Wednesday, July 06, 2016

Arteriosclerosis (6) and Subbotin

It seems a very long time ago that I wrote a series of posts on the mechanism of the development of the arterial tunica intima from a single layer of cells through to a thickened structure of similar or greater thickness than the muscularis layer. I've gone back and re-labelled them under Arteriosclerosis (1) through to (5).

Very briefly: Arteriosclerosis (1) covered the development of diffuse intima thickening (DIT) from birth through to about three years of age. DIT occurs over areas of disrupted elastin, is on the lumenal side of the elastin and is largely composted of glycosaminoglycans (GAG) and a few cells.

Arteriosclerosis (2) covered the role of platelets in supplying ILGF-1 which generates GAG at the site of platelet adhesion. That is where the platelets stick to damaged endothelium and strengthen an area at which the elastic tissue has been ruptured. It is a physiological process of tissue reinforcement.

Arteriosclerosis (3) covered the condition of von Willebrand's Disease, where platelets fail to adhere to damaged tissue. In this condition the intima stays thin and there is no DIT with age, assuming the vWD is not fatal at a young age. The elastin layer gets completely trashed as there no ability to generate reinforcement.

Arteriosclerosis (4) illustrated this process by showing the formation of surface microthombi to deliver platelets and generate GAG, it covered mucoplysaccaride disorders with massive intimal thickening when GAG cannot be degraded/remodelled and introduced the idea of intimal thickening in the arterial supply to the atrioventricular node as a precursor to sudden cardiac death.

Arteriosclerosis (5) is just the pictures to complete part (4).

To summarise: Arteriosclerosis begins as non pathological DIT which is a reinforcement system to maximise the correct development of the arterial tree to best withstand the loads to which it is subjected. It gives a tailor-made cardiovascular system for a given individual.

That's normal.

Subbotin has recently published a review article documenting his view that pathological arteriosclerosis, with lipid infiltration, commences when the tunica intima becomes too thickened to receive adequate oxygenation without developing a vascular supply of its own. It is normally avascular, getting oxygen and nutrients by diffusion from either the arterial lumen or the arterioles embedded in the muscularis layer. Once the thickened tunica intima develops a vascular supply all hell breaks loose with apoB labelled lipids attaching themselves to the GAG on the mistaken basis that this the extra cellular matrix of damaged tissue.

This is a highly plausible scenario and fits with the microscopy much better than any fairytale about apoB lipoproteins sneaking through the arterial endothelium and burrowing deep, deep in to the intima before depositing themselves on the border with the muscularis layer, leaving the surface layer completely unaffected. Which is what the histology shows. Shrug. Never forget: Only purple spotted cholesterol causes CVD, anything else is bollocks.

There are several things which spring to mind about DIT, insulin and oxygenation. If, as I think likely, a general thickening occurs under the effect of chronic hyperinsulinaemia acting on the ILGF-1 receptors which are on the lookout for platelets, we have a reason why insulin, not glucose, drives CVD. Anything which hastens thickening of the tunica intima hastens CVD. Insulin.

Second is that not only do VLC diets drop insulin, but they also reduce tissue oxygen extraction while maintaining normal ATP production. If Subbotin is correct that localised tissue hypoxia is what converts a benign reinforcement area to a fragile pool of lipid, then acetoacetate and beta-hydroxybutyrate (and stearic acid) are your first obvious port of call. AcAc/BHB looks like an excellent tool to blunt the impact of hypoxia on the need for blood vessel invasion of a given tissue.

Third: What happens if you keep insulin high with a diet of complete crap while supplementing ketone esters to reduce tissue oxygen needs? My guess, and it's only a guess, is that intimal thickening will progress apace but will only develop vascularisation at a later stage of the process, when the slack provided by the exogenous ketones has been taken up. Equally, the worry might be that you take ketone esters for a year, living on crap, and then run out of funds while you have thickened avascular DIT which was quite happy under ketones but is then going to need more oxygen per unit ATP under glucose oxidation. At least by going the ketogenic diet route you should have had basal insulin to minimise DIT progression in combination with your AcAc/BHB, up until the time you feel that you'd rather die than continue to live without eating pizza.......



Antonio said...

