Best of Haidut - Part 1

PeatThemAll

Member
Joined
Oct 3, 2015
Messages
280
In no specific order. Feel free to add.

Original Post: viewtopic.php?f=155&t=7991

haidut said:
post 102428 High PUFA diet effectively the same as diabetes, aging and cancer
Postby haidut » Fri Oct 02, 2015 3:24 pm

This must be one of the most comprehensive and convincing studies I have come across in the last year. Both a human and a rodent study combined into one. Pretty telling as to whether you want to eat high PUFA or glucose. The patients were on a high-fat diet (35% of calories) and the fat was at least 80% PUFA. Keep in mind that this actually is NOT a high fat diet, and is close to what most people eat on a daily basis. High fat diet is clinically defined as 45% of calories or more.
Such a good study on so many levels. I suggest it strongly to everyone who has the time to read it!

Several key points:

1. The high fat (PUFA) diet induced the same negative effects on oxidative phosphorylation as established diabetes.

2. Fasting has the same effect on oxidative metabolism as a high fat (PUFA) diet and induced a diabetes-like state.

3. Free fatty acids are NOT elevated by high fat (PUFA) diet but fat influx into the muscle IS elevated and that is what drives the process of insulin resistance.

4. Free fatty acids directly inhibit insulin signaling. So, burning fat is not desirable even if it is saturated fat.

5. High fat (PUFA) diet induced strong inhibition of cytochrome C oxidase (-27%) and PGC1a/b by about 40%.

6. In Peatarian terms - high fat (PUFA) diet creates the same field as fasting, aging, diabetes, and cancer - i.e. inhibition of the ability to oxidize glucose.

http://www.ncbi.nlm.nih.gov/pubmed/15983191

"...In conclusion, HFDs in both insulin-sensitive humans and mice were associated with reduction in the expression of genes involved in oxidative capacity (e.g., genes of the electron transport chain), nuclear genes encoding mitochondrial proteins (e.g., mitochondrial carrier proteins), and those involved in mitochondrial biogenesis (e.g., PGC1α and PGC1β). These studies support the novel hypothesis that HFDs or high-fat flux explain the reduction in OXPHOS genes seen in aging, the prediabetic state, and in overt diabetes."

"...Numerous studies have implicated reduced mitochondrial biogenesis and OXPHOS in the pathogenesis of insulin resistance and type 2 diabetes (31). Our studies suggest that dietary fat is an important factor in the observed reduction in OXPHOS genes in insulin-resistant states. Microarray analysis and real-time quantitative RT-PCR results revealed a downregulation of OXPHOS genes in young men consuming a HFD, as well as transcription factors and cofactors. Additionally, we have shown that the reductions in genes involved in OXPHOS and mitochondrial biogenesis were recapitulated in an animal model of dietary-induced obesity and insulin resistance (32) and were of a much greater magnitude in mice compared with man."

"...The 3-day isoenergetic HFD significantly changed the expression of 297 genes (P < 0.01; Supplemental Table 2). By the HFD, 163 genes were upregulated, and 135 were downregulated. Six were known to be involved in OXPHOS by visual inspection or through gene ontogeny analysis (P < 0.001; Table 3). All of the OXPHOS genes were downregulated. Four genes are components of complex I, and one is a component of complex II. The remaining regulated gene is involved in mitochondrial solute transport."

"...We sought to confirm expression of these six OXPHOS genes by real-time quantitative RT-PCR. All six microarray “hits” displayed the same downward trend with quantitative RT-PCR, and three genes were “confirmed” (Fig. 1A): NDUFB5 (3.19 ± 0.26 to 2.12 ± 0.20 AU [arbitrary units], P < 0.01), SDHB (0.26 ± 0.02 to 0.19 ± 0.02 AU, P < 0.05), NDUFS1 (0.28 ± 0.03 to 0.21 ± 0.02 AU, P = 0.05), SLC25A12 (0.29 ± 0.04 to 0.19 ± 0.02 AU, P = 0.0838), NDUFB3 (0.39 ± 0.05 to 0.26 ± 0.034 AU, P = 0.1355), and NDUFV1 (0.36 ± 0.05 to 0.30 ± 0.04 AU, P = 0.3191). The magnitudes of these changes (∼20–30%) are strikingly similar to the decreases demonstrated by microarray analysis of reduced skeletal muscle OXPHOS gene expression found by Patti et al. (4) and Mootha et al. (3) in diabetic subjects."

"...As a subsequent step in elucidating effects of the diet intervention on expression of genes involved in mitochondrial function, we examined mRNA for genes in complexes III and IV using quantitative RT-PCR (Fig. 1A). Cytochrome C (complex III) and Surfeit one (complex IV) expression levels were reduced (1.13 ± 0.07 to 0.85 ± 0.05 AU, P < 0.01, and 1.10 ± 0.05 to 0.90 ± 0.05 AU, P < 0.01)."

"...Because expression levels of genes involved in the function of mitochondria decreased, we examined expression of genes known to be involved in mitochondrial biogenesis. We observed a 20% and a 25% reduction in mRNA levels in PGC1α and PGC1β, respectively (Fig. 2A); PGC1α (1.44 ± 0.08 to 1.13 ± 0.06 AU, P < 0.01) and PGC1β (2.12 ± 0.16 to 1.59 ± 0.18 AU, P < 0.05). Mitochondrial transcription factor A, TFAM, a key activator of mitochondrial transcription and its genome replication, was not significantly changed (2.00 ± 0.19 to 1.79 ± 0.19 AU, P = 0.3784), nor was nuclear respiratory factor 1, NRF1 (1.89 ± 0.13 to 1.56 ± 0.16 AU, P = 0.1398) (Fig. 2A)."

"...We next tested whether the changes in gene expression we found in the clinic were present in a murine model of HFD-induced obesity. We fed C57Bl/6J mice either a 10 or 45% fat diet for 3 weeks. We chose two murine genes from complex I; one gene each from complexes II, III, and IV; and one mitochondrial carrier protein from the human experiments. Decline in gene expression was of a greater magnitude than those seen in the human experiments. As measured by real-time quantitative RT-PCR, each gene was downregulated in high-fat–fed mice compared with controls (Fig. 1B): NDUFB5 (24.05 ± 7.89 to 2.10 ± 0.44 AU, P < 0.01), NDUFB3 (19.02 ± 6.25 to 1.82 ± 0.29 AU, P < 0.01), SDHB (10.84 ± 3.58 to 1.05 ± 0.20 AU, P < 0.01) SLC25A12 (6.14 ± 1.99 to 0.45 ± 0.11 AU, P < 0.01), CYC1 (10.41 ± 3.40 to 0.79 ± 0.13 AU, P < 0.01), and SURF1 (175.50 ± 57.35 to 13.81 ± 3.20 AU, P < 0.01)."

"...In parallel to the human experiment, we measured both PGC1α and PGC1β mRNA in these same mice. A 90% reduction in mRNA levels was observed for both PGC1α and PGC1β (Fig. 2B): PGC1α (34.63 ± 12.57 to 2.67 ± 0.31 AU, P < 0.01) and PGC1β (25.75 ± 9.03 to 1.85 ± 0.30 AU, P < 0.01)."

"...PGC1α and cytochrome C protein expression levels were reduced by ∼40% in mice consuming a HFD (Fig. 2B): PGC1α (1.31 ± 0.19 to 0.84 ± 0.07 AU, P < 0.05) and cytochrome C (1.35 ± 0.17 to 0.76 ± 0.09 AU, P < 0.01)."

"...Our results support the hypothesis that HFDs and/or high-fat flux through the mitochondria reduce the expression of nuclear genes encoding mitochondrial proteins and transcription factors involved in mitochondrial biogenesis. Both PGC1α and PGC1β were decreased by ∼20% and accompanied by a 20% reduction in OXPHOS gene expression. Previous studies suggest a link between the downregulation of PGC1 and dysregulation of OXPHOS genes. Our results are consistent with this sequence of events, and three of our OXPHOS genes found by microarray analysis were also present in the analyses of Mootha et al. (3) and Patti et al. (4). Therefore, our findings expand the view beyond the relationship between PGC1 and OXPHOS genes. We move upstream to show that increased fatty acid flux through the mitochondria decreases PGC1 expression and associates with a downregulation of expression of OXPHOS genes. It remains unclear from this experimental data whether it is increased fatty acid mitochondrial oxidation per se or some other pathway triggered by fatty acids that is responsible for the effects on gene expression."

