/fit/ - Fitness, Health, and Feels

>>130248

Is ketosis carcinogenic?

Papers are published with both affirmative and negative answers to this question. Upon closer examination, the negative results appear to be a result of confounding variables in experimentation, namely the presence of overtly anticarcinogenic substances mixed into the diet (or overtly carcinogenic substances in controls), a lack of accounting for the ketogenic/antiketogenic balance of nutrition, a lack of elaboration on the predisposition of the organism under study to undergo ketosis, and unknown methodology. Perhaps much mystery could be solved simply by attempting a dietary intervention and then measuring what degree of ketosis and aerobic glycolysis actually happens. Reduction of total weight is a frequently claimed (bragged even) result of ketogenic interventions, but less attention is given to the degree of muscle lost. Cachexia, or muscle wasting, is a well known feature of cancer.

https://en.wikipedia.org/wiki/Cachexia#Cancer

If cancer is associated with an inability or refusal to properly metabolize glucose, cachexia before death by cancer might be seen as an organism stubbornly refusing to give up on life by catabolizing as much antiketogenic substrate and muscle tissue (to release amino acids convertible to glucose) as possible until it can no longer find or use enough material to survive on. Ketosis has been specifically shown to fail at reducing cachexia in cancer subjects.

(1985) Failure of systemic ketosis to control cachexia and the growth rate of the Walker 256 carcinosarcoma in rats

>Systemic ketosis (1-2 mM acetoacetate plus 3-hydroxybutyrate) was induced both in tumour-bearing and in non-tumour-bearing rats with a diet containing 70% medium chain triglyceride. However, in rats bearing the Walker 256 tumour, this dietary ketosis did not reduce the tumour growth rate nor did it prevent the subsequent decrease in host body weight. Host body nitrogen losses were similarly unaffected. The ketosis induced in tumour bearing rats was shown to be abnormal since the blood glucose concentration of ketotic, tumour-bearing rats was significantly higher compared with that of ketotic non-tumour bearing rats

https://www.nature.com/articles/bjc1985153

(1988) Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism.

>The aim of this study was to determine whether a ketogenic diet could decrease nitrogen losses in cachectic cancer patients […] This ketosis was associated with a significant reduction of the concentration in blood of glucose, lactate, and pyruvate (p less than 0.05). There was, however, no significant alteration in host N balance or whole-body protein synthesis, degradation, or turnover rates.

http://ajcn.nutrition.org/content/47/1/42.short

But why did the glucose rise in the tumor-bearing rats? Was the cancer hungry for glucose or did it interfere with the ability to metabolize glucose? If cancer interferes with the proper use of glucose, should medical practioners and nutritionists also interfere with the proper use of glucose through dietary interventions?

>>130250

(1987) [Activation of lipolysis and ketogenesis in tumor-bearing animals as a reflection of chronic stress states].

>In tumour-bearing organisms lipolysis and ketogenesis reflect the tumour-induced chronic stress. Absorption of beta-HB and release of Ac-Ac by brain were observed at all stages of malignant growth. This is probably due to a partial switch-over of brain metabolism to non-carbohydrate energy sources. Besides, certain stages of tumour growth are associated with active assimilation of NEFA by brain.

https://www.ncbi.nlm.nih.gov/pubmed/3676360

(2010) The autophagic tumor stroma model of cancer

Role of oxidative stress and ketone production in fueling tumor cell metabolism

>It is also known that oxidative stress is indeed sufficient to induce ketone production in an animal model of Amyotrophic Lateral Sclerosis (ALS). These mice express a mutant form of SOD1 (G86R) and show progressively increased serum levels of ketone bodies.[26] Furthermore, ALS patients show increased serum levels of ketone bodies, both 3-hydroxybutyrate and acetone, as documented by NMR spectroscopy.[27]

…

>Next, we turned our attention to ketone metabolism (Table 9). For this purpose, we analyzed the transcriptional profiles of the genes associated with both ketone production (ACYL, HMGCS1/2, HMGCL, HMGCLL1 and BDH1/2) and ketone re-utilization (ACAT1/2 and OXCT1/2). Interestingly, only the genes associated with ketone production, but not ketone re-utilization were associated with human tumor stroma. This is exactly as would be predicted, as the epithelial cancer cells should express the genes associated with ketone re-utilization, so that they can re-use 3-hydroxybutyrate as an energy source for mitochondrial oxidative metabolism. Also, many of the stromal genes involved in ketone production are specifically associated with tumor recurrence (ACLY, HMGCS2, HMGCLL1 and BDH1) and/or metastasis (BDH2). Many of these ketone production genes are also transcriptionally overexpressed in Cav-1 (−/−) stromal cells, consistent with our current metabolic analysis.