"Arteriosclerosis begins as non pathological DIT"...

I think it must be one or the other.
I don't see in #1 of your series (also in comments) that you have clearly differentiated the "non pathological" part. Which is actually a normal and healthy thickening.
Anyways I agree mostly with the general view expressed in regards of Subbotin.

Michael Kramer said...

Thank you so much for this. I have been very low carb for years. My LDL-P has been too high at 1533 nmol/L in 2008 and 1831 last year. Given that MESA shows a strong correlation between LDL-P and cardiac events, I decided to stop buying (grass-fed) butter last week and was in the process of eating up my remaining inventory. All this because some low-carbers supposedly see LDL-P decline as saturated fat consumption is reduced.

Although I recognize that the level of speculation is still high, I think I'll stock up on butter on my way home tonight.

ivor cummins said...

Thank you Peter for this post and links. I started a bit of rabble-rousing based on Subbotin's latest paper in recent weeks, and got a bit of interest going. This Pig study also interesting if you've not seen it, and kinda supports good 'ol Subbotin at the end (I'll email it to you):

Down the end of post I've put a couple more links to ApoB chicanery.

I'll admit it - the (1) 'ApoB Particles are inherently dangerous' and (2) 'ApoB's (especially when numerous) sneak in your endo and then detonate' theories....offend me. Especially when stated with smug certainty, simplistically...obvious.

Subbotin appeals to my intuition.
ApoB as problematic only when compromised by other (real) root causes right.

Peter Attia and his mentor Tom Dayspring don't agree though - so maybe I'm all wrong. Oh, and apparently my series of posts attacking ApoB are really annoying some NLA people :-)



Tucker Goodrich said...

The problem with this line of reasoning is that it doesn't really explain how the endothelial damage starts. But there is some evidence about what kicks off that process...

"Whilst relatively low doses of HNE can orchestrate cell signaling events, higher concentrations of HNE appear to modify a further set of target proteins, inhibiting or dysregulating previously functional cellular processes and organelle functions. In particular, endothelial cells, which form the primary vascular interface for potentially oxidized circulating components, appear to be highly susceptible to HNE induced damage [10,85]. HNE can exert a range of pathophysiological effects, including interfering with the synthesis and release of vasoactive mediators, breakdown of the endothelial barrier function and inducing a pro-inflammatory phenotype within the vessel wall."

It also impairs NO, but that's not all!

"Elevated plasma levels of HNE also damage endothelial barrier function [10,87] due to impaired cell–cell communication and inhibition of membrane associated enzymes [85]."

There's also this:

"Cholesterol consumption reportedly increases HNE synthesis [11], with HNE inducing low-density lipoprotein oxidation and increased uptake by macrophages [12], and HNE accumulation within atherosclerotic plaques [13].

"Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease"

Another paper sums it up thus:

"Both HNE and oxysterols then appear to be candidates for a primary role in the progression of the atherosclerotic process."

"4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis"

But even that's not all!

"Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells...."

"The accumulation of 4-HNE-adducts is very high in the intimal aorta, mainly in older patients with high atherosclerosis grade. These data were expected since oxidized LDL and lipids accumulate in the intima in the early lesions and in the lipid core of advanced atherosclerotic lesions [23,24]. These data confirm that 4-HNE is a main marker of oxidative stress and LDL oxidation which could contribute to the evolution of the lesions via its ability to modify proteins and generate cell dysfunction. 4-HNE expression was also increased in the adventitia of the elderly, probably associated with the vasa vasorum, which are involved in the supplying of nutrients and oxygen to atherosclerotic lesions, and the development of angiogenesis in the atherosclerotic plaque [32,42]. The recently reported angiogenic effect of 4-HNE suggests a role for this aldehyde in the development of vasa vasorum and microcapillaries in atherosclerotic plaque [35,43]."

"Elastin aging and lipid oxidation products in human aorta"

karl said...

@Petro wrote:
"What happens if you keep insulin high with a diet of complete crap while supplementing ketone esters to reduce tissue oxygen needs? "

What happens if you don't eat the crap and still supplement with ketones?

hmm.. (great post as always!)..