"...Although an increase in free fatty acid concentrations was not seen in this cohort, fatty acid flux through the muscle is by necessity increased in these subjects as demonstrated by a decrease in 24-h respiratory quotient (data not shown) to match fat intake in this experimental paradigm (14). Another explanation for the reduction in the expression of these genes is that HFD decreases insulin-stimulated gene expression. Fatty acids decrease insulin signaling both in vivo and in vitro. Recent microarray studies demonstrate an upregulation of OXPHOS genes after a short-term insulin infusion (36). A reduction in insulin signaling might reduce expression of these same genes. Our studies do not identify the exact mechanism of the reduction in PGC1α, PGC1β, or their downstream targets. Rather, these studies point toward dietary fat, or increased lipolysis, as a potential source of the previously reported reduction in mitochondrial OXPHOS and subsequent mitochondrial dysfunction."

"...Our studies reveal a key question: “why would increased fatty acid flux decrease the expression of genes needed to oxidize these same fatty acids?”. Fasting is another “normal” physiological condition where fatty acid flux through skeletal muscle is increased. Surprisingly, fasting produces changes in gene expression that are strikingly similar to the pattern of fat-induced changes observed in our studies of HFDs. For example, Jagoe et al. (37) found that CASQ2 (calsequestrin 2), NDUFS1, glycogen synthase, and pyruvate dehydrogenase kinase isoenzyme 4, four genes found on our microarray “hit” list (Supplemental Table 2) and confirmed by quantitative RT-PCR (data not shown), were similarly regulated by fasting in rodents. This may explain the paradoxical decrease in systems needed to oxidize fatty acids (nuclear genes encoding mitochondrial proteins, PGC1α) when fat flux is increased during a HFD. In other words, the parallel results between fasting and HFDs suggest that fat flux through the skeletal muscle might be interpreted as a signal of fasting/starvation by the muscle cell itself. Signaling systems normally reserved for responding to energy deprivation (fasting) may be co-opted when dietary fat is increased. This hypothesis is also consistent with observed changes in the transcription of genes involved in nonoxidative metabolism (e.g., glycolysis) found on our microarray “hit” list (Supplemental Table 2)."

One of the substances that can reverse the inhibition of the ability to oxidize glucose is glycine. It successfully reverted aging cells back to their young phenotype. Here is more info:
viewtopic.php?f=75&t=7736
 
Last edited by a moderator:
OP
P

PeatThemAll

Member
Joined
Oct 3, 2015
Messages
280
Source: viewtopic.php?f=144&t=7619

Haidut's Summary of PUFA

Charlie said:
post 96959 I thought this deserved it's own thread.

haidut said:
post 86912 OK, I will just summarize what I have seen/read and combine with what I have gotten from Peat.

1. The argument for PUFA being essential is not only wrong, it is misguided. While Peat does cite an old study, I have posted several threads on this forum showing that as recently as 1990s there were studies saying that PUFA is at best semi-essential and its daily dietary "requirements" come down to no more than 0.5% of calories. So, at the very least we have an upper bound on how essential PUFA is - i.e. if you are eating more than 1g-2g of PUFA daily at best you are not getting any benefit and at worse you are increasing the risk of cancer.

2. PUFA and its derivative eicosanoids and leukotrienes, are the major pathway to inflammation. Peat has written that his view is quite contrary to the medical dogma in the sense that he does not think there is a "healthy" level of inflammation. As far as I can see from his articles, and he is pretty explicit on this one, he thinks the lower the inflammation the healthier the organism. As such, restricting PUFA (and depleting iron, tryptophan, etc) is perhaps THE definitive approach to controlling inflammation rather than rely on later factors in the cascade such as taking aspirin to combat inflammation. The eicosanoids/leukotrienes are the major trigger of histamine/serotonin synthesis and release and without them, histamine and serotonin become a much smaller burden on the organism.

3. PUFA directly inhibit cytochrome C oxidase, unlike SFA and MUFA. In addition, PUFA are directly estrogenic by activating aromatase, again, unlike MUFA and SFA.

4. PUFA are a major inhibitor of the protective steroid pathways, especially 5-AR, but at the same time are activators of 11b-hydroxylase and aldosterone synthase. So, PUFA tend to shift the steroid pathway towards the end products cortisol, estrogen and aldosterone.

5. PUFA activate TPH, which synthesizes serotonin from tryptophan. As such, PUFA are a major metabolic inhibitor. Combined with the fact that they also promote estrogen and cortisol I am not sure there is another substance that can rival PUFA in terms of metabolism inhibition with the possible exception of ionizing radiation, which mimics PUFA effects on the body remarkably well. So, maybe the next time somebody wants to make an argument in favor of PUFA, try to think of a way to frame radiation in a positive light. If you can give me an argument for radiation, then I will listen to the argument in favor of PUFA.

6. Animals depleted in PUFA have uncoupled respiration and their metabolism and their oxygen consumption is about 70% higher than "normal" animals. The same effect was observed with people who got accidentally depleted in PUFA. You may argue for PUFA all you want, but even mainstream medicine wisened up to the fact that uncouplers are a viable treatment of several (maybe all) degenerative diseases. Go to http://www.clinicaltrials.gov and search for "uncoupler" or "uncoupling" and you will see for yourself. So, if having super fast metabolism is viable treatment for many diseases of old age and maybe aging itself then why on Earth would anybody want to consume a well-known metabolic inhibitor.

7. PUFA are immunosuppressive. This is such common knowledge that there are even several established products on the medical market based on a combination of linoleic and linolenic acid that is given IV to organ transplant patients. As far as I know the daily dose is 20g, and even though it is given IV the effects from oral intake are very similar. This should not come as a surprise given how much PUFA boosts cortisol production. Anything that suppresses your immune system chronically is likely to result in cancer in the long run.

8. PUFA is one of the main inhibitors of endogenous cholesterol synthesis. In fact, to this day this is one of their main selling point, especially the EPA/DHA kind. Anything that suppresses your cholesterol synthesis increases the risk of cancer. Statins are major carcinogen, not to mention their link to diseases like ALS and other muscular distrophies. If statins and PUFA work similarly on cholesterol and muscle then I am not sure what person in their right mind would want to load up on PUFA given the several class action lawsuits against statins and their connection to ALS, dementia, liver failure, etc.

9. PUFA is insanely hepatotoxic. I must have posted at least 10 studies on this one. Saturated fat is so far the only known substance shown to reverse chirrosis in both humans and animals. High dose vitamin K2 (MK-4) and caffeine have similar effects but probably can't fully match effects of saturated fat on fibrotic tissue. Not even acetaminophen comes close to the toxicity of PUFA to things like cytochrome P450 and glutathione reserves.

Finally, if you have read enough studies, and especially if you have worked with some sick people to see what got them better and what got them worse, then you should have enough information to decide if you want to deplete PUFA or not. Experiment is the ultimate arbiter and no amount of bickering and arguments and studies will make a difference. So, for anybody who wants to finally clear up any doubts on whether Peat is right about his stuff or not - in as little as 3-4 weeks of low fat diet, you can find out for yourself and then no amount of arguments from me or anybody else would matter.
 