…

>So, just as ketones are a “super-fuel” under conditions of ischemia in the heart and in the brain, they could fulfill a similar function during tumorigenesis, as the hypoxic tumor exceeds its blood supply. So, stromal ketone production could obviate the need for tumor angiogenesis.

…

>Similarly, diabetic patients show both high serum levels of ADMA and ketones.[60][61] Thus, our current observations may also explain the close and emerging association between diabetes and cancer susceptibility.[62] A number of elegant studies have been carried out in mouse animal models to assess this association and chemical induction of diabetes in rats (with streptozocin) is sufficient to enhance tumor growth.[63] Similarly, acute fasting in rodent animal models is also sufficient to dramatically increase tumor growth.[64] Both of these experimental conditions (diabetes and fasting/starvation) are known to be highly autophagic and ketogenic and thus, are consistent with our current hypothesis that autophagy/ketone production fuels tumor growth and metastasis. Thus, the combination of ADMA and ketones may also play a crucial and causal role in promoting tumorigenesis, by providing oxidative stress and the simultaneous release of high-energy nutrients from the tumor micro-environment.

http://www.tandfonline.com/doi/full/10.4161/cc.9.17.12721

>>130251

(2011) Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer

>Previously, we showed that high-energy metabolites (lactate and ketones) “fuel” tumor growth and experimental metastasis in an in vivo xenograft model, most likely by driving oxidative mitochondrial metabolism in breast cancer cells.

…

>Briefly, human breast cancer cells (MCF7) were cultured with lactate or ketones, and then subjected to transcriptional analysis (exon-array). Interestingly, our results show that treatment with these high-energy metabolites increases the transcriptional expression of gene profiles normally associated with “stemness,” including genes upregulated in embryonic stem (ES) cells. Similarly, we observe that lactate and ketones promote the growth of bonafide ES cells, providing functional validation. The lactate- and ketone-induced “gene signatures” were able to predict poor clinical outcome (including recurrence and metastasis) in a cohort of human breast cancer patients. Taken together, our results are consistent with the idea that lactate and ketone utilization in cancer cells promotes the “cancer stem cell” phenotype, resulting in significant decreases in patient survival.

http://www.tandfonline.com/doi/full/10.4161/cc.10.8.15330

(2012) Ketone bodies and two-compartment tumor metabolism: Stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells

>We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer-associated fibroblasts. […] In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the “two-compartment tumor metabolism” model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers.

http://www.tandfonline.com/doi/abs/10.4161/cc.22136

(2012) Ketone body utilization drives tumor growth and metastasis

>We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm “two-compartment tumor metabolism.” […] Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. […] Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease.

http://www.tandfonline.com/doi/abs/10.4161/cc.22137

>>130252

(2014) Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth

>Fibroblasts are the most abundant “non-cancerous” cells in tumors. However, it remains largely unknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, driving chemotherapy resistance and poor clinical outcome. […] These catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support tumor growth, via the local stromal generation of mitochondrial fuels (lactate, ketone bodies, fatty acids, glutamine, and other amino acids).

http://www.sciencedirect.com/science/article/pii/S1044579X14000212

(2017) Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth

>• Dietary fat promotes ketogenesis to enhance BRAF V600E tumor growth

…

>Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice.

http://www.cell.com/cell-metabolism/abstract/S1550-4131(16)30643-X

tl;dr?

>>130254

Keto and nofap being a bunch of fags is all.

>>130257

I got that, question is, is OP saying keto = cancer, or (((doctors))) say keto = cancer therefore keto = good?

>>130259

>(((doctors))) say keto = cancer

This was not said.

>>130260

ah so OP is a fag, got it, thanks

>>130259

OP is saying that he doesn't know how to read studies and interpret data

>>130250

>aerobic glycolysis

I think I meant to say aerobic respiration but either glycolysis pathway consumes glucose and is in contrast to ketosis.

Aerobic glycolysis

>The conversion of glucose to lactate in the presence of oxygen has been termed aerobic glycolysis.

http://www.metabolic-database.com/html/aerobic_glycolysis.html

>>130250

Is ketosis carcinogenic partly via ketone bodies stimulating chaperone-mediated autophagy?