It seems to me that we did not evolve to eat high carbs and end up with higher insulin day after day - this exposure appears to be a factor in CAD.

But there is more - the immune system and growth factors over-lap - once again, evolution is not engineering - the reuse of bits of protein that end up having multiple functions seems to be the rule rather then the exception.

Ferinstance - insulin is not just part of a system to regulate BG - it is a growth factor

Immune response also overlaps growth factors and more.. and lipoproteins don't just move lipids around - they are also part of the innate immune system( and probably have other functions as well(moving vitamins).

The point is, when we label something as doing 'X' we are most likely creating a false narrative - biology doesn't work that way - most proteins wear multiple hats.

One such false narrative is the cholesterol mantra that needs a prompt burial. If we bury this false narrative perhaps science can move forward? The cholesterol theory corpse is dead and rotting - time to bury it next to N-rays...

Of course the 'bad LDL' is simpler than understanding the complexity of the immune system. This tendency to want to simplify medicine is understandable, but intellectually lazy and has hurt a lot of people.

What is missing is any conversation about the macrophage receptors that are triggered by oxLDL - which could be LA mediated? Is this effect causative or just accelerates CAD.

My hunch has been that infections occur that trigger a cross sensitivity that starts one of the factors of the disease process of CAD. Sure seems like immune/growth factor stuff. Could be someday we will know - very important to know what we don't know - the folks that 'know' it is cholesterol apparently have stopped looking for any other real cause.

If we humble ourselves and keep looking - there are bits and pieces that we know about cytokines, interleukins, growth factors, and more that form an insanely complex evolved system that is probably only understandable when we understand the evolutionary history of eukaryotic cells. We really need some advanced AI about now..

Jeffrey Patten said...

How does coronary artery calcification work in your scenario?
What function does it perform precisely?
How might one leach it out once it's function is no longer necessary?

Gert van der Hoek said...

Great post, this is a post I was waiting for, Subbotin is in the air lately. He did not point to causes of DIT.

Insulin - rather than glucose - causing DIT seems plausible, could you elaborate on insulin causing DIT?

Tucker Goodrich said...

@Jeffrey Patten:

"How does coronary artery calcification work in your scenario?
"What function does it perform precisely?
"How might one leach it out once it's function is no longer necessary?"

I'll take a swing at this... You can make calcification happen by giving a rat warfarin (coumadin) aka rat poison, in small doses. This blocks production of vitamin K1, which affects clotting (which is why warfarin is used to prevent clotting), but since it's blocking K1 it also is blocking conversion of K1 to K2. K2 affects calcification, and seems to be the driver for calcifying things you want calcified, like bones and teeth. K2 is used to treat osteoporosis in Japan, for instance.

Give a rat warfarin, they get calcification. Give them K2, and it goes away.

K2 is mostly found in foods that we're not supposed to eat because of evil-saturated-fat, so arterial calcification may simply be a factor of Modern-American-Diet-induced malnutrition.

Or warfarin.

My father's idiot cardiologist prescribed him warfarin for atrial fibrillation, and then had to do stents (was quite pleased to do stents I'm sure) to deal with subsequent calcification.

Gert van der Hoek said...

Once the endothelium has been damaged, more predators come in? Causing more damage?

"Zonulin Regulates Intestinal Permeability and Facilitates Enteric Bacteria Permeation in Coronary Artery Disease"

Peter said...

Hi folks, not much time now but these might shed some light on calcification:


Tucker Goodrich said...

Peter, I'll see your "may" and I'll raise you:

"With respect to CV calcification, the only consistent inverse associations to date are between dietary and serum MK4 and the calcium score, which may be reflected in a lower incidence of CHD. In addition, human and animal trials show that both MK4 and phylloquinone significantly reduce CV calcification. While the mechanism may be principally through the γ-carboxylation of MGP, vitamin K also has anti-inflammatory and other properties."

But for sure there's a influence of glucose/insulin, as diabetic patients are also most at risk for calcification, although they're obviously also the ones eating the worst diet...

Passthecream said...

