Tuesday, October 01, 2013

Polycystic Kidney Disease and mTOR

I think I'm pretty well out of blogging time for the next month or so, so the post looking at fatty acids, uncoupling and insulin resistance will have to sit on the back burner while I work on an anaesthesia project. A friend emailed me a paper with this rather nice diagram of the probable aetiopathology of polycystic kidney disease. Whenever I see mTOR driving pathology I always think of ketogenic eating to obtund the process. If you carry PKD genetics I don't see any other remotely sensible option...























No Reverse Warburg Effect here. I love the 2-deoxyglucose too. If there was ever a way of faking a ketogenic diet, this is it. More so than ketone esters! A bit of physiological insulin resistance or a drug to block glycolysis? Or how about a modern mTOR inhibitor? I'll leave it open to guesswork (or Pubmed if you must) what a ketogenic diet does to mTOR signalling.

Peter

37 comments:

George Henderson said...

Co-incidentally this turned up today
http://www.ncbi.nlm.nih.gov/pubmed/10397635
2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: evidence for the involvement of stress proteins.

Linked to this great Scientific American article about ketogenic diets for neurological diseases
http://blogs.scientificamerican.com/mind-guest-blog/2013/10/01/the-fat-fueled-brain-unnatural-or-advantageous/

liv said...

They know for almost a decade that mTOR is out of control in PKD. Clinical trials are currently at Phase III(whatever that means) concerning Everolimus ( "new" mTOR inhibitor) and Rapamycin (the "old" one).
This is a 2011 article: The ketogenic diet inhibits the mTOR pathway

How come noone thinks about trying the KD in PKD?

ItsTheWooo said...

Another disease that responds well to KD warranting clinical trials... yet no 1 curr.

Drugs = $$$$

Bacon & almonds = No $$$$ :( :( :(

Galina L. said...

There are many deceases of an abnormal tissue proliferation. I am thinking at the moment about the macular degeneration, which is caused by the abnormal blood vessel growth. I know a person who is suffering from it.

kulimai said...

8 years ago one might have reasonably conjectured that mTOR blocking might be sufficient or helpful by itself for this disease. But by now this does not seem too likely:


Only a limited amount of clinical evidence from randomized controlled trials is currently available to evaluate treatment options. This includes ... a set of studies that fail to show a clear therapeutic benefit of everolimus or sirolimus in PKD progression. PMID: 23538311



Based on the current limited clinical trials, this study suggests that short-duration mTOR inhibitor therapy is relatively safe to slow down the increase in kidney volume in patients with early-stage ADPKD, but it has limited impact on slowing down the decrease in GFR PMID: 22902868

In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. PMID: 20581391

Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment PMID: 20581392

...

Jane said...

Peter, have you seen the new paper about beta-hydroxybutyrate inhibiting histone deacetylases?
http://www.ncbi.nlm.nih.gov/pubmed/23223453

You will remember that butyrate is the classic HDAC inhibitor. It never occurred to me that beta-hydroxybutyrate might do it too. I think this is a really big deal. Suddenly there's no mystery any more about how ketogenic diets work.

'Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress. ...Mitochondrial superoxide dismutase (Mn-SOD) and catalase are two other well-defined FOXO3A targets that contribute to its protective activity against oxidative stress (15, 17). Protein immunoblotting of kidney tissue isolated from PBS- or βOHB-treated mice showed increased expression of FOXO3A, Mn-SOD, and catalase...'

Our old friend MnSOD again. Who'd have thought it.

BTW, inhibition of mTOR works by increasing autophagy, I expect you know all about that.

Peter said...

kulimai, thanks. Are they trying 2deoxyglucose yet? I know it has been looked at for basic toxocity in humans and there is a tolerable dose. It has always puzzled me that simply altering the transcription factors might be beneficial when you don't actually alter the metabolism in a manner appropriate to the transcription factor change. But Cynthia Kenyon's review a few years ago suggest that this might work. Seems doubtful to me. A better approach would be to alter the whole metabolism.

Jane, again I'm not comfortable with dropping ketones on a glucose based metabolism, but under LC, all well and good. I can't see from the abstract and no time for the paper, but can you explain the changes in terms of dropping delta psi as the trigger for all of the down stream changes in transcription factors?

George, just thinking around; blocking glucose metabolism in in-tact brains might stop the drive of hyperglycaemia through mtG3Pdh to limit reverse electron flow through complex I...

The cell culture was 10mmol/l glucose (brownie points for being up front with glucose concentration to the group) which is 180mg/dl, well above our rule of thumb of 140mg/l for glucotoxicity...

Peter

Bill said...

Ha! Result #6 from a Pubmed search of ketogenic and mTOR:

"The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076631/

O Numnos said...