(2005) Ketone Bodies Stimulate Chaperone-mediated Autophagy

>Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradative process that is activated in higher organisms under conditions of prolonged starvation and in cell culture by the removal of serum. […] Here we have investigated the hypothesis that ketone bodies induce CMA. We found that physiological concentrations of β-hydroxybutyrate (BOH) induced proteolysis in cells maintained in media with serum and without serum; however, acetoacetate only induced proteolysis in cells maintained in media with serum. Lysosomes isolated from BOH-treated cells displayed an increased ability to degrade both glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A, substrates for CMA. Isolated lysosomes from cells maintained in media without serum also demonstrated an increased ability to degrade glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A when the reaction was supplemented with BOH. […] However, pretreatment of glyceraldehyde-3-phosphate and ribonuclease A with BOH increased their rate of degradation by isolated lysosomes. Lysosomes pretreated with BOH showed no increase in proteolysis, suggesting that BOH acts on the substrates to increase their rates of proteolysis. Using OxyBlot™ analysis to detect carbonyl formation on proteins, one common marker of protein oxidation, we showed that treatment of substrates with BOH increased their oxidation. […] The induction of CMA by ketone bodies may provide an important physiological mechanism for the activation of CMA during prolonged starvation.

http://www.jbc.org/content/280/27/25864.short

(2006) Proteolytic and lipolytic responses to starvation

>During long-term starvation, oxidation of free fatty acids by the liver leads to the production of ketone bodies that can be used for energy by skeletal muscle and brain. Tissues that cannot use ketone bodies for energy respond to these small molecules by activating chaperone-mediated autophagy.

http://www.sciencedirect.com/science/article/pii/S0899900706001766

(2011-6) Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth.

https://www.ncbi.nlm.nih.gov/pubmed/21700219

(2011-11) Chaperone-mediated autophagy is required for tumor growth.

https://www.ncbi.nlm.nih.gov/pubmed/22089453

(2014) Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells.

>Therefore, we propose that the up-regulated [chaperone-mediated autophagy] activity characteristic of most types of cancer cell enhances oncogenesis by shifting the balance of PED function toward tumor promotion. This mechanism is consistent with the notion of a therapeutic potential for targeting CMA in cancer, as inhibition of this autophagic pathway may help restore a physiological ratio of PED forms.

https://www.ncbi.nlm.nih.gov/pubmed/24477641

>>130248

Is ketosis diabetogenic?

It is well known should be? that elevated blood ketones is associated with diabetes.

(1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes

>Diabetes is the most common pathological cause of elevated blood ketones.

http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1520-7560(199911/12)15:6%3C412::AID-DMRR72%3E3.0.CO;2-8/full

This is not proof of a cause and effect relationship of course, but it is enough reason to investigate further. If diabetes is a degenerative disease that involves increased presence of ketones, it seems reasonable for those promoting dietary means to induce ketosis as a way to improve health and quality of life to first rule out that ketosis is not a fundamental actor in the gradual progression of such an illness.

In 1909, it was known that inhibited or abnormal glycolysis is a feature of diabetes, and again in 1923 it was reconfirmed with more sophistication.

(1923) ON GLYCOLYSIS IN DIABETIC AND NON-DIABETIC BLOOD.

>One of the most popular themes has hinged on the subject of a possible difference in the glycolytic power of normal and of diabetic blood. From the work of Lepine (3) and his pupils it would seem that diabetic blood is capable of less active glycolysis than is the blood of non-diabetic individuals;

http://www.jbc.org/content/56/3/739.short

As early as 1963, ketone bodies were shown to inhibit glycolysis.

(1963) Inhibition of Phosphofructokinase in Rat Heart Muscle by Fatty Acids, Ketone Bodies, Pyruvate, Diabetes and Starvation

>IN perfused rat heart, glycolysis is accelerated by anoxia and uncouplers of respiratory chain phosphorylation and inhibited by the respiration of fatty acids, ketone bodies and pyruvate1–4.

https://www.nature.com/articles/200169a0

And as glycolysis is the pathway through which glucose is metabolized, it becomes no surprise that when it is inhibited, unused glucose may begin to accumulate.

(1981) Autoregulation by glucose of hepatic glucose balance: Permissive effect of insulin

>In hepatocytes from diabetic rats, there was no autoregulation, tissue glycogen was unmeasurable both before and after incubation, glycolysis was markedly curtailed and gluconeogenesis was increased. It may be concluded that (1) glucose autoregulates its own production or utilization by modulating the glycogen and glycolytic pathways, (2) autoregulation is lost in severe diabetes leading to fasting hyperglycemia,

http://www.sciencedirect.com/science/article/pii/0026049581901529

Therefore, there is evidence to support the idea that ketones cause or promote hyperglycemia, a key feature of diabetes. With that known, does the solution then become to restrict the intake of glucose or carbohydrates in general in order to avoid their careless accumulation as is prescribed by ketogenic dietary protocols? The information so far presented says no, as the mere presence or absence of “regular” dietary carbohydrates is not strictly connected to the amount of glucose available. The aforementioned antiketogenic substances as a whole either from diet or catabolism of tissues such as muscle will take their place, as was partly revealed to Claude Bernard in 1848:

>he was surprised to find glucose in blood samples - from animals and man - that were eating a diet completely free of carbohydrate; indeed, even if they had been fasting for several days.

http://www.claude-bernard.co.uk/page7.htm

so what is your point OP?