation have been suggested as targets for anticancer therapy [13, 14, 16]. In reviewing the work of the Lisanti group [20-22], Grabacka et al. noted “that cancer cells actively contributed to the stromal fibroblasts’ metabolic reprogramming and took advantage of the subsequent ketone body consumption for energy generation. This is a special property of epithelia-derived tumors" [23]. This observation is pivotal as ~90% of all human cancers are derived from epithelia [24, 25].

In conclusion, it is our assertion that the evidence presented by Poff and colleagues does not adequately represent human GBM, nor is it reflective of the natural progression of invasion and metastasis. To meet the minimum requirements necessary for clinical translation, multiple experimental models should be conducted, including orthotopic transplantation, combination therapy, and genetically engineered models.


FOTCM Member
Re: Ketogenic Diet - Path To Transformation?

Gaby said:
Assessing the Role of the Ketogenic Diet as a Metabolic Therapy in Cancer. Is it Evidence Based?

In contrast to the Warburg effect, aerobic glycolysis can take place in tumor-associated fibroblasts rather than in cancer cells. Cancer biologists refer to this as the “reverse Warburg effect” [14]. In the stromal environment, tumor-associated fibroblasts stimulate both autophagy and mitochondrial biogenesis, as well as increase radiotherapy resistance [15]. The stromal environment also provides lactate and ketones, using monocarboxylate transporters to shuttle those substrates into cancer cells (Figure 1) [16]. This method of obtaining fuel from stromal fibroblasts is facilitated by oxidation and can be viewed as weaponized autophagy [17].

Interestingly enough, just recently a new pro-anti-cancer Ketogenic diet research paper was published.

Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras


Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration. We now reveal an evolutionary conserved mechanism linking fermentation to activation of Ras, a major regulator of cell proliferation in yeast and mammalian cells, and prime proto-oncogene product. A yeast mutant (tps1∆) with overactive influx of glucose into glycolysis and hyperaccumulation of Fru1,6bisP, shows hyperactivation of Ras, which causes its glucose growth defect by triggering apoptosis. Fru1,6bisP is a potent activator of Ras in permeabilized yeast cells, likely acting through Cdc25. As in yeast, glucose triggers activation of Ras and its downstream targets MEK and ERK in mammalian cells. Biolayer interferometry measurements show that physiological concentrations of Fru1,6bisP stimulate dissociation of the pure Sos1/H-Ras complex. Thermal shift assay confirms direct binding to Sos1, the mammalian ortholog of Cdc25. Our results suggest that the Warburg effect creates a vicious cycle through Fru1,6bisP activation of Ras, by which enhanced fermentation stimulates oncogenic potency.

Well, obviously it isn't cut and dry, especially not with cancer, since it is highly poliethiological. But then how to know what approach or therapy works best? Just by experimenting and seeing what works? But then with ketogenic diet it takes time for the benefits to kick in, so it does take some patience AND time. Would just restricting sugar and making sure to eat a lot of good fats without switching to a full blown keto, coupled with periodic detoxing may already have some benefits? Sorry, perhaps these questions and points were already examined in the past.

Also, some time ago a friend shared the following video with Dr. Kevin Hall (apparently he is famously anti- keto diet), where he shares his reservations when it comes to the keto diet effectiveness in losing weight. Does anyone see any problems with his explanation? Or does it make sense? My personal problem with his conclusions that his experiment was too short. But then many people don't go beyond 3 weeks to see if any particular method is beneficial.


FOTCM Member
Well, obviously it isn't cut and dry, especially not with cancer, since it is highly poliethiological. But then how to know what approach or therapy works best? Just by experimenting and seeing what works? But then with ketogenic diet it takes time for the benefits to kick in, so it does take some patience AND time. Would just restricting sugar and making sure to eat a lot of good fats without switching to a full blown keto, coupled with periodic detoxing may already have some benefits? Sorry, perhaps these questions and points were already examined in the past.

Keit, can I just ask... how do you define sugar? Do you mean processed white sugar, are you referring to raw orange juice, or does the term "sugar" encompasse all 'high glycemic index' foods like starches as well?

If you look at several renowned cancer therapy diets, they contain significant amounts of sugar. IMO, sugar is not a problem as long as someone has enough co-factors, minerals, and vitamins to process it. Sugar is just pure energy... The problem seem to occur when the person cannot metabolise "pure energy" because they have depleted themselves of the tools necessary to operate the machinery to extract the energy in a utilisable form. So white sugar is pretty darn bad, because it contains practically zero else. On the other hand, raw sugar cane is pretty dense with the minerals required to metabolise it.