Last edited by a moderator:
OP
P

PeatThemAll

Member
Joined
Oct 3, 2015
Messages
280
Generative Energy Podcast with haidut (forum member)

Source: viewtopic.php?f=73&t=8011#p102682

Danny's blog: http://www.dannyroddy.com/weblog/polyun ... lorgnanism
Danny's podcast: http://www.generativeenergy.com/main/20 ... l-organism
haidut's profile: memberlist.php?mode=viewprofile&u=570
Support Danny: https://www.patreon.com/dannyroddy
haidut's Ideal Labs: http://haidut.dyndns.org/idealabs/

d: Hello Everyone, welcome to the Generative Energy Podcast. I'm Danny Roddy at dannyroddy.com and today I'm talking with Georgi (aka haidut) of raypeatforum.com. Georgi is an independant health researcher and owner of IdealLabs, a small company producing high-quality boutique supplements with a focus on supporting a healthy metabolism. Today, Georgi and I will present a physiological argument against the so-called Essential Polyunsaturated Fats (or PUFA), and we'll detail why we think that they are the main promoters of inflammation, stress and aging. In addition to thanking Georgi for talking with me today I wanted to thank my Patreons, and you can become a Patreon by going to patreon.com/dannyroddy. I my heart goes out to all those people supporting me and making this content possible. So, without further ado, let's talk with Georgi (aka haidut). And Georgi, I just wanted to say I found your posts a few years ago, they were so filled with content and they were so clear; it was obvious that you had a zest for learning on your own and confirming a lot of things Ray has said in interviews and his newsletters. I was curious how your own journey started.

h: Finding Ray Peat: it all started back in 2009. I was a little bit into health even before that, I was an active athlete in college and I was always mindful of what I ate. I got influenced, unfortunately, like many people I think, by the whole Paleo diet circle and I went low-carb for a long time, between 2006-2009 I was eating pretty strict hardcore Paleo diet. While that initially gave me a lot of energy, I felt that something was just not right. It was taking longer for me to recover from workouts, I wasn't sleeping well, things like that, but anybody that I talked to, they basically said: well, what do you care, this is like the most energetic you've ever felt, so it must be a good thing. Only later I realized that cortisol is this thing that will make you - cortisol and estrogen - will make you feel energized, but they're really sort of a devil in a mask because eventually they do contribute to the pathology of most degenerative conditions that we're witnessing nowadays. Around 2009 I started getting this weird sinus infections, unfortunately spread to my ear, I started having balance issues, you know, I kept seeing ??? my private care physician at least once a week; I went on several rounds of antibiotics, which seemed to clear things up but then invariably they'd come back, and you know, they'd ultimately it all came down to cortisol because given how high it was, it was supressing my immune system. I started to get this weird neurological symptoms, so I got referred to a neurologist, I got a lot of MRI scans, all kind of scans; I knew radiation was bad even before that so I managed to avoid most of the X-Rays and CT scans that were all ??? to me; so I mostly got MRIs. But it basically, long story short, after a year and a half of testing, everybody said that there's nothing structurally wrong with you, but I kept deteriorating. I think the first time I heard about Ray Peat was on Reddit, I was commenting on some studies that showed basically that the paleo diet was good for you and things like that, and then some random user, I don't think he or she is even a member of Reddit anymore, said: well, I think all you guys are wrong, this thread is full of BS, you should really read more, check out this guy, he knows his stuff <I think he/she was mentioning pboy back then>. I just clicked on that link and the first article from the very top, when I started reading I realized: this guy knows his stuff. It's not so much about being right, but eveything that he says makes sense, and everything that I managed to check made sense. That was really how it all started. So, between 2009-2011 I was essentially focused on regain my health and ??? since I have not had any of this weird neurological symptoms. I don't want to say that it convinced me that Ray Peat is right but it convinced me that the guy has a point. That got me researching even more and I was naturally curious, got interested in this stuff and I found this nice hobby, so to speak, which is so different from my day job, but it gives me a way to recover from the prevails of the dayjob by researching and getting involved with Ray Peat ideas. And also, of all the people that reached out to me for advice, I feel good about knowing that I've managed to help some people, even though the FDA doesn't wanna hear that.

d: Well, you helped me too. You're a prolific poster on Ray Peat Forum. And the way you kinda of highlight and make the studies - truth be told, I sometimes can't interpret the really complex studies and they're just over my head - but you have a way of presenting things, it's like: oh, I can understand that. But I was curious, what was like the giveaway when you went to Ray's site, were you like: this guy has something different to say about cortisol that made you interested in them!?

h: No, It was actually aspirin, because I know for a long time - I'm originally from Bulgaria, and in Eastern Europe aspirin has this reputation of a drug that cures it all. And I've always thought that it was just what old people say, modern medicine really has an answer for all this things; they just think aspirin cures it all, but it's really you know, it's just old-people stuff, they don't really know what they're talking about. But when I read his article on aspirin, I think it's called Aspiring, brain, and cancer. I started reading it and it backs up everything that I've been hearing since very early childhood. That aspirin is the best thing that you can do for heart attack preventions, for stroke prevention, even for like basically slowing down the aging process so to speak. Both of my grandmas are still alive, they're both on their late eighties, and they're very active. I wanna say that they're more active now than I was back in my paleo diet phase, and both of them take aspirin on a daily basis, they've done so over the last 60 years, they started back on their twenties. So after I started reading his articles, followed up on all of the links, checked the research; if you go to PubMed, there are like literally millions of articles on aspirin and not a single one is negatively framed.

d: Was it aspiring that made you more curious about the polyunsaturated fats and their role in inflammation, stress and aging?

h: Yeah, basically there are several inflammation markers, after I quited going to doctors - I still see my primary giver once a year just to keep him happy <check> because he's a nice guy, he does agree with a lot of what Ray Peat has to say - but I basically started doing my own blood tests and I noticed that initially my inflammation markers were elevated but they were close to their upper range, like the C-reactive Protein, the Erythrocyte sedimentation rate and I also measured some of the prostaglandins; so basically they were all borderline high. And then I noticed that after taking aspirin - which is actually really to summarize what got me into Ray Peat and got me out of my troubles for the biggest part it was probably aspirin, I was taking high doses - and the within a month all of these inflammation markers went down. Officially aspirin is just a COX inhibitor, none of these things that aspirin manage to do are explainable by the COX mechanism, so there must've be something else that aspirin was doing. As I started researching I noticed that one of the things that aspirin does is that it inhibits lipolysis, it will lower the elevated Free Fatty Acids in the blood. Ray says that saturated fat is fine if those are the fatty acids in the blood but it's still not a good thing. So I noticed that aspirin is helping and then I did some experiments; I would stop aspirin, only eat coconut oil and I noticed that my inflammation markers would stay low; but if started eating "regular foods" (quoted because it's not regular, it's poison but you don't have a choice with commercial foods), even a tiny bit of commercial foods, like something you buy from 7-eleven, CVS or Safeway; my inflammation markers would immediately jump, even from a tiny amount. ??? <Brutally missed>. Basically, without aspirin, saturated fat kept my inflammation markers down, and then polyunsaturated fats raised them, even a very small amount. So I would say around 2013 I started consciously avoiding any kind of PUFA (including fish oil).

d: And you list 1-2g. Is that based on research that you've done?

h: Yeah, I have provided the link on the forum but the bottom line is: there have been a lot of disagreements over the essentiality of PUFA going back to the 1950s, and even to this day there are PubMed studies that pop-up that say: look, even we assume that PUFA are essential, I think you guys (by you meaning the FDA, the USDA have determined the dietary requirements per day) are vastly overestimating the essentiality of PUFA. It was shown that even in situations when you feed the rats just a little bit of PUFA, all of these symptoms that are claimed to be caused by EFA deficiency disappear immediately, any intake on top of that was not shown to be beneficial; at the very best you can say, if you believe that PUFA is essential - and I don't - you can get away with eating no more than a gram or two of PUFA per day, which you can get from just eating the eggs, just like you mentioned. Eating non-essential fats and knowing how fat metabolism contributes to degenerative diseases, even if we're assuming that PUFA is not bad, having more fat than what is necessary and essential is not a good idea in my opinion.

d: So, Georgi, you mentioned that metabolism of the unsaturated fats or the PUFA, they're synthesized into the eicosanoids and the leukotraienes, and these are major pathways to inflammation.

h: Basically, eicosanoids and leukotrienes are types of prostaglandins, and they're mostly derived from arachidonic acid, which is one of the omega 6 acids, it's widely known ever since the early 20th century to be the main mediator of inflammation, and actually cellular growth and division. Believe it or not, in some circles of bodybuilders, arachidonic acid is injected intravenously so that they can spare muscle growth. This tells you immediately that both that Ray is right and how stupid some people are. The primary purpose of every cell is to grow, all primitive cellular life forms, that's really all they do: they just eat and grow. We are in a sense a mechanism for supressing excessive growth, and excessive growth is mainly due <check> to inflammation. So if PUFA are the main driver, if not the only driver, of inflammation, then basically PUFA are the main driver of cellular growth and dead <?> differentiation. In other words, they cause you to revert to a primitive organism, like a yeast or some kind of bacteria, that all it does is eat and as a primitive metabolism it divides, because the energy from a primitive metabolism is sufficient only for that. If you eat PUFA, this means high inflammation, means your cells will prefer to divide versus differentiating; in other words, you're getting closer to a cancer metabolism.

