Decline In Mitochondrial Function Is What Triggers Cancer

[haidut]

According to this study, the process of mitchondrial function decline, as seen in aging, creates a state of chronic hypoxia by inducing HIF-1 (which also happens to powerfully promote cancer). In fact, the following quote form the study reads like it could have been written by Ray Peat himself.

http://www.cnd.mcgill.ca/~ivan/age-reve ... mpound.pdf

"...Next, we sought to understand how SIRT1 regulates mitochondria independently of PGC-1alpha. Analysis of SIRT1 KO animals indicated that genes involved in glycolysis were upregulated, with increased lactate levels and a switch from slow-twitch oxidative fibers to fast-twitch glycolytic fibers. These metabolic changes were reminiscent of Warburg remodeling of metabolism in cancer cells, which is known to be mediated, in part, by the stabilization of the transcription factor HIF-1."

The mitochondrial decline process is mediated through falling levels of NAD+ and thus lower NAD/NADH ratio, putting the cell in a reduced state. The scientists used carolic restriction to raise NAD, which is something we know Ray does not endorse as he thinks the process will actually put the body in a stressed mode and further damage cells.
However, as we know, niacinamide raises NAD levels and thus the NAD/NADH ratio so this could be another strategy in reversing the decline in NAD and NAD/NADH.

 

[Such_Saturation]

Re: Decline in mitochondrial function is what triggers cance

I wonder if "explosive workouts" naturally benefit "fast-twitch" fiber.

 

[haidut]

Re: Decline in mitochondrial function is what triggers cance

I wonder if "explosive workouts" naturally benefit "fast-twitch" fiber.

That's the part that concerned me a bit. Slow-twitch fibers are associated with endurance training and fast-twitch ones with weight lifting. Does the study suggest that things like walking and running are better for the mitochondria and cancer than resistance training? If yes, that would go against Ray's preference for building up muscle to burn fat at rest.

 

[Such_Saturation]

Re: Decline in mitochondrial function is what triggers cance

I wonder if "explosive workouts" naturally benefit "fast-twitch" fiber.

That's the part that concerned me a bit. Slow-twitch fibers are associated with endurance training and fast-twitch ones with weight lifting. Does the study suggest that things like walking and running are better for the mitochondria and cancer than resistance training? If yes, that would go against Ray's preference for building up muscle to burn fat at rest.

It looks like they use ATP in the first second and phosphocreatine in the first ten or so seconds, so anaerobic without lactic acid. If we keep sets very short and give about three minute intervals we should be fine. One maximal repetition should necessarily deplete phosphocreatine. This is all from Wikipedia of course. Ray Peat only advocates slow movements with light weights as far as I know. He also claims that anything faster than walking pace would not be "aerobic" regardless of the type of fiber, at least in the real world.

 

[M Scott]

Re: Decline in mitochondrial function is what triggers cance

So if I understand the paper correctly decreased NAD+ increases the actions of HIF-1 which damages mitochondrial function, so the cell resembles a hypoxic cell but may not necessarily be low in oxygen?

Thanks for linking this paper, it's quite interesting. I've been doing a lot of research on hypoxia's effect on cancer by increasing HIF-1, damaging mitochondria, and leading to lactic acid glycolysis (helping explain the Warburg effect) but this seems to provide an alternative road to this end.

I find the explanation that cancer is driven heavily by a destructuring of the cell's structure a compelling mechanism behind many of these observations but it's hard to find studies with methods designed to confirm this. Does anyone know of some good ones?

 

[Suikerbuik]

Re: Decline in mitochondrial function is what triggers cance

M Scott, basically reduced NAD+/NADH ratio means your electron transport chain isn't functioning well. Also ask Such_Saturation, he made some post recently one with a paper called "energy management - a critical rle in cancer induction" :).

 

[M Scott]

Re: Decline in mitochondrial function is what triggers cance

Suikerbuik - ah yes, that makes sense now, since the ECT turns NADH into NAD+. So I wonder what factors are responsible for this loss of function. This paper seems to focus on aging as a cause and NMN as a solution but I'm sure there's a lot more to it.

 

[Such_Saturation]

Re: Decline in mitochondrial function is what triggers cance

I think you're right! That Garland J. is particularly progressive in his explanation of the "new" boatload of evidence that is being thrown around. Konradin Metze reviews some experiments about structure that target the tidiness of nucleus packing. It's hard to do these experiments because you would want ideally a three-dimensional scan of the DNA which needs very advanced techniques. Also, compression of this data means you can't use the mathematics to extract a meaningful result anymore so ideally you need raw data to show the fractal characteristics. You can find them here viewtopic.php?f=10&t=4535

 

[Suikerbuik]

Re: Decline in mitochondrial function is what triggers cance

So I wonder what factors are responsible for this loss of function.