In response to your question about restricting sugar, I think for someone with a functional carnitine deficiency or some other related error in lipid metabolism, it would be irresponsible to recommend a low-carb diet. That could derail someone completely. The same could be said for recommending low-fat diet for someone who has trouble metabolising glucose. The safe way seems to be more like: find which fuel you are best at burning, stick with it, and slowly reintroduce the other fuel while simultaneously attempting to identify, target, and fix the underlying problem.

Also, some time ago a friend shared the following video with Dr. Kevin Hall (apparently he is famously anti- keto diet), where he shares his reservations when it comes to the keto diet effectiveness in losing weight. Does anyone see any problems with his explanation? Or does it make sense? My personal problem with his conclusions that his experiment was too short. But then many people don't go beyond 3 weeks to see if any particular method is beneficial.

His research is backed up by the fact that ketones suppress lipolysis of adipose tissue:

Weight loss = sustained caloric deficit ( increasing rate/efficiency of mitochondrial respiration to increase energy expenditure while limiting food intake somewhat and increasing physical activity ). It doesn't necessarily matter what fuel is put into the system, as long as it doesn't mess with the machinery.


FOTCM Member
Re: Ketogenic Diet - Path To Transformation?

Gaby said:
Yas said:
That's very interesting Gaby, thanks for sharing!

I too feel much better when I eat two times a day, one time early in the morning and the next around 4:30 pm. I sometimes eat at 6pm due to my schedule but I guess that seems to work well as well. Sometimes I eat a late diner because I'm invited to diner with the family or friends, and then I feel a bit less energetic the next day...

According to Rhonda Patrick, you can take a break a couple of times per week and still see results, or so the research says. So those days when you eat with family or friends can be the break. Works for me too! She does emphasize that supplements and caffeine does count as breaking the fast too.

Rhonda does say that time-restricted feeding should ideally be done earlier in the day because feeding is like a signal for your circadian rhythm and it helps you balance hormones. I think that whatever we can adjust to our lifestyle and daily demands would work though.

I should clarify that the study of intermittent fasting was independent of food sources and composition. That is, people still saw benefits of doing time-restricted feeding independently from what they ate. According to research, it does seem that we metabolize food better (with lower blood glucose levels) in the morning. They have done a study where people eat the same thing AM and PM. The food in AM will always be metabolized better, which points to the fact that we are diurnal creatures (or should be).

I think intermittent fasting (whenever possible) will also be very good for those of us who work night shifts: less inflammation, better hormone balance, restores our tissues through autophagy, etc. It promotes ketone production too.

She also said that if you don't eat enough soluble fiber, the microbiome will cannibalize (!) the gut lining to get its much needed food. So it is important in intermittent fasting or a keto diet to get enough of the good soluble fiber that your body can tolerate.

I was surprised to hear that she is very pro Omega 3 supplementation. She quotes studies and the fact that our brain's fatty composition is mostly essential fatty acids. She is aware about the problem of their oxidation and takes precautions with her supplements. You know you're hearing a doctoral chemist picking her supplements when you hear Rhonda Patrick! She quotes a company (Nordic Naturals) which uses a nitrogen environment during the isolation process of Omega 3s from fish. This way, the Omega 3s are not oxidized from exposure to to oxygen. She says she has taken Omega 3 supplementation for 9 consecutive years and thinks it has only benefited her.

She says that if you are getting an extra dose of IGF-1 in the ketogenic diet from meat consumption, then the wisest thing is to build up muscle mass. Otherwise IGF-1 may act against you.

She also speaks of water fasting and how your organs shrink during the process. Then, when it is time to eat again, the organs re-build themselves with the nutrients provided. The best results are seen with a water fasting of 4-5 days, but it is something very difficult to make. It can be contraindicated for some folk. She says that there was a mouse model study with a 2-3 day water fasting which had very good results. A lot of folk quote this study thinking that humans could do 2-3 days and they're good. Apparently for the human equivalent, it is more (4-5 days) to see similar results.

Really interesting Gaby, and thanks for sharing the information. I recently listened to the talk she had with Joe Rogan and one thing came to mind just now, it's really early here, and I won't eat or take supplements for a few hours yet I did just have a cigarette. But Rhonda spoke of enzymatic processes that occur in the liver when drinking coffee outside of the 8-9 hour window, and that supplements ideally should be taken within that window as well, so I'm wondering about tobacco. Considering the effects it has on dopamine and acetylcholine and our neuochemistry, would that be something included as say, a supplement, ideally to be smoked within a certain range of the day similar to when to eat and supplement?


FOTCM Member
Re: Ketogenic Diet - Path To Transformation?