d: And the problem with the growth and not differentiating the cells is that it interferes with renewal of the organism.. Correct?

h: Exactly. Cells, they act as a part of a field as Ray said and by reverting them back to their growth potential in other words, due to high inflammation or intake of PUFA, the organism loses its coherence; you're no longer a human, you're just a collection of cells but they're not guided by any coherent field. <???> very powerful with a coherence, collection of cells, but these cells every human being is perceived as a coherent field <Brutally missed> just a collection of cells, they're independent of each other and the only purpose is survival, and how to survive is by dividing a growing.

d: You mentioned that the polyunsaturated fats, the producs that they're metabolizing into, the eicosanoids and leukotrienes, are major triggers of histamine; which might be agreed that histamine is a problem in excess, but also serotonin, and serotonin will probably have to demistify this until the end of our lives, but that is also a problem: increasing serotonin synthesis.

h: Yeah, it's a huge problem because you can look at the organism in two ways: a low metabolism, in other words glycolysis; versus high metabolism, through the phosphorylation. It has been shown that in animals that hibernate, serotonin is the primary driver of hibernation. Serotonin actually causes their metabolism to slow down and it increases the ability of glycolysis versus oxidative phosphorylation. In other words, <???> which PUFA increase histamine. So, histamine drives serotonin synthesis directly, but PUFA have another way of increasing serotonin. First of all, it interferes with cytochrome c oxidase, which we'll talk about later, and it also, another thing it does is that it displaces tryptophan from albumin. Normally tryptophan in the blood is bound to albumin, <Brutally missed> to the blood-brain barrier. The levels of serotonin in the brain is determined by the ratio of tryptophan versus the so-called large neutral amino acids, in other words the branched-chain amino acids tyrosine and phenylalanine. So, the more tryptophan gets to the brain and <check> the lower the other amino acids, the more serotonin you'll synthesize. <???> the main driver of increased tryptophan availability in the brain. More PUFA means more tryptophan and more serotonin in the brain; it means lower metabolism.

d: And that's indepedent of the serotonin's production in the bowel, is that right?

h: That's correct. 90% of the serotonin is produced in the bowel and I posted a study that showed that this production in the bowel is mainly driven by bacteria in the gut. Animals that had their gut bacteria killed by antibiotics produced about 90% less serotonin in the gut than other animals. However, brain serotonin is separate, it's synthesized by the enzyme called tryptophan hydroxylase-1, the peripheral serotonin, the one in the gut, is synthesized by tryptophan hydroxylase-2. When tryptophan floats around freely in the blood, it gets to the brain and there's nothing there to inhibit it, unless you take a specific tryptophan hydroxylase-1 inhibitor such as Fenclonine, which Ray also talked about. In other words, the brain serotonin production is indepedent of the gut serotonin production even though the two are related. If you have high brain serotonin this will slow down metabolism, make the gut bacteria more active, so you'll end up with high gut serotonin aswell; but the production of the two is generally separate.

d: And for the people that are doubting the veracity of the problematic serotonin, they can look into effectiveness of Cyproheptadine as pretty much a wonder drug in addition to Ondansetron which can treat a lot of different problems. You mentioned a couple of other anti-serotonin drugs..

h: <???> likes to call them serotonin recepetor antagonists. In reality, there's no such thing as the receptor; like Ray said, the entire cell is the receptor. What gets into the cell and what is kept out is determined primarily by the energetic status of the cell. So, if a cell is low on energy so to speak, more bad stuff will get in and your cell will have a hard time getting it out. But some of the other anti-serotonin <???> that have been found to be beneficial includes Ketanserin, <unknown>, all of the -rins that the <???> likes to call them. They all act mostly on the so-called serotonin receptor type 2, and then there are some of the older drugs that are derived from LSD such as Bromocriptine, Cabergoline, Lisuride, they're considered to be more dopamine agonists. However, it was just recently discovered that dopamine itself inhibits the enzyme tryptophan hydroxylase-1. <check> so, taking a dopamine drug means that you'll synthesize less serotonin in the brain as well.

d: You mentioned keeping the cell in its high oxidative-metabolism state was essential to be able to maintain its coherence and structure, and a main part of that is by the activity of cytochrome c oxidase. An easy argument against the polyunsaturated fats is that they're extremely detrimental to this enzyme..

h: Sure. It was shown that whenever animals were fed a diet high in PUFA, and what the studies determine as high is really what constitutes the average intake of most human beings in the western world, so basically your regular western diet dramatically decreases the levels the levels of cytochrome c oxidase, which is a copper-depedent enzyme in the organism by up to 90%, without that you cannot have oxidative phosphorylation. It was just discovered that many brain diseases are actually symptoms of COX deficiency. I posted some studies that showed that animal models of diseases like ALS <check>, Parkinson's, Alzheimer's, were all greatly helped and survival was extended by added supplemental copper to the diet. Now basically, the more PUFA you eat, the less COX you'll have, and the less oxidative phosphorylation your cells can perform. In the absence of that, the only other thing your cells can do is glycolysis. So, eating a diet chronically high in PUFA will force your cells to essentially adopt a cancer metabolism.

d: And that's Warburg's discovery I think in 1931, winning a nobel prize for discovering COX.

h: That's correct. What's stunning to me is that even though the guy had <???> two nobel prizes, he's virtually unknown. If you talk to anybody with a medical degree, the only they know about it is the Warburg effect. Warburg talked a lot more about, including things that can inhibit, not so much inhibit glycolysis but preventing glycolysis from becoming excessive. Some of those things Ray touched upon but they're really coming from Warburg's original research; and these include thiamine (which is vitamin B1), biotin (which is another one of the B vitamins), and niacinamide. So it's amazing that the combination of PUFA and the supression of COX play such a large role in health and metabolism in general and it was known back in the 1930s, but up to this day it's <??? something about not being worth invest> if you want to do research on metabolic causes of diseases. I've actually talked to some people that worked with NIH, they've told me that <???> is considered largely a dead end. If you really want funding from the government, you should not be working on metabolic causes of diseases; genetics is a preffered field.

d: The mitochondria of the cell is not only where energy is produced along with carbon dioxide but it's also where steroids are produced. You don't often hear some of the pro-PUFA people ever talk about steroids in general, let alone the idea that PUFA damages the mitochondria and inhibits steroids synthesis.

h: It was discovered as soon as some of the drugs that were currently available on the market to treat - so-called treat because I don't believe in treating it - to treat hairloss and a condition called benign prostate hyperplasia (in other words, enlarged prostate) but it's not cancerous yet; so these drugs what they do is they inhibit the enzyme 5-alpha reductase. That enzyme is well known, again in the bodybuilding world, to convert testosterone into its more powerful androgen cousin, dihydrotestosterone. In addition, this is also the enzyme that converts progesterone into another neurosteroid called allopregnanolone. As soon as these drugs were approved, even during the clinical trials two things were noticed: one is that the people who were on these drugs suffered from some kind of depression which was really not amenable to be treaten with the current available SSRI drugs - that's a whole other story whether they are effective or not - but these people immediately started suffering from depression and also they started suffering from muscle loss. This tells you basically that the drug interferes with an enzyme that is very important for both your brain and your musculature, and how muscle you have largely determines how fast your metabolism is. You can fairly said that <???> or PUFA basically destroy your muscles and destroy your brain. Allopregnanolone is one of the most powerful steroids - protective steroids - in the brain <???> but its precursos pregnenolone, progesterone, there's also pregnanolone, premenedione, there are a number of steroids that are all derived from pregnenolone and 5-alpha reductase is a crucial enzyme into converting them from one to the other, and without that enzyme we're inhibiting strongly; essentialy means suboptimal brain function, which the designers of the drug freely admited upon applying for approval of the FDA, they said that for unknown reasons at that time, the drug causes severe depressive symptoms in the majority of the population that was studied.

d: In medical culture there's a widespread belief that androgens are involved with acne, baldness, PCOS; is that a mistaken belief do you think?