That's what Peat's work is all about :), pufa, low thyroid, chronic inflammation (allergies for example), serotonin, toxins (including excess iron), stress, excess estrogen, ...

 

[charlie]

Re: Decline in mitochondrial function is what triggers cance

Ray Peat talks about NADH in the latest radio interview on "Longevity".

viewtopic.php?f=41&t=5042

 

[Peata]

Re: Decline in mitochondrial function is what triggers cance

Haidut, do you (or anyone else here) know where Metformin (glucophage) fits into this?

This is from wikipedia:

Metformin decreases hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis).[66] The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.[85] The molecular mechanism of metformin is incompletely understood: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP), and consequent activation of protein kinase A (PKA), inhibition of mitochondrial glycerophosphate dehydrogenase, and an effect on gut microbiota have been proposed as potential mechanisms.[86][87][88] Activation of AMPK, an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats,[89] was required for metformin's inhibitory effect on the production of glucose by liver cells.[90]

Activation of AMPK was required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes Phosphoenolpyruvate carboxykinase and glucose 6-phosphatase.[91] Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. More recent studies using mouse models in which the genes for AMPKα1 and α2 catalytic subunits (Prkaa1/2) or LKB1, an upstream kinase of AMPK, had been knocked out in hepatocytes, have raised doubts over the obligatory role of AMPK, since the effect of metformin was not abolished by loss of AMPK function.[86] The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate).[92] Increased cellular AMP has also been proposed to explain the inhibition of glucagon-induced increase in cAMP and activation of PKA.[86] Metformin and other biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.[93] Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice and this may contribute to its mode of action possibly through an effect on glucagon-like peptide-1 secretion.[87]

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation,[94] and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors.[95] The increase in insulin binding after metformin treatment has also been demonstrated in patients with NIDDM [96]. AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle.[97] AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.[98

 

[Peata]

Re: Decline in mitochondrial function is what triggers cance

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

William W Wheaton, Samuel E Weinberg, Robert B Hamanaka, Saul Soberanes, Lucas B Sullivan, Elena Anso, Andrea Glasauer, Eric Dufour, Gokhan M Mutlu, GR Scott Budigner, Navdeep S ChandelCorresponding Author

The Feinberg School of Medicine, Northwestern University, United States; University of Tampere, Finland
DOI: http://dx.doi.org/10.7554/eLife.02242Published May 13, 2014 Cite as eLife 2014;3:e02242
Abstract

Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.

Full Text

 

[thebigpeatowski]

Re: Decline in mitochondrial function is what triggers cance

Eegads, I sure wish I could understand all of this. Unfortunately I don't have anywhere near the brain capacity...sigh.

So Peata, you have taken Metformin and also gone for periods without it , correct? What differences do you notice? How is your gut flora affected by Metformin? This stuff fascinates me, I just wish I could grasp it better.

 

[haidut]

Re: Decline in mitochondrial function is what triggers cance

Haidut, do you (or anyone else here) know where Metformin (glucophage) fits into this?

This is from wikipedia:

Metformin decreases hyperglycemia primarily by suppressing glucose production by the liver (hepatic gluconeogenesis).[66] The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.[85] The molecular mechanism of metformin is incompletely understood: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP), and consequent activation of protein kinase A (PKA), inhibition of mitochondrial glycerophosphate dehydrogenase, and an effect on gut microbiota have been proposed as potential mechanisms.[86][87][88] Activation of AMPK, an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats,[89] was required for metformin's inhibitory effect on the production of glucose by liver cells.[90]

Activation of AMPK was required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes Phosphoenolpyruvate carboxykinase and glucose 6-phosphatase.[91] Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. More recent studies using mouse models in which the genes for AMPKα1 and α2 catalytic subunits (Prkaa1/2) or LKB1, an upstream kinase of AMPK, had been knocked out in hepatocytes, have raised doubts over the obligatory role of AMPK, since the effect of metformin was not abolished by loss of AMPK function.[86] The mechanism by which biguanides increase the activity of AMPK remains uncertain; however, metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate).[92] Increased cellular AMP has also been proposed to explain the inhibition of glucagon-induced increase in cAMP and activation of PKA.[86] Metformin and other biguanides may antagonize the action of glucagon, thus reducing fasting glucose levels.[93] Metformin also induces a profound shift in the faecal microbial community profile in diabetic mice and this may contribute to its mode of action possibly through an effect on glucagon-like peptide-1 secretion.[87]