Hmmm...

The vaguely commical presentation of the diseased kidney in that graphic led me to do an image search for "polycystic kidney disease" .. I now really wish I hadn't..

Regarding IGF1 stimulating the mTor pathway. A while back I radically reduced my milk consumption (standard UK pasteurised milk) as I was concerned about insulin/IGF1 spiking. However, I'm currently consuming a lot of milk, approx 1500ml/day.

There appears to be a lot of "agenda" driven opinion about milk consumption and IGF1 in particular.

Should I be concerned about consuming milk in this context at all or perhaps not so much in the case of a ketogenic diet?

liv said...

This one (2013 october) sounds promising.

http://link.springer.com/article/10.1007%2Fs00109-013-1057-6

Jane said...

Hi Peter
Yes I think it all works. Delta psi is about superoxide, according to your Protons series. The magic is done by H2O2, which is made from superoxide by MnSOD. This H2O2 goes to the nucleus and activates transcription of many genes, which is how MnSOD makes flies and worms live longer.
http://www.ncbi.nlm.nih.gov/pubmed/18067683

So the pathway goes beta-hydroxybutyrate --> FOXO3A --> MnSOD --> many genes. Now interestingly, these genes include ones for autophagy. I don't see how ketogenic diets could be remotely beneficial if they didn't increase autophagy, and we know they do, just like mTOR inhibition does.

kulimai said...

"alter the metabolism in a manner appropriate to the transcription factor change" Yes indeed, in principle (for curative intent) but is it likely to help here? Consider calorie restriction, another strong mTOR blocker. With zillions of PKD patients on a diet a positive effect would have been difficult to miss.

Peter said...

kulimai,

I'm not so sure you would pick this up epidemiologically in humans. Would you expect the see the longevity effects seen in caloric restriction models as a clear cut effect in Weight Watchers members???? Not so sure on that one.

Now anorexics might be more interesting, but only if they were as well nourished as a weight-stable ketogenic eater might be...

Peter

Galina L. said...

But starvation is very socially appropriate (unless it is a medical condition like anorexia). Weight Watchers always present self-deprivation as the enjoying-food-in-moderation activity.

js290 said...

http://youtu.be/hHbYqrv3Dq8?t=2m49s

"Sugar and protein are the two nutrients that regulate the three parallel pathways that control again in humans: Leptin, Insulin, mTOR." --Dr. Ron Rosedale

Dr. Rosedale pointed out in his AHS13 talk that fat was essentially a "free fuel" that didn't stimulate leptin, insulin, or mTOR. Nature knew exactly what to do with a fuel that supplied more ATP.

Beta Hydroxybutyrate said...

js290,

I believe Rosedale is right about fat being a free(er) fuel. I had a CRONie show me a study supposedly supporting his claim that fat restriction will lead to longer life than carb restriction.
http://www.pnas.org/content/109/19/E1201.full

When I looked at the study for myself, I saw that the ad-lib, high fat mice had indeed died earlier but they had also become obese. When I compared the calorie restricted HF group with the ad-lib LF group, I saw they had similar calorie intakes and the HF group lived longer.

LF (mean = 127, 148.7 ± 3.1 maximum)
HF+CR (mean = 137, 161.9 ± 1.5 maximum)

LF (12.29 kcal)
HF+CR (12.03 kcal)

HF+CR gained 10 weeks mean and 13 weeks maximum life span over LF.


It does look like, calorie for calorie, fat is the "freer" fuel. And unlike these mice, humans tend to spontaneously reduce calories and LOSE weight on LCHF, delivering a one-two punch to the grim reaper.

Beta Hydroxybutyrate said...

... and I doubt above HF mice were even ketogenic. Keto mice actually don't gain weight. They lose the same amount as CR mice. http://www.ncbi.nlm.nih.gov/pubmed/17299079

I'm willing to bet they'd have lived even longer had they been ketogenic.

Peter, sorry for going off topic. Love your blog and your work!

kulimai said...

Peter, if you think about it, the CR and longevity epidemology metaphor, while an interesting issue, may not be relevant. With PKD the setup is quite different. There is a large population that will have had say a yearly GFR test and US. You don't have the intuition that if CR had any noticeable effect on progression then (almost by definition) it would have been noticed and conjectured? There would have been so many opportunities and so many people have been on the lookout for anything that might be remotely helpful. k.

Jack Kruse said...