h: I don't know about PCOS but I think that as far as baldness, prostate cancer, I think this is actually in my opinion is close to a criminal negligence. Ray wrote in one of his early articles that not only he disagrees that androgens are the cause of prostate cancer but he thinks that they should be used as a treatment. And lo and behold, about two years after he wrote that article the pop. <check> press published a reference to a study in which they showed that patients with terminal prostate cancer, in other words these were people who were told they had no more than 3-4 months to live, when they got testosterone injections directly into their prostate, they all fell into remission. Not only that but the metastatic masses that grew in their livers and lungs, they all disappeared. So, I don't know what else will tell you that this theory of the androgens causing prostate cancer is wrong, other than showing that using an androgen in a disease that is terminal, stops it in its tracks. So, as far as prostate cancer is concerned I think that the medical field is dead wrong. I also think that the medical field is wrong on the cause of baldness because if testorone and the androgens were the cause of baldness, 20 years old men would be bald and 60 years old men would have a full stock <check> of hair.

d: ~Cracking~ That's the most simple observation, I frequently go to baldness forums and every now and then somebody will say that exact thing and they'll be crucified in the forum for how stupid that <???> is, which boggles the mind.

h: I'll be curious to see what the argument against the androgens is because frankly, even if you look at the official studies they'll admit at this point that androgens are not the only agent. Now they're saying estrogen, prolactin and cortisol, things that Ray said 20 years ago, that they also <cut> but they are still claiming that the androgens <???> involved. The funny thing is, in the simplistic medical theory here that's saying that the elevation of these agents is what's causing baldness, right? Well, a lot of them are actually inversely correlated. You can really have a high estrogen in a high dihydrotestosterone at the same time, I just don't know of a case like that, and there's a good physiological reason; usually, people with high androgens, because androgens like dihydrotestosterone themselves are actually estrogen receptors antagonists and aromatase inhibitors. So, if you have a high dihydrotestosterone you'll have low estrogen, so something there doesn't add up, it's one or the other or the whole theory is wrong.

d: The DHT increasing, if that were to happen, that would be a protective mechanism, do you think?

h: I think this is one of the most protective steroids that both men and women can produce. There were recently some studies, originally they were done in rats but recently they were repeated in humans, and were repeated successfully. It has been known that <missed> Dehydroepiandrosterone (or DHEA), which is also precursor to DHT, works really well in preventing and even treating osteoporosis in postmenopausal women. Now, the official statement is that the osteoporosis in these patients is caused because of low estrogen; however, when one group was given estrogen and the other one was given DHEA, the estrogen group had actually had higher rates of fractures versus the DHEA group, and when they measured the blood level of the hormones they found that people supplementing with DHEA had a "abnormally" high levels of DHT. When they administered an androgen receptor antagonist, in other words, when they blocked the effects DHT, the women that were given DHEA also had fractures. It shows you that DHT like the androgens in general are crucial for bone health, and they're also active neurosteroids. It's well known that men with low testosterone, actually both men and women with lower levels of androgens, are much more prone to depression and other psychiatric conditions.

d: You mentioned osteoporosis and something that might surprise some people is that serotonin is involved in osteoporosis <???> estrogen. And you compared the polyunsaturated fats ability to activate tryptophan hydroxylase to radiation. I thought that was an interesting comparison and if someone were to try to explain the benefits of polyunsaturated fats, they have to explain the benefits of radiation - which I've ironically heard.. I think a paleo advocate once, I had an email back and forth with them, and they were telling me that radiation was hormesis. Which seems to be kind of like the standard argument for anything that's slightly toxic or overly toxic. They'll say: oh, it's hormetic, you should still take it!

h: The "funny" part, in quotes because it's really not funny at all, but the funny part about all these people is that they say: low dose radiation is hormetic and at the same time they'd admit that radiation, the danger of radiation, is cummulative. So, how can something be hormetic if I keep doing it, in theory, in low doses it should be beneficial; but at the same time if a cross some sort of threshold - which by the way turned out to be fraudulent, and I posted a study about it on the forum as well - it becomes carcinogenic. <missed, missed, missed!> it accumulates and so it cannot be good for you in the long run. So, any talk about hormesis, even if <missed> can only apply to a single or at most just a few times exposure over a lifetime, not like these hundreds of X-Rays, CT scans that people are having on an annual basis to "prevent disease".

d: So, another strike against the essentiality of the unsaturated fats is that animals made deficient in the so-called essential fatty acids have extremely high metabolic rates and they're really hard to kill with things like endotoxins.

h: Yeah, that's right. One of the reasons is that basically one of the main mechanisms to which endotoxin causes <check> its detrimental effects on the body is by raising the production of serotonin itself. You can actually get a serotonin syndrome if you get a decent dose of endotoxins in your blood stream. What happens is that because the animals that are deficient in PUFA, in these animals the enzyme tryptophan hydroxylase is really low, both in the gut and in the brain, so, even if you give them endotoxins it won't trigger the production of serotonin that it does in animals that eat a normal PUFA laden diet. That's one of the main mechanisms why a PUFA deficiency will protect you from endotoxins. There are others as well..

d: Back up just a second, w-w-w-what is endotoxin?

h: E-e-e-endotoxin is produced by bacteria, basically when bacteria digest food, it's a by-product of bacterial digestion, its official name is Lipopolysaccharide. So, in a sense, it's a type of sugar; however, when the white blood cells in the blood stream sense that, they interpret this as a sign of infection; you get an immune response whenever there's a significant dose of endotoxins in your blood stream. People with good immune system can probably brush it off pretty easily or at most get a symptom of a mild flu - which is <?> another topic that we can talk about, whether the flu is caused by virus or it's a symptom of endotoxin poisoning -, people with compromised immune system cannot really muster up an immune response and also the overload of serotonin can cause the lungs and heart to fail. Serotonin is one of the primary mediator of fibrosis in the human body, antiserotonin drugs are currently getting approved and pretty quickly so could be treating things like cystic fibrosis, heart failure, liver cirrosis (which is actually fibrosis); it shows that serotonin has a very quick and detrimental effect on many organs and tissues, and endotoxins raise serotonin tremendously in people who eat a decent amount of PUFA.

d: The fibrosis is an excess production of collagen within the tissue, and the tissue presumably being de-energized by serotonin..?

h: You can think of collagen as type of scar, which it really is, it's like when you get a wound on your skin, on the surface of the skin, the cells around it in the process of healing sort of overdivide and overgrow, that's really why you get a scar. The scar is a tissue that is not very permeated well by blood vessels, so it doesn't get good nutrition, and in absence of good nutrition it solidifies and hardens, even calcifies at some point. The calcification thing is one of the hallmarks of cancer. Anything that has a fibrotic effect, and PUFA does have that effect, will cause at the very least fibrosis and at worst will cause some sort of undivided, uncontrolled growth, in other words cancer.

d: You mentioned previously but the polyunsaturated fats are strongly immuno supressive, they're found in higher levels in AIDS patients and then they're used to supress the immune system for organ transplants?

h: That's correct. First started in the 1960s, in the UK, I forgot the name of the researcher but I can provide it to you later, but what he noticed was that as he was doing experiments with rats and doing kidney, liver transplants, he noticed that whenever the rats where fed on a high PUFA diet, specifically linoleic acid, one of the main examples of omega 6 PUFAs, whenever he fed a diet high - and again, when I say high, it's high by the animal standards, when you really look at it and convert it to a human dosage it comes down to about 10g per human per day, which is probably what most people end up getting nowadays anyways - they didn't reject the organs, when he investigated further, he found that this was due to the fact that in this animals the PUFA raised the production of cortisol and serotonin, and both of these substances are immuno supressive, so it's a well established practice in transplantations to administer immuno supressive drugs, sometimes for life <check>. I guess this is probably one of the few so to speak valid reasons for using PUFA in a person who has had liver transplant, but even that I think there are other ways to achieve the same with less side effects. Anything that supresses your immune system ultimately will give you a life threatening infection. Recently there has been a huge increase in cases of so called PML <something missed> (... multifocal leukoencephalopathy), and it's caused by the JC virus, which about 90% of the world carries, but in the vast majority of people it's kept under control by the immune system, but in immuno supressed people this virus gets activated and essentialy causes a very rapid deterioration of the nervous system, with an invariably lethal effect. It was noticed by the same researcher that these rats, evne though they did not reject the organs that were transplanted, they died of some kind of neurological deterioration, and I don't know if it was PML but it matches with the current data that is known on humans, the immuno supressed people have a much higher chance of dying from a viral encephalic disease like PML.

