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  #151   ^
Old Sun, Dec-02-18, 23:23
teaser's Avatar
teaser teaser is offline
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Plan: mostly milkfat
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https://peterattiamd.com/tomseyfrie...KwHB-uKMfY2pFJM

Quote:
Thomas Seyfried, Ph.D.: Controversial discussion—cancer as a mitochondrial metabolic disease? (EP.30)


If you've already seen a dozen Seyfried interviews, this one is refreshing, Peter Attia asks some harder questions and gets a different interview than usual. Seyfried makes some points about cells in a petri dish versus how they behave in the human body, fairly good points. Cell behaviour depends largely on their environment. A sticking point for me in this area is the contention that protein intake has to be zero to stimulate autophagy, and even tiny levels of amino acids will switch it off. That observation is one based on cell monocultures. In cell monocultures, you can get environmental amino acid levels down below what they can get to in a living organism--resulting in superphysiological levels of autophagy. If somebody suggests that the amino acids in a cup of coffee may prevent autophagy initiation--they do not understand the relevant science. They just don't. Maybe I shouldn't be using Seyfried's contention here to tilt at my own personal windmill. I guess it's relevant since Seyfried also contends that periodic fasting might prevent initiation of cancer in the first place.
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  #152   ^
Old Mon, Dec-03-18, 05:57
JEY100's Avatar
JEY100 JEY100 is offline
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Plan: P:E/DDF
Stats: 225/150/169 Female 5' 9"
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Thank you for posting. Most of Attia's interviews are over my head, but I will struggle through this one...with a big travel mug of coffee in hand.
Plus I do have to read along with those detailed show notes and slides I can not be driving around only listening like a usual podcast. Taking it on in sections.

Last edited by JEY100 : Tue, Dec-04-18 at 03:50.
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  #153   ^
Old Mon, Dec-03-18, 18:09
Ms Arielle's Avatar
Ms Arielle Ms Arielle is offline
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Plan: atkins, carnivore 2023
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Quote:
Originally Posted by teaser

Good stuff. Thanks.
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  #154   ^
Old Wed, Dec-05-18, 06:58
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patriciakr patriciakr is offline
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Plan: CALP with Primal Leanings
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Following.
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  #155   ^
Old Thu, Dec-06-18, 16:22
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WereBear WereBear is offline
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Subscribed! Lots of good stuff here.
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  #156   ^
Old Mon, Dec-10-18, 07:36
JEY100's Avatar
JEY100 JEY100 is offline
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Plan: P:E/DDF
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New article by Dr. Siddhartha Murkerjee in The New York Times Magazine.

https://www.dietdoctor.com/prominen...to-fight-cancer

It’s Time to Study Whether Eating Particular Diets Can Help Heal Us


https://www.nytimes.com/2018/12/05/...lp-heal-us.html
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  #157   ^
Old Wed, Dec-19-18, 09:52
teaser's Avatar
teaser teaser is offline
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Plan: mostly milkfat
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Another cancer as a metabolic disease link...

https://www.sciencedaily.com/releas...81213142153.htm

Quote:
Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth -- this was discovered by researchers from the University of Basel's Biozentrum two years ago. In a follow-up study, recently published in Cell Reports, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the treatment of diabetes is too low to inhibit cancer growth. The previous study of Prof. Hall's group at the University of Basel's Biozentrum revealed that the antihypertensive drug syrosingopine enhances metformin's anti-cancer efficacy.

In the follow-up study, jointly performed at the Biozentrum and Basilea Pharmaceutica International Ltd, the scientists shed light on this phenomenon: The combination of the two drugs blocks a critical step in energy production thus leading to an energy shortage, which finally drives cancer cells to "suicide."

Drug cocktail cripples sophisticated machinery

Cancer cells have high energy demands due to their increased metabolic needs and rapid growth. A limiting factor in meeting this demand is the molecule NAD+, which is key for the conversion of nutrients into energy. "In order to keep the energy-generating machinery running, NAD+ must be continuously generated from NADH," explains Don Benjamin, first author of the study. "Interestingly, both metformin and syrosingopine prevent the regeneration of NAD+, but in two different ways."

Taking a closer look at the mode of action

Many tumor cells shift their metabolism toward glycolysis, which means that they generate energy mainly via the breakdown of glucose to lactate. Since the accumulation of lactate leads to a blockade of the glycolytic pathway, cancer cells eliminate lactate by exporting it from the cell via specific transporters. "We have now discovered that syrosingopine efficiently blocks the two most important lactate transporters and thus, inhibits lactate export," says Benjamin. "High intracellular lactate concentrations, in turn, prevent NADH from being recycled into NAD+."

Lethal combination

Because the anti-diabetes drug metformin blocks the second of the two cellular pathways for NAD+ regeneration, combined metformin-syrosingopine treatment results in complete loss of the cell's NAD+ recycling capacity. The depletion of NAD+ in turn leads to cell death, as the cancer cells are no longer able to produce sufficient energy. Thus, pharmacological inhibition of lactate transporters by syrosingopine or other similarly acting drugs can increase the anti-cancer efficacy of metformin and may prove a promising approach to fighting cancer.