In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation,[94] and decreases absorption of glucose from the gastrointestinal tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors.[95] The increase in insulin binding after metformin treatment has also been demonstrated in patients with NIDDM [96]. AMPK probably also plays a role, as metformin administration increases AMPK activity in skeletal muscle.[97] AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some metabolic actions of metformin do appear to occur by AMPK-independent mechanisms; the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.[98

I posted some stuff on Metformin months ago. As far as I can remember it was not very positive in light of Peat's ideas and he has also said he does not recommend using it. I think most of the negatives come from the fact that the drug increases fat oxidation, which will increase the tress response even more. Fr diabetes, instead of reducing gluconeogenesis and increasing fat oxidation, you need a drug that inhibits fat oxidation and sensitizes the cells to glucose. In Peat land, the combination of taurine (insulin mimetic) and niacinamide (fatty acid oxidation inhibitor) should achieve these two goals. Niacinamide is well known on this forum, but if you want more info on taurine and its anti-diabetic effects just Google "taurine insulin". Or read this post as a start:
http://suppversity.blogspot.com/2011/08 ... sulin.html

 

[Peata]

Re: Decline in mitochondrial function is what triggers cance

Eegads, I sure wish I could understand all of this. Unfortunately I don't have anywhere near the brain capacity...sigh.

So Peata, you have taken Metformin and also gone for periods without it , correct? What differences do you notice? How is your gut flora affected by Metformin? This stuff fascinates me, I just wish I could grasp it better.

Haven't noticed anything either way over the last several years. I went off it back in April. Then went back on it in Aug or Sept. just to see if it would do anything, but no effect.

 

[Peata]

Re: Decline in mitochondrial function is what triggers cance

I stopped taking it today.

 

[Peata]

Re: Decline in mitochondrial function is what triggers cance

I posted some stuff on Metformin months ago. As far as I can remember it was not very positive in light of Peat's ideas and he has also said he does not recommend using it. I think most of the negatives come from the fact that the drug increases fat oxidation, which will increase the tress response even more. Fr diabetes, instead of reducing gluconeogenesis and increasing fat oxidation, you need a drug that inhibits fat oxidation and sensitizes the cells to glucose. In Peat land, the combination of taurine (insulin mimetic) and niacinamide (fatty acid oxidation inhibitor) should achieve these two goals. Niacinamide is well known on this forum, but if you want more info on taurine and its anti-diabetic effects just Google "taurine insulin". Or read this post as a start:
http://suppversity.blogspot.com/2011/08 ... sulin.html

Sounds like an energy drink per day would be good (plus it has the caffeine). I have some niacinamide around but stopped taking it a while back. Taurine, I'll have to look and see if I have any. I wonder about taking the doses 3 x per day like I was doing with metformin.

 

[Amazoniac]

Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate

"The recognition that proliferating cells do not maximize ATP production through mitochondrial oxidative phosphorylation has contributed to the continuing misconception that proliferating cells, particularly cancer cells, do not utilize mitochondria. In fact, most cancer cells and proliferating normal cells still derive a significant fraction of their ATP through oxidative phosphorylation. However, in proliferating cells, in contrast to quiescent cells, this oxidative phosphorylation-dependent production of ATP appears secondary to the use of mitochondrial enzymes in the synthesis of anabolic precursors."

Cancer: disorder and energy
"What has received little appreciation since the work of Krebs and his colleagues is that for many proliferating cells, the major problem is not how to maximize ATP yield, but rather how to maximize the flux of carbon into macromolecular synthetic pathways. In fact, it was first demonstrated in 1973 that glycolysis in proliferating cells is limited by the rate of ATP consumption and not ATP production, as glycolytic enzymes can be inhibited when ATP levels are high (Scholnick et al., 1973). Recent work has revisited how proliferating cells maintain glycolytic flux by either minimizing ATP production or enhancing ATP consumption."

Proliferation is a basic attribute of life... | Ray Peat Forum​

"Unlike ATP, cytosolic NADPH might be limiting for cell proliferation. It is critical for providing reducing equivalents for fatty acid and cholesterol biosynthesis, as well as for modulating oxidative stress."

 

[EndAllDisease]

Yeah absolutely. Cancer is not complicated nor is it anything to fear.
Expose a cell to any poison that disables the highly-sensitive cytochrome c oxidase enzyme and the cell will revert to the cancer metabolism. The other way to cause cancer is by not providing the cell with the vitamin or mineral it needs to produce the enzymes that power metabolism.

The only thing to fear is anybody saying they want to cut you with a knife, inject poison into you or direct ionizing radiation at your body.