d: So, some of the people that are advocating polyunsaturated fat intake or think that restriction is ridiculous, this is the same people that advocate lowering the cholesterol, and you've noted that the accumulation of polyunsaturated fats inhibits the endogenous cholesterol production, so perhaps if you paint this picture, which I think is incorrect, if you're consuming polyunsaturated fats you're ~vibrato starts~ decreasing your endogenous production, you're lowering your bad cholesterol LDL, and increasing your so called good cholesterol HDL, and perhaps this is a reason to consume polyunsaturated fats.

h: <missed> if you believe this things, but even the main medical establishment has already admitted that cholesterol, at least dietary cholesterol, is no longer a concern. They haven't gone as far as saying that endogenous cholesterol production is not a concern but the FDA officially about two months ago said: you can eat all the cholesterol you want, it really doesn't matter in terms of cardiovascular disease, stroke and things like that. So, 30 years of <missed> billions of dollars of research and producing all of these drugs, and now they're saying that it just doesn't matter, it's not that important, at best, right? And we know that cholesterol is the precursor for all of your steroids. If you lower your cholesterol, which by the way the cholesterol production in hypothyroid people is already low, so if you deprive them of the nutrient that has many other properties on its own, Ray talked about some of them such as protection against viral infections, it can neutralize some pathogens that enter the system if their white blood cells count is not high enough; anyways, in compromised people, if you lower their cholesterol even more, you're exposing them to all kinds of sort of assaults from the environment, and even internally, they would've been able to handle better if their cholesterol levels were higher. I provided a study which shows that low levels of LDL predate a cancer diagnosis by more than a decade. And that was independent of any other lifestyle choices such as smoking, <missed> excessively, doing drugs, living next to a power plant - I don't know if the researchers had control over that but they claimed to have control over a lot of lifestyle factors. So, it shows that it's a pretty powerful thing, it's probably not as good as the actual blindly lowered <check>, especially considering the fact that the official period doesn't say that we know with certainty that cholesterol is causing these plaques to form on the arteries. If you actually take these plaques, you really see that it's a combination of PUFA, calcium and a few other things; cholesterol may be there, but it's more like to protect from the damage and inflammation in vessel wall that the PUFA and calcium deposits are causing, so it's there by <missed>, not as a causative agent.

d: Were the fats damagin the ability of the cell to make the steroids? Is it the reducing agent, like any DPH?

h: Yeah, basically, if you eat a diet high in PUFA - and actually there's some evidence that excess fat intake, whether is saturated or not, will do the same but to a much smaller degree - but if you load up on PUFA, which will raise your inflammatory markers, in order for the body to sort of quench them, it uses the substance called NAD (which is nicotinamide-adenine dinucleotide), NADH is the reduced version of it, so, NAD is the oxidized and NADH is the reduced version of it; and it has been shown that the NAD to NADH ratio is perhaps the best health biomarker currently available. The higher the ratio is, the healthier you are, the longer you'll live, and the more resistant you'll be to a disease; the lower the ratio, the more prone you are to a disease, as a matter of fact high NADH levels are one of the diagnostic biomarker, not the only one, for several cancers, for parkinson's disease, for alzheimer's disease, in other words, they show that your body is in a reduced state, and PUFA is one the most powerful substances that lowers the NAD to NADH ratio, in other words, it raises the levels of NADH, it puts you in a reduced state. You don't want to be there.

d: The growth cancer state.

h: Exactly. So, in a reduced state, with not enough oxygen, basically the NAD to NADH ratio determines how well your body is oxidizing, how much oxygen is available to the cells; actually, how well they're using it because just providing oxygen to the cells is very often counter-productive. So it shows you how much carbon dioxide you're producing and how well oxigenated are your tissues. PUFA really put you far away from that state, is one of the few agents that - also radiation does the same, I think it's one of the reasons why I compare PUFA to radiation, because the two are very powerfully at lowering the NAD to NADH ratio, putting you in a disease state, and they've done, I don't know for how long, but you don't want to be in that state, is a disease state even if it's there temporarily.

d: My absolute favorite thing you listed in this post that kind of inspired us to chat was: you can take all this information but experiment is the ultimately arbitre, no amount of bickering or arguing over this or that study will make any difference if you don't test it out on yourself and try to gather information about yourself to get a better understanding of what's going on on your own body.

h: Yeah, I strongly encourage everybody to really do that. I mean, I don't wanna sound like - or Ray, I'm sure he doesn't wanna sound like the ultimate authority on the subject, he does say that something along the lines of the ultimate human faculty is the one that experiences, then experiment is the ultimate knowledge, something along those lines. So, go ahead, try it out yourself, and see how it makes you feel, if possible try to confirm that with some tests, I do have some suggested tests on the forum and I'm sure, Danny, you also provide a list of valuable test to people that they can do themselves. But you'll see the results yourselves, I'm pretty confident, in as little as one month which is one study <brutally missed>, actually in as little as two weeks on a fat free diet and one month on a very low fat diet, their tissues got fully depleted of PUFA and their metabolism increased 2x, all the animals lost all the excessive fat that they had and essentially their respiration became uncoupled. I think it's not that difficult for people to actually experiment and find it out for themselves, I think that that is the ultimate goal, you should find out what works for you. All Ray Peat's, and I personally am doing this trying to provide some directions for personal experimentation, <missed> I really don't <know it all>.

d: That was amazing. The last part I wanted to touch upon was if you had to eat out and have a meal higher in PUFA, what are some things that you can do to mitigate some of that damage?

h: Some of the best things that you can do to prevent the damage from even occurring is probably take a little dose of vitamin E; Ray has said that as little as 200IU would be sufficient, there'll be about 2/3 of 200 is about 150mg would be sufficient if you prefer in miligrams, most capsules on the market provide 400IU or above, that should be enough to prevent the damage that PUFA does, and one of the ways that vitamin E prevents the damage is that it turns the PUFA into saturated fat, the exact mechanism is still not known, but it's known that it happens. So, when you eat this PUFA and you take vitamin E, even if you end up storing that fat, it should be stored as saturated fat which is a lot more benign, both as stored fat and as actively burned fat than PUFA.

d: Georgi, thank you so much for chatting with me. That was extremely informative and I'm gonna have to chew on a lot of it, before you go, go ahead and let everyone know where they can find you on Ideal Labs as well as raypeatforum.com.

h: Sure. My information is pretty easy for people that are members of the forum - user haidut - when you log into the forum you'll be able to find me very easily, I comment on a lot of posts, I put a lot of new posts, to get to one in special just use the search box and search for haidut and you'll find me. My profile on the forum has a link to my website where I sell some supplements, I would like to point out that I'm not a salesman, I don't want you to buy my supplements, they are there simply to let you experiment if you don't have the time to experiment for yourself, but I actively encourage you to go out there, if you're willing to and you have the time, find the ingredients yourself and perform the experiments yourself and make your own supplements if you want to. But if you're interested in my supplements, you can find them in the profile of the forum. If you want to send me an email, again, is very easy: haidut at g-mail dot com; skype: haidut3; so far I've answered every email that was sent to me, so probably the email is prefferable <prepare for the flood..>. The forum is really the best because whenever I have a discussion with people I would like to be possible for the rest of the forum members to see it because it gives them additional knowledge, some people might have the same issue, some people might have additional comments and suggestions. Really, the purpose of the forum is to <missed> the discussion and get the collective knowledge going, not so much to help one individual person or listen to only one member of the forum.

d: Georgi, thank you so much for talking with me today.

h: Thank you, Danny. I really appreciate it and good luck with all of your endeavors, I look forward to speak to you again soon!

d: <Wrap up summary: Leave comments with suggestions for future podcasts using via his social media or whatever>
 
OP
P

PeatThemAll

Member
Joined
Oct 3, 2015
Messages
280
A must-read PUFA primer (The Haidut Edition)

Source: viewtopic.php?f=155&t=8033

haidut said:
post 103059 The key points are too many to summarize again, but they basically match my recent discussion with Danny Roddy. I have extracted some of the salient points from the studies I reviewed and they are shown below. However, I strongly recommend reading the full studies for those who have the time and are interested in the foundations of perhaps the central tenet of Peat's philosophy.
IMHO, this can be used as decent starting reading point for people new to Peat's ideas and questioning the veracity of his PUFA claims. Similarly, this can probably be used a good conversation starter with proponents of PUFA, who often dismiss Peat's claims on PUFA as "anecdotal". Well, not only are they not anecdotal but they go back to at least the 1960s as shown by the studies below. The studies are listed in chronological order, starting with the oldest study first.
Enjoy!