The former Basel-based company Ciba originally developed syrosingopine for the treatment of hypertension in 1958. The identification of syrosingopine as a dual inhibitor of the two main lactate transporters is an important discovery, as currently there is no pharmacological inhibitor available for one of these two transporters (MCT4). The potential application of syrosingopine in cancer therapy could trigger a second career for this old drug.




Quote:
We have now discovered that syrosingopine efficiently blocks the two most important lactate transporters and thus, inhibits lactate export," says Benjamin. "High intracellular lactate concentrations, in turn, prevent NADH from being recycled into NAD+."



Interesting to know how this relates to ketones.


Converting lactate to pyruvate, which can be used to produce acetyl-CoA, is a reaction that also includes conversion of NAD+ to NADH. So high lactate is also sort of a chemical push towards NADH. The reverse reaction, pyruvate to lactate, pushes NAD in the other direction. Also, production of ATP produces NADH from NAD+... true of glycolysis as well as mitochondrial respiration. Fermentation from glucose to pyruvate produces NADH--so pyruvate-->lactate "rescues" NAD+ levels from the effect of fermentation... Pyruvate to lactate doesn't produce ATP directly, it just increases NAD+ so that energy production can continue.

If this crosses anybody's eyes, sorry. I'm largely trying to uncross my own eyes, going through this.

There's a similar relationship with acetoacetate and betahydroxybutyrate--producing acetoacetate from betahydroxybutyrate also involves oxidation of NADH to NAD+ and vice versa. So acetoacetate-->betahydroxybutyrate has a similar effect to pyruvate-->lactate on NADH/NAD+ ratio. Ketones also use the same mono-carboxylate transporters as lactate and pyruvate to get in and out of cells. Then things are a little different, because lactate is largely produced locally, and ketones produced in the liver (although a fair amount of conversion of acetoacetate to betahydroxybutyrate might occur outside the liver).

Something all this suggests to me--the contention that some cancer lines, at least, cannot produce energy through mitochondrial respiration--glycolysis itself, by greatly increasing lactate production, under some conditions (like the artificial one produced here, where lactate can't be exported) might inhibit mitochondrial respiration...

Earlier drugs related to metformin didn't make it as diabetes drugs--too much danger of lactic acidosis. Likely why those larger doses of metformin that are effective against cancer aren't practical.
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  #158   ^
Old Wed, Dec-19-18, 10:44
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s93uv3h s93uv3h is offline
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Plan: Atkins & IF / TRE
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Quote:
Originally Posted by JEY100
New article by Dr. Siddhartha Murkerjee in The New York Times Magazine.

https://www.dietdoctor.com/prominen...to-fight-cancer

It’s Time to Study Whether Eating Particular Diets Can Help Heal Us

https://www.nytimes.com/2018/12/05/...lp-heal-us.html
His book: The Emperor of All Maladies: A Biography of Cancer (2010) is outstanding. After listening to the first few minutes, I just borrowed his other book: The Laws of Medicine: Field Notes from an Uncertain Science (2015).

A great podcast with Dr. Siddhartha Mukherjee & Peter Attia:

Siddhartha Mukherjee, M.D., Ph.D.: new frontiers in cancer therapy, medicine, and the writing process 12-10-2018

In this episode, Siddhartha Mukherjee, oncologist, researcher, and author of the Pulitzer Prize-winning book, The Emperor of All Maladies: A Biography of Cancer, discusses his writing process, his thoughts about medicine, cancer, immunotherapy, and his recent collaboration on a study combining a ketogenic diet with a drug in mice that provided remarkable and encouraging results.

We discuss:

Sid’s background [5:00];
How Sid and Peter met [6:00];
Sid’s Pulitzer Prize-winning book: The Emperor of All Maladies [8:00];
Sid’s writing process: the tenets of writing [12:30];
Our struggle to find preventable, human, chemical carcinogens of substantial impact [23:30];
The three laws of medicine — Law #1: A strong intuition is much more powerful than a weak test [26:30];
Law #2 of medicine: “Normals” teach us rules; “outliers” teach us laws [32:00];
Law #3 of medicine: For every perfect medical experiment, there is a perfect human bias [35:00];
The excitement around immunotherapy [38:15];
The story of Gleevec [46:00];
How does the body’s metabolic state affect cancer? [49:30];
Can a nutritional state be exploited and/or a drug sensitivity be exploited through a nutritional intervention? [52:00];
How does Sid balance his family, writing, research, laboratory, and patients? [1:00:30]; and
More.

Last edited by s93uv3h : Wed, Dec-19-18 at 10:50.
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  #159   ^
Old Wed, Dec-19-18, 12:03
Ms Arielle's Avatar
Ms Arielle Ms Arielle is offline
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teaser--- love your stuff... definitely an eye crossing read but well written enough for me to follow it...... and leave me with a basic question. How does this cocktail of drugs ONLY target the cancer cells? Seems to me all cells generate NAD+... and id there a benefit to long exercise like running where lactic acid comes into play ( if Im remembering correctly)...???