@Peter, perhaps the Lp(a) posts also belong in this or a related series. I particularly enjoyed the hedgehog material. Then there's the vit d stuff. So many valuable and stimulating insights in all this that it's hard to know where to point first

@Karl, my experience and that of several others is that mct or ketone salt intake can stimulate an insulin response (fly-crash-burn) even without carbs. Its a suspiciously familiar addictive-type pattern.


Jeffrey Patten said...

Thanks, folks. But . . .
My agatston score of two years ago - age 70 - was 1,640. Surprise!
My A1C has never been above 5.7%. A bit highish, but THAT high?
Don't know what my insulin levels were back a few years when I was doing diet according to "guidelines". Guidelines, of course, called for low fat, high carb - whole or whatever.
For the last ten years I've turned that diet gradually upside-down, anticipating the Establishment.
I know about the K and D connections. Remains to be seen about insulin.
My two questions remain:
K might be the mechanism. But why? What does calcification accomplish? Punishment for a poorly conceived of diet? Heel spurs result from chronic physical abuse and not quite healing properly. Are coronaries the same?
And, is boosting my dietary K2 (menaquinone or menatetranone?) going to improve that Agatston? (I am in vivo and human myself.) :-)
It's a fascinating puzzle. Medical science hasn't really confronted it in depth, it seems.

karl said...

K2-MK4 K2-MK7 apparently has some effect. (really important to not confuse with K1).

I know of a guy that was watching his aortal calcium increase every year with his coumadin therapy. He started K2 supplements and has seen his calcium scores retreat each year.

Of course, that does not mean it is doing good - there is quite a debate if the calcium is better or worse than just unstable plaque. So the question is if regressing the calcium is a 'good thing'. I sort of want hard data - not speculation.

K2 is not likely to see the type of research we need as it isn't patentable - you can get it in natto. There is something of a correlation between the Japanese natto eaters and long lives. But, there is more than K2 in natto - nattokinase acts as a blood thinner. see -

I tried eating natto - not for the squeamish - worse than Limburger.. stringy fermented soybeans - Then there is the smell .. not my cup of tea.

I think the real question is if the increase in CAD is caused by insulin, or LA - or the combination. Let the debate begin.

rjanusonis said...

@Jeffrey Patten

As far as your HbA1c, 5.7-6.4% is considered Metabolic Syndrome/Prediabetes where I practice.

As far as reversing your CT Coronary Calcium (Agatston) Score, with Ketogenic or VLCHF diet with adequate K2, yes it is possible (in my own personal case, I started with Calcium Score of 42, and in 18 months it reversed to 0/Zero). I personally shoot for HbA1c as low as I can achieve (my last was 4.7%).

I get my K2 from a supplement (capsule) and grass-fed butter.

TedHutchinson said...

May I draw your attention to the role of Vitamin D3 in preventing/reducing infection.
Here we see how DAILY cholecalciferol in amounts sufficient to keep 25(OH)D at the level typically found in indigenous peoples and at which bioavailable cholecalciferiol is measured in tissue, reduces H Pylori and other pathogens while improving diversity and number of commensal gut flora.

Infectious and coronary artery disease

Having measurable amounts of vitamim D3 in the basic form, cholecalciferol (half life 24hrs), as a result of DAILY dosing (or UVB exposure) also stabilizes endothelium.
Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium

It is possible Vitamin D3 regulates oxygen supply
1α,25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells.

karl said...

Vit D is interesting - but way too much is read into correlations - (correlations do not show causation) - frail people don't go outside as much as healthy - thus have lower vit-D -- we need better studies - double blind controlled stuff they won't do for un-patentable D3.

My hunch is that it matters/

I also share a suspicion about infection causing CAD...

How about this: We measure LA content of peoples fat tissue ( NMR methods would do) as an objective proxy (I don't trust diet surveys) for the amount of LA consumed - then measure the coronary intima thickness and look for a correlation. Would someone please do this!!

raphi said...

Subbotin's review might be one of the best I've read this year so far.

I tweeted to Attia that 1) the tunica intima doesn't remain 1 cell thick throughout our life (and is non-pathological) 2) that it is thicker than the tunica media. These were 2 points Subbotin drew a lot of focus to. I'm not holding my breath for him to acknowledge the mistaken pathology in his & Dayspring's description of coronary atherosclerosis...