We have to get biology back to reading basic physics. I completely explains why ketosis works and why mTOR gets inhibited. Electrons give chemicals their specific chemical phenotype in chemistry. It seems many biochemists and paleo folks may have forgotten that very basic natural truth too, when we speak about foods. When electron density goes down in chemistry, life also begins to simplify because of a lack of energy to split electrons from water. This limits life ability to survive. This is why water chemistry matters huge to life and to the marine food chain. This is where we need to be focusing attention and not on macronutrients. When you realize what I am saying at avery foundational QED level it begins to make sense why carbs only give 36 ATP and why fat gives us 147 ATP via beta oxidation. Everyone seems to forget the energy of the sun, the photoelectric effect carries power to energize of excite electrons. These electrons are what give chemicals and foods their specific ability to act in a biologic system. Einstein showed us definitively that energy changes the structure of matter. Proteins are matter........proteins are the stage that biochemistry occurs upon...........if electromagnetic energies are varied...........you get structural changes in proteins to change what biochemistry does. The cytochromes of the inner mitochondrial membrane change and alter their quantum behavior as the environment changes around them too. They are designed to perform quantum tunneling of electrons to oxygen. They also couple to protonicity in membranes that respond to specific electromagnetic frequencies in cells.......and that info is channeled to telomeres. When the variables change biochemistry changes. People find it hard to fathom, but it is precisely what happens on a star. It burns hydrogen to helium and helium eventually to iron before it blows up. The physics of a star are the same ones in us, contrary to what biology believes........hence why the literature of yester year matters little to today......what they studied then is not the electromagnetic field we see today. This is why researchers were wrong on their prediction of primates and CRON data with respect to mTOR activation and it is why obesity researchers remain completely clueless on matters tied to obesity. The world is no longer as it was in 1930's when the calorie restriction data were done at Cornell........all the data obesity researchers hang their hat on was done in a world without non native EMF. Again, if your target is wrong.........what good is your literature? My target is QED for a deep reason. Its the way nature works.

Sabine said...

This has nothing to do with this blog, which I still have to read.

http://www.sciencedaily.com/releases/2010/12/101222131125.htm

This article talks about reduced abilities to manufacture ketone bodies in aging mice. I wonder, if this applies to humans, and how this will affect me on a ketogenic diet.

Does anybody know?

Peter said...

Sabine, "And when the mTORC1 pathway was turned off in very young mice that were subsequently aged, these older mice did not experience the decline in ketogenesis found in normal mice. Their ketogenesis levels were similar to younger mice, confirming that continual inhibition of the mTORC1 pathway prevented the aging-induced decline in ketone production"

Ketosis inhibits mTOR in young mice as well as old mice...

kulimai, I guess we will have to wait until a group of PKD patients are encourage to run dipstick +++ 24/7 for ketonuria.

Peter

melchiormeijer said...

Sabine, I'm re-reading 'Survival of The Fattest; The Key to Human Brain Evolution' by Stephen Cunnane. I was surprised to learn that humans are uniquely capable of inducing ketosis among mammals. Infants and toddlers, with their fuel guzzling growing brains are always in ketosis, no matter how many carbs they eat, just because the brain needs this superior fuel, according to Cunnane. In fact this capacity to create relatively huge amounts of ketones allowed us to become sapiens. As we get older this capacity decreases somewhat. I'm starting to suspect that Alzheimer's and other neurodegenerative diseases are at least partially a result of a structural lack of BHB, due to constant (and very unnatural) carbohydrate availability.

I'm sure this is not new to Peter, but I just had to vent what I read (and this time understood) last night ;-).

Jack Kruse said...

@melchiormeijer this is why the human brain does it....Cunnane and Crawford's work in human brain evolution is critical to figuring this maze out if youre going to come at from biology's side. I have said this for three years. But coming at it from physics is way easier to understand...http://www.jackkruse.com/energy-epigenetics-1-the-infant-brain-is-unique/

Jane said...

Peter, I've been trying to find out how ketogenesis inhibits the mTORC1 pathway, and I found something very interesting. It turns out that FOXO3A induces the mTORC1 inhibitor TSC1.
'FOXO3A regulates glycolysis via transcriptional control of tumour suppressor TSC1'
http://www.ncbi.nlm.nih.gov/pubmed/20371605

So the pathway goes beta-hydroxybutyrate --> FOXO3A --> TSC1 --> mTORC1 inhibition. This means TSC1 would increase autophagy, and here's a paper showing that.
'TSC1 (hamartin) confers protection against ischemia by inducing autophagy'
http://www.nature.com/nm/journal/v19/n3/full/nm.3097.html

Since mTORC1 blocks ketogenesis by inhibiting PPAR alpha, this means that FOXO3A induces PPAR alpha and ketogenesis. So the complete pathway goes like this.
Beta-hydroxybutyrate --> FOXO3A --> TSC1 --> mTORC1 inhibition --> PPAR alpha --> ketogenic genes.