Essentially, would an exercise regime that induces lactic acid be beneficial to killing off cancer cells??????
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  #160   ^
Old Wed, Dec-19-18, 12:39
teaser's Avatar
teaser teaser is offline
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Plan: mostly milkfat
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Non-cancerous cells should be able to serve their energy needs more through free fatty acids, producing less lactic acid. There might be a problem here for exercise tolerance with the drug combination.

Lactate is mostly cleared after exercise by cells that can use it for energy, the brain and heart like it. In heavily fat adapted states, like prolonged fasting or probably in a high fat ratio ketogenic diet that sort of approaches the fasted state, lactate released by muscle is mostly preserved for gluconeogenesis by the liver. I could see exercise being good or bad, on the one hand it's a glucose sink, on the other hand, releasing lactic acid produced through exercise is one of the ways that muscle can contribute to whole body glucose metabolism, by providing carbon for gluconeogenesis.

It's not as easy as increasing lactic acid, cancer cells already do that themselves, you'd have to keep it in the cell somehow.
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  #161   ^
Old Thu, Dec-20-18, 09:05
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GRB5111 GRB5111 is offline
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Plan: Very LC, Higher Protein
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teaser, the link you provided above takes me to "Neanderthal genes give clues to human brain evolution" Science Daily article. Don't think that's where you intended it to go, but interesting nonetheless. Now I know that when accused of being a Neanderthal, I can enthusiastically agree . . .
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  #162   ^
Old Thu, Dec-20-18, 10:03
teaser's Avatar
teaser teaser is offline
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Plan: mostly milkfat
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https://www.sciencedaily.com/releas...81211113024.htm

Whoops. Must have hit the back button or something when I went to get the link.
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  #163   ^
Old Thu, Dec-20-18, 12:49
Ms Arielle's Avatar
Ms Arielle Ms Arielle is offline
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Plan: atkins, carnivore 2023
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Quote:
Originally Posted by teaser
Non-cancerous cells should be able to serve their energy needs more through free fatty acids, producing less lactic acid. There might be a problem here for exercise tolerance with the drug combination.

Lactate is mostly cleared after exercise by cells that can use it for energy, the brain and heart like it. In heavily fat adapted states, like prolonged fasting or probably in a high fat ratio ketogenic diet that sort of approaches the fasted state, lactate released by muscle is mostly preserved for gluconeogenesis by the liver. I could see exercise being good or bad, on the one hand it's a glucose sink, on the other hand, releasing lactic acid produced through exercise is one of the ways that muscle can contribute to whole body glucose metabolism, by providing carbon for gluconeogenesis.

It's not as easy as increasing lactic acid, cancer cells already do that themselves, you'd have to keep it in the cell somehow.


Am I understanding this correctly---

with a keto diet, the blood level is maintained at standard 1-2 tsp of glucose, but the total energy needs of the cells cannot be met via glucose, nor gluconeogenesis, hence the current thinking that a body in ketosis at all times could starve the cancer cells. Can the cancer cells get enough fuel thru gluconeogenisis? There is one place I learned that while in fasting state the body "cleans" itself of extraneous cells including the cancer cells......so Im thinking there is a tipping point in this balance of energy where the body must goto the body itself for supplies because no food inake for X length of time. Perhaps due to ketosis the body can make the adjustment with ease when ketosis and fasting are a regular event.
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  #164   ^
Old Thu, Dec-20-18, 12:56
Ms Arielle's Avatar
Ms Arielle Ms Arielle is offline
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Plan: atkins, carnivore 2023
Stats: 200/211/163 Female 5'8"
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https://www.sciencedaily.com/releas...81213142153.htm
THis neanderthal skull looks much like the binding seen in ..... ancient Egyptians, as I recall.

A separate article/ documentary looked at the inclusion of neanderthal genes in the current modern human; we all have a few of the original genes, and when many people looked at together as a resource, the entire genome still exists.
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  #165   ^
Old Thu, Dec-20-18, 22:56
teaser's Avatar
teaser teaser is offline
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Posts: 15,075
 
Plan: mostly milkfat
Stats: 190/152.4/154 Male 67inches
BF:
Progress: 104%
Location: Ontario
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A tumor might have a high metabolic rate. But as a percentage of the total body mass, it's pretty small-- a rate of gluconeogenesis that couldn't keep the whole body ticking away on glucose might still be substantial for any cells or groups of cells self-serving enough to take more than their share.

In the case of exercise, glycogen depleted muscle is likely to want to take in glucose, so cancer would probably have to compete with muscle for that glucose anyways.

Setting aside exercise itself--metformin does work in part by reducing gluconeogenesis, making it obvious why related predecessor drugs had the problem of inducing lactic acidosis.

A quick google gives a bunch of stuff leaning towards a protective effect of exercise--including a paper called "Cancer and Exercise: Warburg Hypothesis, Tumour
Metabolism and High-Intensity Anaerobic Exercise"

You hardly ever get anything that on target. I haven't read it yet. Google linked to a direct download of the pdf, so I can't link to it, but I'm sure you'll get the same link if you search the title.
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