PS: hadn't read your 1-5 Atherosclerosis series Peter, very cool! i know better understand why you were so excited about BhB+AcAc increasing pO2 pressure in rats.

raphi said...

since we're talking heart disease, i thought I'd link to Chris Masterjohn's dietary recommendations for Familial Hypercholesterolemic Heterozygotes.

CM: "Herein, I discuss why I believe the Kitavan diet should serve as an ancestral diet on which to model dietary management of HeFH. It is a low-fat, low-cholesterol, high-carbohydrate diet where most of the fat is highly saturated because it comes from coconut, some of it is is from fish, and where the carbohydrate mostly comes from starchy tubers but some comes from fruit."

NY said...

I wonder to what extent other factors than high insulin play into CVD: smoking, lack of sun exposure, lack of sleep and stress etc. Is keeping insulin low THE startegy or one of the strategies?

ivor cummins said...

My high-level musings NY - there's a lotta interaction with those variables you mention - contributing to IR and more directly...!

I'm still having great difficulty believing the 'dangerous BB bullet' theory of ApoB particle inherent toxicity - but there you go...



Tucker Goodrich said...

"I'm still having great difficulty believing the 'dangerous BB bullet' theory of ApoB particle inherent toxicity - but there you go..."

I don't think there's any evidence that they are inherently toxic. It's a classic case of looking for your keys under the street light because that's where the light is...

If there's an environmental element to this, and there clearly is, then you need to go outside that environment to see what's "normal". CVD researchers or popularizers of CVD research like Dayspring don't do that.

On the other hand, there's a long line of evidence that explains what's going on. 4-hydroxynonenal (HNE) is a product of oxidation of a novel addition to the human diet: high quantities of omega-6 fats, specifically linoleic acid. This is from 1989. Note the effect on apoliprotein:

"Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages."

All the evidence I've been able to find indicates that oxidized linoleic metabolites (like HNE, MDA is the other one commonly found) are involved at every stage of CVD progression. These metabolites are *always* found in atherosclerotic plaques, for instance, and can induce endothelial cell function, and cause apoptosis in cells.

But the medical community has polyunsaturated fats on the brain, and diligently ignores the evidence that what they're pushing is most likely the cause. Iatrogenic, anyone?

Tucker Goodrich said...

That should have been "induce endothelial cell dysfunction", of course.

Tucker Goodrich said...

How about this: We measure LA content of peoples fat tissue ( NMR methods would do) as an objective proxy (I don't trust diet surveys) for the amount of LA consumed - then measure the coronary intima thickness and look for a correlation. Would someone please do this!!"

Correlation with CVD? Why not just look at the direct relationship: oxidized linoleic acid metabolites that are involved in CVD directly? That work has been done...

Jonty said...

Peter, How about low vitamin C as an initial cause of diffuse intimal thickening?

Insufficient vitamin C weakens GAG since we lost the ability to synthesize the stuff from glucose. Torn collagen exposes lysine residues for which lipoprotein(a) has receptors which bridges the tear, initiating the formation of plaque.

This is Pauling and Rath’s theory of course I believe in it because I’m a 35-year Type I diabetic with a calcium score of zero, i.e. no plaque, and I’ve taken grams of C daily for 32 of those 35 years because Cathcart’s bowel tolerance scheme cured my CFS and I was terrified of a relapse.

My lowcarb diet and avoidance of sugar are competing/synergistic explanations but I'm confident it's not a placebo effect because Pauling and Rath published a decade after I started taking C :)

kellyt said...

elevated Uric Acid fits into this story, as well.. I'm still working to understand how important.

I continue to read and learn as much on the subject of UA as I can… if I never get gout again, it’ll be too soon! Unfortunately, once they found a pharmacological way to control UA levels in gouty patients most of the research monies dried up😦 Taubes makes the point in his “missing chapter” that never made it into his book:

There’s a gentleman in my neck of the woods (Colorado USA) named Richard J. Johnson who continues to do great work on the subject. I enjoy his youtube lectures and papers, his arguments make sense to me.. Here’s one such paper that discusses the role that elevated UA plays in Hypertension and CVD..

“We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction).”