Ketogenesis induces ketogenic genes! Don't you think that's interesting? This has to be how ketogenic diets work. The only problem would be in getting enough Mn for MnSOD. You know in Anglo-Saxon England, epilepsy was treated with lupine, which is 'exceptionally high in manganese'.
http://www.ncbi.nlm.nih.gov/pubmed/11420453

Jack Kruse said...

And if you knew what non native EMF does to Mn you'd really get why some people keep think they need carbs to perform.

Jack Kruse said...

http://www.emf-portal.de/viewer.php?aid=21860&l=e

The manganese study

Jack Kruse said...

TSC1 gene is the tuberous sclerosis one gene. A disease my specialty knows very well. This gene is the target when MnSOD is affected by non native EMF. One of the things it alters is neurogenesis. Tuberous sclerosis is one disease it catches but the big one is autism. Autism now affects 30 to 60% of patients with tuberous sclerosis complex (TSC). Biology has not made the linkage yet to the genetic mechanism because there is not one. It is epigenetic and mediated by the hydroxyl free radial altering DNA methylation of the TSC1 gene Jane mentioned. Through the small G-protein R-heb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. This is how it happens. mTORC1 plays a pivotal role in neuronal translation and synaptic connectivity, so dysregulation of mTORC1 signaling becomes a common feature in many spectrum diseases. Pam, an E3 ubiquitin ligase, binds to TSC proteins and directly regulates mTORC1 signaling in the brain and spinal cord. The FBXO45-Pam ubiquitin ligase complex Jane mentions above plays an essential role in neurodevelopment by regulating synapse formation and growth. The best treatment for these disease......is a ketogenic Epi-paleo Rx template. This is why and I am trying to show many just how the infant brain is different for a deep deep reason.....y'all are just hitting it from the complex end. I can play in both world's. I believe if you understand the problem both ways you can really help patients stay optimal.

melchiormeijer said...

Another pearl from Cunnane's book: sufficient iodine is crucial for proper ketogenesis. If I understand him correctly, cretinism is just as much about impaired (or absent) ketogenesis as it is about hypothyroidism.

Isn't that wonderful :-)?

Sorry if this is off topic.

James said...

Look, it's a low carb diet in a pill:

http://www.reuters.com/article/2013/10/09/us-novonordisk-oramed-oralinsulin-idUSBRE99804N20131009

Richard Weir said...

Peter, enormous and pre-emptive apologies for this off-topic diversion, but I have an appeal for help I'd like to make.

My uncle is on the wrong side of brain cancer battle, and it has come to the point where any option is on the table (some relatives called a faith-healer, who made his excuses and hung up). I've decided to speak up and advocate ketosis, working on the theory that starving cancer cells of glucose is a means of fighting it. Maybe it will work, I don't know; someone tell me if it's worth the time of day.

Now, I understand that ketosis has been used in stage IV patients before, but I have no idea where or when, or the degree of success (though I do recall having a feeling of vindication, as a pro-fat kinda guy).

I'm asking if anyone here has any input about such a proposal? I'd very much like to keep my uncle around, he's one of the good guys.

Again, apologies, and thanks.

Neil F said...

Richard.

Contact Dr. Thomas N. Seyfried at Boston College. He wrote the book, "Cancer As A Metabolic Disease".

Or:

Dr. Dominic D'Agostino at the University of South Florida:

http://ketonutrition.org/

milecar said...

Paul Wasserman–son of French food dictionary wine importer Becky–has just launched EatDrink, a company that sells gorgeous reprints of old wine books like 1927's Bouquet (above) by G.B. Stern, which follows a couple's journey through the vineyards of France.

js290 said...

@Richard Weir:

Targeting insulin inhibition as a metabolic therapy in advanced cancer. Part 2. The hypothesis.

Jack Kruse said...

js290 that hypothesis is very adult centric and misses the big factor.......all human infants require massive amounts of ketosis by human brain design....Moreover the infant brain is an unreal energy hog and it can not properly use glucose to fully develop. This is why iodine, DHA, fat, and sleep are part of the witches brew for optimal human brain development and function. Once the adult brain is complete at 25-27 yrs old this hypothesis is fine......For a sick human brain you'd be wise to revisit how evolution built the brain in an infant minus the human hypothesis biases. ..and the amount of glucose the brain needs is badly over estimated by most.

Peter said...

Been away,

The links look useful. Hope they help

Peter

Richard Weir said...

Thanks for the input everyone, particularly the wine reprints!

Too soon to hear back from the home front on the other side of the planet; if anything comes of this, I'll let you all know.

steve whitaker said...

@richard weir

try the following also, might be worth a read.

http://www.naturalhealth365.com/ketogenic_diet

steve w