1. http://www.sciencedirect.com/science/ar ... 3271900383

"...“…“Essential fatty acids” is a generic term originally applied to all fatty acids which stimulate growth when supplemented to a fat-free diet or which prevent or cure dermatitis. When investigations in this field were begun, the best preparations of individual acids were not pure, and some investigations did not make observations of both growth and dermatitis. Hence, essentiality has been claimed for a variety of substances, which in the light of more recent knowledge resulting from more sophisticated experimentation, might not now be included in lists of active substances. Moreover, early experiments for the same reasons could not distinguish between different biological activities of groups of polyunsaturated acids. Thus, “linoleic, linolenic and arachidonic acids” are the acids traditionally considered to be essential, yet linolenic acid has been shown to be distinct from the other two in the biological activities they possess. Linoleic acid thus far has not been shown to be essential in the sense that it substitutes fully for fat in the diet. With better diets, with better balance of all known required nutrients, the difference between the performance on a fat-free diet plus linoleate and on a natural diet diminishes."

"...It seems unlikely that linolenic acid can support all normal functions, for in short term experiments it has been shown to be unable to replace linoleic acid in some respects. Thus, linolenic acid is strictly not proven to be an essential fatty acid, and that term properly should be applied to acids of the linoleate family only."

"...In a human, low EFA diet caused loss of weight and increased metabolic rate . These studies suggest that EFA is required for proper metabolism or utilization of saturated even chain acids.”

"...The prevention of scaliness of skin by EFA has been demonstrated in a number of species (see Chapter 8). In addition to these, the activity of these acids in prevention of scurf in silver fox pelts has been demonstrated. Acrodynia of rats, a complex deficiency disease could be cured by rice bran concentrate (B6) or by essential fatty acids. Claim has been made, but not confirmed, that rice bran concentrate likewise could cure the EFA deficiency syndrome.”

“…Corn oil affected plasma cholesterol less than did cod liver oil. The study suggests arachidonate is a potent hypocholesteremic fatty acid, and that the higher the degree of unsaturation of an acid, the greater is its effect. Nicolaysen and Ragatrd demonstrated that the long chain highly unsaturated fatty acids of fish and synthetic arachidonic acid possessed greater hypocholesteremic effect than does linoleic acid.”

“…The lowering of cholesterol concentration in blood plasma, which is currently considered desirable, may be accompanied also by an increase in the cholesterol content of tissues such as heart, aorta, liver, intestines and muscle. For example, tissues from rats fed 2 or 10% corn oil as a source of EFA contained more cholesterol than tissues from rats fed a low-fat diet. Thus, plasma cholesterol is not a suitable sole measure of the changes of cholesterol metabolism induced by ingestion of polyunsaturated acids or by other agents.”

“…Ahluwalia et al. [14] have investigated the incorporation of acetate, cholesterol and progesterone into testosterone and androstenedione in testis tissue in normal and EFA deficient rats. In the EFA deficient animal, conversion of acetate and cholesterol into testosterone and androstenedione was approximately double that from normal rats.”

“…The saturated acid 16:0 improved the rate of fertilization, whereas 18:1 reduced the rate. Within a restricted range of concentration, 20:1 enhanced the rate. Both 18:2-omega6 and 20:4omega6 exerted negative effects upon the rate of fertilization. Linolenic acid (18:3omega3) enhanced the rate of fertilization when sperm were pretreated with it, but it had negative action upon the egg. However, 22:6omega3 had a strong negative effect upon both sperm and eggs. In these experiments, exclusion of air is not possible, and the effects of oxidation products cannot be separated from those of the native acids.”

"...The somewhat lower content of body fat in EFA deficiency may be related to the excessive metabolism in that condition, as supplementation of EFA deficient animals with arachidonate causes the loading of adipose tissue with fat.”

"...EFA deficiency influences the metabolism of steroids, for in deficiency the synthesis of androgens from cholesterol was double that of rats fed linoleic acid.”

“…Slagsvold observed that cod liver oil poisoned cattle, with stiffness and muscle lesions as symptoms. In another study the toxicity of cod liver oil in calves was manifested as a severe muscular dystrophy. The effect was traced to the unsaturated acids and not the non-saponifiables in which vitamins A and D occur. Thus the effect is not due to hypervitaminosis. Similar lesions were observed in a variety of herbivors fed cod liver oil.”

“…The swelling of mitochondria in vitro is also used as a measure of membrane impairment, and dietary EFA diminishes such swelling (see page 292). Mitochondria from fat-deficient rats differ physically from normal mitochondria, their oxidative capacities are higher, and during isolation they are easily changed in form.”

“…Although mitochondria from all the species carry out many analogous metabolic reactions, no specific PUFA seems to be required for normal mitochondrial function. The requirement may be a more general one for some or any polyunsaturated acid available.”

“…Cardiolipin (CL) is known to contain a very high proportion of linoleic acid. In EFA deficiency, the content of linoleic acid in CL decreases. Refeeding linoleic acid (corn oil) for 16 days reverses that change and restores the linoleic acid content. Cardiolipin, which contains often as much as 80% linoleic acid seems to be specifically a target of linoleic acid, and whatever function this lipid has, it is also a function of linoleic acid.”

“…These studies amply prove the "downward" conversion of polyunsaturated acids to more saturated, shorter chain length compounds. The convertibility of the PUFA precursors to longer chain more saturated products is well known. Thus, it is clear that mammalian tissue is capable of converting PUFA either up or down, and to discuss "which is the real essential fatty acid" is without meaning.”

“…MacKenzie et al. determined the prophylactic dose to be 23 mg (linoleic acid) per rat per day, allowing normal growth and reproduction.”

Haidut: The above dose in rats amounts to about 13mg/kg daily for a human.

“…The amount of dietary linoleate needed to induce the synthesis of normal amounts of these metabolites was estimated to be 0.5% calories from the appropriate exponential dose-response curves.”

“…Current studies involving more sophisticated experimentation are again bringing into consideration the possibility that PUFA may have deleterious effects, and that the popular concept that "if a little is good, much will be better" may not apply to PUFA. It may be well to re-examine the current medical and advertising policy which attempts to substitute a plethora of PUFA for a relative deficiency of essential fatty acids.”

“…Harmon has investigated the effects of fat level and degree of unsaturation of fats upon longevity in mice and rats. In female mice of the C3H strain fed 5, 10 or 20% of either lard, olive oil, corn oil, safflower oil or menhaden oil, the survival at 16 and 20 months of age decreased with increasing fat content of the diet or with increasing unsaturation of the fat.”

“…Sterility in male chickens can be induced by diets with a high content of linoleic acid and low content of vitamin E. After sterility is induced by this regimen, it can be reversed by re-supplementing with tocopherol, and semen production is improved by the supplementation. This study shows that the adverse effect of high dietary polyunsaturated acids and low tocopherol is not irreparable.”



2. http://www.ncbi.nlm.nih.gov/pubmed/2120529

“…It was surprising to find that low levels of dietary linoleic acid (0.3% of calories, 150 mg/100 g food intake) did not have any effect on reproduction, gestation, perinatal mortality, body weight increase, or overall mortality.”



3. http://www.ncbi.nlm.nih.gov/pubmed/14559071


“…The term ‘essential fatty acid’ is ambiguous and inappropriately inclusive or exclusive of many polyunsaturated fatty acids. When applied most rigidly to linoleate and a-linolenate, this term excludes the now well accepted but conditional dietary need for two long chain polyunsaturates (arachidonate and docosahexaenoate) during infancy. In addition, because of the concomitant absence of dietary a-linolenate, essential fatty acid deficiency is a seriously flawed model that has probably led to significantly over-estimating linoleate requirements. Linoleate and a-linolenate are more rapidly b-oxidized and less easily replaced in tissue lipids than the common ‘non-essential’ fatty acids (palmitate, stearate, oleate). Carbon from linoleate and a-linolenate is recycled into palmitate and cholesterol in amounts frequently exceeding that used to make long chain polyunsaturates. These observations represent several problems with the concept of ‘essential fatty acid’, a term that connotes a more protected and important fatty acid than those which can be made endogenously. The metabolism of essential and non-essential fatty acids is clearly much more interconnected than previously understood. Replacing the term ‘essential fatty acid’ by existing but less biased terminology, i.e. polyunsaturates, omega-3 or omega-6 polyunsaturates, or naming the individual fatty acid(s) in question, would improve clarity and would potentially promote broader exploration of the functional and health attributes of polyunsaturated fatty acids.”