A case of “the dose makes the poison” I suppose.. Chronic high UA (in western societies this is usually cause by alcohol and fructose consumption) leads to endothelial damage..

A quick search reveals a possible negative effect of high UA on Coagulation and Platelet Economy..

“Platelet adhesiveness and plasma thromboplastic activity were correspondingly increased in the gouty subjects.”

Ally Houston said...

Hi All,

I'm interested in high blood pressure in the context of arteriosclerosis.

It strikes me as exactly the kind of variable that is held up as causal but may just be corollary, like cholesterol.

We are told by the NHS and The British and American Heart Foundations that we must have low blood pressure. One reason is that the heart muscle walls thicken over time to push harder, which I agree does seem bad. But the main problem appears to be atherosclerosis, which is attributed to high blood pressure because: high blood pressure causes damage to the tunica intima, LDL (bad) cholesterol forms plaque on the artery wall, and so it continues until even a small clot causes a big problem.

Something doesn't sit right with me that coffee is known to acutely increase blood pressure for up to greater than three hours after consumption, yet it is not associated with an increased risk in CVD to long-term users.

Can anyone explain this to me?



Boundless said...

re: coffee is known to acutely increase blood pressure for up to greater than three hours after consumption, yet it is not associated with an increased risk in CVD to long-term users.

Adverse response to coffee appears to be phenotype-specific to a measurable degree. CYP1A2 has been known for over a decade. Here's a 2014 paper on others:
Mol Psychiatry: Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

In those with genetic risk factors, the question then arises: what's the etiology? Without having looked into it, I can see BP playing a role. Interaction with diet would be interesting. I suspect that all work to date has been on random (i.e. full-time glycemic) diets.

Ally Houston said...

Interesting, thanks.

So coffee interacts differently with different individuals dependent on their genetics. Which could explain large studies showing no statistical negatives to drinking coffee long term, those who do suffer may easily get lost in the noise.

As you suggest, the interaction with diet could be a vital component in understanding how long term acute BP increases from stimulant use could cause CVD through atherosclerosis. (Specifically thinking of atherosclerosis here, the thickening heart muscle thing may happen regardless of diet).

A large cohort analysis ( yielded negative correlation for CVD in coffee drinkers, but a positive correlation for smokers for lung cancer. I would take from that (as a former / recovering smoker) that when a smoker takes a stimulant like coffee, they want to smoke more. I would also suggest that when you take a stimulant, like coffee, you want to eat less. it may even be that coffee increases the risk of CHD through BP increase, but cancels some of that through stimulant induced dietary changes. Hard to say...

Robert Whigham said...

Here is a mitochondrial effect which looks interesting

"Urolithin A eliminates faulty mitochondria from muscle cells, and is potential a cure for mitochondrial myopathy, a major wasting disease of aging. It also acted very quickly in aged mice, and had them running on a treadmill with the youngsters in a matter of days."

Download the research paper here (it may dissappear soon),%20Nat%20Med%202016.pdf

80% of people can get Urolithin A by ingesting ellagic acid (a cheap supplement)

"Three phenotypes for urolithin production after ellagitannin and ellagic acid intake are consistently observed in different human intervention trials. Subjects can be stratified into three urolithin-producing groups. "Phenotype A" produced only urolithin A conjugates, which included between 25 and 80% of the volunteers in the different trials. "Phenotype B" produced isourolithin A and/or urolithin B in addition to urolithin A, this being the second relevant group (10-50%). "Phenotype 0" (5-25%) was that in which these urolithins were not detected"

Richard said...

For me the issue is something like this: There is probably not ONE cause... that is, there are MULTIPLE feedback and corrective systems, each working to do similar things. And those things would work well enough in a natural environment. But we are not in a natural environment. We are in an environment as unnatural as any lab rat.

Measuring any one factor in isolation is what science does, and it may be the best path to a complete understanding, but it's sort of like democracy in terms of government. The best still only means least bad. Taken in isolation these various views of "scientific" tests mean little, and the key is to integrate them properly.