Turgon said:
Considering the effects it has on dopamine and acetylcholine and our neuochemistry, would that be something included as say, a supplement, ideally to be smoked within a certain range of the day similar to when to eat and supplement?

I wouldn't necessarily take it that far. The idea is to rest your digestive system from processing any molecule.

I tried time restricted feeding within 9-10 hours, combining a second concept which is doing two main meals and fast the rest of the time to promote insulin sensitivity, autophagy and ketone production during the day as well. I must say that I was very impressed with the results: more energy, better sleep, less food cravings. I took my supplements with my meals and the rest of the time drank water. I did smoked too and ate freely two days per week.

As far as I'm aware, this was the study that Rhonda Patrick was discussing on the podcasts. It is a mouse model though, hopefully human studies will be forthcoming:

Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges
Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8-9h food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse nutritional challenges, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with pre-existing obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia.



Diseases like obesity, arising from nutrient imbalance or excess are often accompanied by disruptions of multiple pathways in different organ systems. For example, the regulation of glucose, lipids, cholesterol, and amino acids homeostasis involve the liver, white adipose tissue (WAT), brown adipose tissue (BAT) and muscle. In each tissue, nutrient homeostasis is maintained by balancing energy storage and energy utilization. Pharmacological agents directed against specific targets effectively treat certain aspects of this homeostatic imbalance. However, treating one aspect of a metabolic diseases sometimes worsens other symptoms (e.g., increased adiposity seen with insulin sensitizers), and beneficial effects are often short-lived (e.g., sulfonylureas) (Bray and Ryan, 2014). Furthermore, recent studies have shown that early perturbation of nutrient homeostasis can cause epigenetic changes that predispose an individual to metabolic diseases later in life (Hanley et al., 2010). Hence, finding interventions that impact multiple organ systems and can reverse existing disease will likely be more potent in combating the pleiotropic effect of nutrient imbalance.


Gene expression and metabolomics profiling, as well as targeted assay of multiple metabolic regulators, have revealed that a defined daily period of feeding and fasting is a dominant determinant of diurnal rhythms in metabolic pathways (Adamovich et al., 2014; Barclay et al., 2012; Bray et al., 2010; Eckel-Mahan et al., 2012; Vollmers et al., 2009). Accordingly, early introduction of time-restricted feeding (TRF), where access to food is limited to 8-hour during the active phase, prevents the adverse effects of HFD-induced metabolic diseases without altering caloric intake or nutrient composition (Hatori et al., 2012). However, it is unclear whether TRF: (i) is effective against other nutritional challenges, (ii) can be used to treat existing obesity, (iii) has a legacy effect after cessation and, (iv) can be adapted to different lifestyles. In lieu of the metabolic imprinting that renders mice susceptible to disease later in life, the therapeutic effect of TRF on pre-existing diet-induced obesity (DIO) remained to be explored. The effectiveness of TRF as a single 8-h feeding duration prompts exploration of the temporal window of food access that would still be effective against nutrition challenge. This is important before any human study can commence, given the incompatibility of an 8h-restricted diet with a modern work schedule. Additionally, a change in eating pattern between weekday and weekend even when the mice are fed a standard diet has been suggested to contribute to obesity and metabolic diseases. This intimates that occasional deviation from TRF might exacerbate the disease. Addressing these questions is fundamental to elucidate the effectiveness and limitations of TRF and will offer novel insight into the relative role of eating pattern and nutrition on metabolic homeostasis.


Mice fed NC did not show profound differences in body weight between ALF and TRF. Nevertheless, there were other positive consequences of TRF. In the 38 weeks long TRF, mice on NC (NAA, NTT, NAT, and NTA) exhibited equivalent body weights, yet NTT mice had significantly more lean mass and less fat mass than other NC cohorts (fig S2D). Furthermore, NT mice were protected from mild hepatic steatosis, which is usually observed in old mice fed NC ad libitum (Jin et al., 2013). Similarly, mice fed a Fr diet did not show any significant change in body weight between ALF and TRF cohorts, yet FrT mice had less fat mass, increased lean mass and better glucose tolerance relative to FrA mice (fig S2E, fig S4B). [...]

I think it was Joe Rogan who later reported his results with this concept in another show (with Robb Wolf?) and he was saying that he was very impressed. He was practically there in terms of fasting before knowing the time restricted feeding concept, minus the coffee and some supplements that he thought didn't counted as a fast.


FOTCM Member
Re: Ketogenic Diet - Path To Transformation?