The idea that there is such a thing as "bad" cholesterol is bizarre, as is the whole idea that arterial calcification is normal. But calcification may be "normal" (that is to say typical) IF a proper diet (and entire way of life) is abandoned. For a more comprehensive view of the entire system I recommend Jason Fung's website, Intensive Dietary Management. His point is (as I understand it) that constant (continual) elevation of insulin is the MAIN driver of all these unfortunate processes and outcomes. And it is not solely based on the macronutrient levels, but instead on the body having to cope with continued and continual ingestion of carbohydrates and (excessive) protein. We can call it diabetes if we like, but the problem is broader than that.

Insulin does a lot of things, but as I see this, the modern diet has entirely substituted cooking for fermentation, modern life allows people to live comfortably entirely sheltered from the sun, and there is always plenty to eat. People live quite comfortably through the period of life required for reproduction. In order to properly replicate the ancestral "diet" we would have to make sure of proper sun exposure, eat a sufficient amount of fermented foods, such as natto (which I think tastes just fine), and occasionally, and regularly, go hungry for extended periods: days, even, not just a few hours.

What is almost entirely missing in this discussion of the intima thickening and arterial plaque is the significant role of autophagy during nutrient deprivation. Not eating for 20 hours (for example) appears to greatly increase the activity of autophagy, as the body ramps up its hunt for fat and protein from all possible sources within the body. But what disturbs me about all discussions of autophagy is that when you read the research about it the usual approach is to "induce" autophagy by administration of some drug or chemical, instead of simply letting our test animal get very hungry. And then the researchers wonder why their drug induced autophagy seems less effective than predicted, or has some unintended result.

Ultimately the body does nothing wrong: all the things that seem to be "negative" are simply the result of the real inputs and the body then doing its best to stay functional for the longest time possible.

So what is the best approach? Avoid excessive consumption of insulin producing foods. Sugar and refined carbs are the worst, and excessive protein is on the list. Fat does not drive insulin at all, and leafy green vegetables don't move the needle much. No one in their right mind would eat corn oil or soy oil, but coconut oil and olive oil are entirely different and fine.

I highly recommend fasting: I do one or at the most two meals per day, which results in daily periods of low insulin production of 16-22 hours. Supplement with K2 of both Mk4 and MK7, eat fermented foods, get enough Vit D by supplement and natural sunlight, and exercise and sleep regularly. Take Vit C.

Jeffrey Patten said...

Robert Whigham:

How confident are you about the 80% who would benefit from ellagic acid supplementation?
It often happens that a logical seeming idea turns out, after a few years of double blinded randomized controlled trials and a few more years of accumulated clinical experience, to be useless or even harmful. But maybe, just maybe, as with vitamin D, we can get in there ahead of the game and not waste all those years. Frustrating, isn't it?
What possible harm from such ellagic acid supplementation? (I'm wondering about more substantial harm than to one's wallet: Expensive pee.)

ivor cummins said...

Get a load of this paper dudes...Subbotin LIVES ! ;-)

cavenewt said...

Richard's comment about autophagy is right on. I've been fascinated by the work of Valter Longo, a longevity researcher who is studying intermittent long term fasting as a way of resetting the immune system. Not only that, he's actually doing studies that involve fasting, rather than trying to find some pharmaceutical to mimic it. It's not just the immune system. His studies involving fasting to reduce the side effects of chemotherapy for cancer patients have been surprisingly successful.

Prolonged Fasting reduces IGF-1/PKA to promote hematopoietic stem cell-based regeneration and reverse immunosuppression

One of my fondest wishes is that Peter might take enough interest to blog about it...

Rattus said...

Random pseudo-science side note. Have guys you ever heard of Bigu, aka the ancient Taoist fasting technique of "avoiding the five grains in order to obtain immortality"? Lots of interesting stories and tie-ins to the advent of agriculture on the Wiki page.

Taoists also had seemingly similar views on semi-abstinence from ejaculation, once a month being ideal, but more frequent was ok. They even had a formula for it. Your age minus seven divided by 4.

In my experience, this practice does some pretty crazy stuff to energy, motivation, need for sleep, etc. Taoists believed it increased lifespan, which I think has been corroborated by a few studies, albeit in lower organisms. It feels pretty similar to low carb in its effect, which makes me think that the hormonal fluctuations caused by orgasm might have a similarly deleterious impact to spiking insulin constantly with a high carb diet.