Gaby said:
It is a mouse model though, hopefully human studies will be forthcoming:

Here is some related info from human studies:

Daily Eating Patterns and Their Impact on Health and Disease

Cyclical expression of cell-autonomous circadian clock components and key metabolic regulators coordinate often discordant and distant cellular processes for efficient metabolism. Perturbation of these cycles, either by genetic manipulation, disruption of light/dark cycles, or, most relevant to the human population, via eating patterns, contributes to obesity and dysmetabolism. Time-restricted feeding (TRF), during which time of access to food is restricted to a few hours, without caloric restriction, supports robust metabolic cycles and protects against nutritional challenges that predispose to obesity and dysmetabolism. The mechanism by which TRF imparts its benefits is not fully understood but likely involves entrainment of metabolically active organs through gut signaling. Understanding the relationship of feeding pattern and metabolism could yield novel therapies for the obesity pandemic.


TRF in Humans

Although no studies in humans have yet specifically tested TRF, some small studies about timed eating suggest that restoring feeding/fasting cycles with light/dark circadian rhythms can have weight-loss benefits [67]. For example, in a cohort of patients undergoing a behavioral weight-loss treatment, those who consumed their calories earlier in the day were more likely to lose weight, compared to those who ate later [68]. Another study, where two groups of obese women were randomized to consuming an isocaloric meal during breakfast or dinner, showed that high-calorie breakfast consumers had much better fasting glucose, insulin sensitivity, and improved lipid profile compared to the high-calorie dinner consumers [69]. As discussed above, recent studies have demonstrated that the timing of feeding in the general population is diverse [60], suggesting that more precision medicine is needed to identify those who have poor feeding patterns, and selectively recommend behavioral changes in these individuals to improve their metabolism. Ongoing effort to monitor the daily pattern of food intake, sleep, and activity using smartphones ( in a large cohort will quantify the epidemic of circadian disruption and identify at-risk individuals.

Multiple studies show that TRF, where feeding has been restricted to the active time phase, has significant metabolic benefits. TRF prevents obesity and improves glucose and lipid homeosta-sis, and has beneficial effects on other metabolic organs such as the liver, heart, and brown adipose tissue. These affects are accompanied with synchrony and more robust oscillation between circadian effectors and metabolic regulators that are entrained to feeding/fasting cycles. However, although restoration of circadian and metabolic synchrony is correlated with improved metabolism, the mechanism by which this improvement occurs is not yet fully understood. There are still many gaps in understanding the relationship between light-entrained central circadian oscillations with those in the periphery that may be entrained by other external stimuli such as feeding. In addition, although it is clear that light-entrainment occurs with specialized retinal ganglion cell signaling to the SCN, feeding entrainment from the gut to metabolically active tissues such as the liver, muscle, and adipose tissue is not entirely understood.

Circadian Clocks and Metabolism: Implications for Microbiome and Aging.

The circadian clock directs many aspects of metabolism, to separate in time opposing metabolic pathways and optimize metabolic efficiency. The master circadian clock of the suprachiasmatic nucleus synchronizes to light, while environmental cues such as temperature and feeding, out of phase with the light schedule, may synchronize peripheral clocks. This misalignment of central and peripheral clocks may be involved in the development of disease and the acceleration of aging, possibly in a gender-specific manner. Here we discuss the interplay between the circadian clock and metabolism, the importance of the microbiome, and how they relate to aging.
I wanted to share a youtube channel I have been following lately. Lots of quick, informative videos related to the ketogenic diet. He does many videos that explain the various hormones and their functions, and how they are affected by eating various foods, fasting ect. I know Life without bread explained a lot about hormones and insulin as well, but these videos are very well done, easy to follow, and generally only a few minutes long.


Jedi Council Member
FOTCM Member
Re: Ketogenic Diet - Path To Transformation?

While reading about sodium citrate as glycolysis inhibitor in treatment of cancer (you can read about it here: Effect of Citrate on Malignant Pleural Mesothelioma Cells: A Synergistic Effect with Cisplatin) I was wondering what kind of effect would happen if the person would be in ketosis in the same time. And I found one article that talks exactly about that:

Although, in their study they used a different kind of glycolysis inhibitor. But the method is still the same: chronically starve the cancer cell by producing ketones, and then pulse it with something that inhibits glycolysis:

You can read more about that study here: Drug/diet synergy for managing malignant astrocytoma in mice: 2-deoxy-D-glucose and the restricted ketogenic diet
This is their result:

I found another more recent study in Nature(22 Sep 2017), here: Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP
but its focus is not cancer, but trying to discover how a ketogenic diet can reduce inflammation.
The Abstract
The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.
Microglial and macrophage activation is suppressed by 2DG
The reduced glycolytic flux resulting from caloric restriction and ketogenic diet can be mimicked by the glycolytic inhibitor 2DG27, 28. To determine whether 2DG can replicate the effect of ketogenic diet on brain inflammatory responses, we treated rats with intraperitoneal injections of lipopolysaccharide (LPS) or with LPS + 2DG. The systemic LPS injection induced a robust activation of brain microglia, and this was strikingly reduced by co-administration of 2DG (Fig. 1a). In organotypic brain slice cultures (Fig. 1b), 2DG likewise suppressed the effect of LPS on microglial activation and on the expression of inducible nitric oxide synthase (iNOS), a hallmark of inflammatory activation in microglia and macrophages29. Primary microglial cultures similarly showed an attenuated response to LPS in the presence of 2DG (Fig. 1c), thus confirming that the effects of LPS and 2DG on microglia are not dependent upon indirect, systemic effects of these agents.
The initial observation by Zhang et al.26 that NADH binding promotes CtBP dimerization suggested that CtBP could regulate transcription in response to metabolic changes. Subsequent studies confirmed that CtBP mediates effects of 2-deoxyglucose, hypoxia, pyruvate, and other metabolic influences on gene expression27, 41. Since NAD+ and NADH recognize the same binding site on CtBP, changes in the concentration of either nucleotide could, in principle, regulate CtBP interactions with its binding partners. However, the relative changes in NADH caused by shifts in the cytosolic NADH:NAD+ ratio are several hundred-fold greater than the reciprocal changes in NAD+ because the cytosolic NADH:NAD+ ratio is normally in the range of 1:70035. The sensitivity of CtBP to changes in NADH thus makes it particularly responsive to changes in energy metabolism42. Inflammatory responses can also be modulated by NAD+—dependent deacetylases of the sirtuin family, notably Sirt143, but unlike CtBP sirtuins are not responsive to changes in NADH concentrations, and it remains uncertain whether their activity is significantly affected by the relatively small changes in NAD+ concentrations that result from changes in energy metabolism44.

So it is interesting that a mechanism may have been found explaining how a ketogenic diet reduces inflammation.
I suspect that a pill/injection may be forthcoming as an emergency response to head trauma for example if this pathway proves valid, which I think could be a good idea for ER. I sure hope some pharmaceutical company doesn't come out with a 'headache' pill as the hubris of thinking we are smarter than the body could have poor unintended consequences, although if the side affects can help to sell more pharmaceuticals, who knows.

I was also interested in the Sirt1 point, remembering Elliott's description of Sirt1 with regard to smoking.


The Living Force
FOTCM Member
I have been hearing people talk about keto these days. They know that I eat a lot of fat and we discuss once in a while. Interest seems to be from fitness programs and word-of-mouth testimonials. They try it, get excited about the results, drop out to again try later.

Recently, I heard ( from my colleague) a person named Veeramachaneni Ramakrishna (who happens to be an accountant in Telugu language state in India) promoted what is dubbed as "Andhra Keto". As the story goes, In order to solve his overweight, Diabetes problem, he adopted a program from Canadian nephrologist, modified for his purpose and promoted word-of-mouth fashion. He became a sensation in Telugu speaking media and he has millions of following. It looks he enters into debates with professional doctors that produced a lot of viewership for the TV channels and that made him household name. There are almost 80 million Telugu people in India and decent size in US that seems to have contributed for his diet propagation.

His diet program includes 70g to 100g of fats ( only coconut, butter, olive oil - he includes cheese too), No sugar, no major grains, no milk, no sweet. etc. during the program period. Most of the "No No" items are familiar to the forum, so I won't go in details. He has lot of video's with millions of views and he says he gets positive reviews from telugu folks all over the world and some discussion threads on the net.

In Andhra Pradesh there is a new diet … it’s Andhra keto

Couple of days back, i watched "The Happy Pill" Netflix documentary which i think conveys powerful message. Many reviews are positive, though sizeable negative reviews which is expected. Most of the negative reviews belong "I am a doctor, this doesn't work" etc rather than "I tried it didn't work".

There is a lot of subtleties in the Keto process, none the less I am happy to see diet is getting LOT of traction.


Jedi Council Member
FOTCM Member
That Canadian nephrologist was undoubtedly Dr Jason Fung, and one site is: Dr. Jason Fung, M.D. - Diet Doctor
Intensive Dietary Management: Intensive Dietary Management (IDM Program)
I have his book on Fasting, and The Diabetes Code, and The Obesity Code is on order,
He writes well, and goes into detail but makes it easy to understand, so I'd recommend his books, though I don't think many people here would need them, he does provide a good understanding of the bodies energy systems especially with regard to Obesity and Diabetes, and I read his Fasting book before or during fasts.
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