“…The dietary refinements were that nutritional studies involving low or deficient levels of linoleate and a-linolenate required diets with relatively pure components (both macronutrients and micronutrients). Requirements for several other nutrients, especially minerals, were also being identified at this time, so many studies on PUFAdeficiency were simultaneously plagued by inadequate levels of minerals such as zinc.”

“…This problem is exemplified by the recent proposal from the Institute of Medicine in the USAthat current linoleate intakes are an adequate surrogate for estimating actual linoleate requirement despite the fact that the current linoleate intake in the USA greatly exceeds what reasonably appears to be needed (see Section 11—Problem 9).”

“…By designating all fatty acids derived from linoleate and a-linolenate as EFA, the inclusionists avoid the problem of excluding long chain PUFAthat are ‘conditional’ EFA. Effectively, but perhaps unintentionally, this creates the opposite dilemma of giving the status of ‘essential’ to over 30 PUFA (Table 1), most of which have no known function and are certainly unlikely to be demonstrated to be truly necessary in the diet throughout the life cycle. “

“…However, the opposite experiment is perhaps more instructive; what is the tissue PUFA profile at the lowest dietary level of linoleate (or a-linolenate) that supports apparently normal growth and development in the rat? How much of these fatty acids is needed to support normal physiology, irrespective of tissue fatty acid profile? This experiment was done by Mohrhauer and Holman 30 years ago [17]. When a-linolenate was present as the only PUFAbut at a level sufficient to permit apparently normal growth (>1.4% of energy), linoleate was as low as 0.3% and arachidonate as low as 0.5% of liver fatty acids. When linoleate or arachidonate alone were the only PUFA in the diet but were present in amounts sufficient to permit normal growth (0.6 and 0.5% of energy, respectively), docosahexaenoate could be as low as 0.14% of total fatty acids (Table 2).”

“…This report [17] shows that tissue levels of the ‘key’ PUFA(linoleate, arachidonate and docosahexaenoate) can be extremely low (collectively < 5% of liver total fatty acids) yet normal growth can still be achieved in the rat. This contrasts with estimating linoleate requirement on the basis of the plateau in tissue arachidonate, which occurred at a forty fold higher dietary level [7] than in Mohrhauer and Holman’s study [17]. Rather than emphasizing a match between normal growth and the level at which tissue PUFA plateau at a maximal concentration, the emphasis should be on the lowest dietary level at which growth (and associated criteria of physiological wellbeing) is indistinguishable from normal. There was no difference in growth in either of these examples but there was at least a 3–4 fold difference in the total tissue PUFA concentration [7,17].”

“…If, as suggested by physiological data in the study by Bourre et al. [7], linoleate intake at 1% of energy turns out to be roughly double the true linoleate requirement, the excess above the required intake might well be disposed of by oxidation. The apparently high rate of linoleate oxidation would then be explained by the fact that 1% linoleate in the diet generously exceeded its requirement.”

“…Whole body fatty acid balance studies bring to light the interesting point that various forms of undernutrition can markedly stimulate oxidation of the two parent PUFA. Undernutrition increases fatty acid oxidation, which is how ATP is regenerated when there is an inadequate supply of glucose. It is surprising, though, how actively linoleate and a-linolenate are utilized in this process. In fact, during fasting/refeeding or weight cycling, they are sufficiently oxidized that tissue PUFA depletion rapidly occurs in both animal and human models ([28–30]; Table 5). Again, this is counterintuitive; in principle, EFA should be conserved, at least depleted less rapidly or restored more rapidly than non-EFA. This is not the case.”

“…Perhaps it is self-evident that if a fatty acid can be synthesized endogenously or obtained from the diet, then it should be easier to replace in tissues after a period of undernutrition than a fatty acid that can only be replaced from the diet. Still, a fundamental contradiction arises when fatty acids of supposedly greater importance to the body (EFA) are depleted more easily and replaced less easily in tissues than fatty acids of supposedly no dietary importance (non-EFA). I have a problem accepting that palmitate and oleate are non-EFA if indeed the body is capable, after a period of food depletion, of replacing them in tissues faster not only than the 18 carbon PUFA but faster even than the arguably more important long chain PUFA, arachidonate and docosahexaenoate[28].”

“…This argument challenges the suitability of defining the need for a fatty acid on the basis of whether or not it can be synthesized endogenously. Glucose is no less important because it can be synthesized endogenously. Palmitate should likewise be considered no less important than linoleate. We don’t know very much about what palmitate does but it is present in most membranes at levels than match (or, in the case of the brain, greatly exceed) those of linoleate and we now know it has a key role as one of the lipid ligands in the expression of hedgehog proteins that control normal embryonic development [15]. Under these circumstances, thinking of it as a non-EFA is scientifically and philosophically inappropriate and should be abandoned.”

“…If palmitate and oleate can be widely designated as non-EFA, cholesterol fits the same description as a ‘non-essential lipid’ since it, too, is readily made endogenously. Does it make sense that EFA are actively used to make non-EFA and cholesterol at rates that can exceed by 30-fold their use as precursors of long chain PUFA, i.e. in the developing rat brain[34]? Why oxidize or otherwise consume valuable EFA carbon in the synthesis of non-EFA even under circumstances when that EFA (linoleate) is extremely limiting due to severe and prolonged dietary PUFA deficiency [32,33]? Why oxidize docosahexaenoate[35], which is in great demand during early development, and recycle it into palmitate, stearate and oleate even when there is no dietary docosahexaenoate present[36]? It may be unavoidable for all PUFAto undergo some degree of oxidation but carbon recycling short-circuits oxidation before the acetyl CoAgets to CO2 and sees it recovered in newly synthesized lipids (and perhaps many other molecules that have not yet been identified or studied). What results is a largely nonsensical situation in which EFA (including docosahexaenoate) are actively used to make non-EFA. Is that part of the reason EFA are ‘essential’? If we discontinue the terms EFAand non-EFA, we relieve this situation of bias and encourage exploration of the meaning and possible importance of these observations.”

“…Even the minimalists adhere to designating linoleate and a-linolenate as EFA. The rationale is simple. Linoleate and a-linolenate cannot be synthesized de novo in mammals and they, or their long chain PUFA derivatives, have functions in the body not fulfilled by other compounds and for which symptoms occur when they are deficient in the diet. That is reasonable except that PUFA deficient rats can synthesize linoleate and a-linolenate by elongation from their sixteen carbon homologues, hexadecadienoate (16:2o6) and hexadecatrienoate (16:3o3)[12]. Even tetradecadienoate (14:2o6) and tetradecatrienoate (14:3o3) can be elongated to linoleate and a-linolenate, respectively, but the twelve carbon homologues cannot[12].”

“…Hence, rodents (and humans) on a mixed diet containing a variety of green vegetables are synthesizing a low but measurable amount of linoleate and a-linolenate from hexadecadienoate and hexadecatrienoate, respectively.”

“…Thus, contrary to received wisdom, mammals can synthesize linoleate and a-linolenate because their precursors are not only readily chain elongated through an existing and active pathway but also because the precursors are common in the human diet. The point is that the statement that ‘linoleate and a-linolenate cannot be synthesized’ (in mammals) is incorrect unless it is qualified by the addition of ‘de novo’.”

“…Few if any well-controlled studies have ever been done looking at linoleate requirements in humans. None have been done recently. The best estimates arising from experimental measurement (as opposed to epidemiological assessment of average linoleate intake) suggest that about 1% of energy intake as linoleate is sufficient to meet omega-6 PUFA requirements in healthy adults[3–5]. Higher requirements are assumed to exist during pregnancy, lactation and early development but are still thought not to exceed 3% (ISSFAL). These values are still confounded by the absence of omega-3 PUFA in the original dietary studies, a problem that conservatively inflates the linoleate requirement of rats by 50% [7]. Thus, a more realistic linoleate requirement in humans should vary from about 0.5% to about 1.5% of energy intake depending on physiological status. At present in North America, average linoleate intake is about 8% of energy intake, i.e. at least five times and up to as much as 16 times the reasonable estimate of its requirement in most healthy people (8% versus 0.5–1.5% of energy intake).

“…A recent report commissioned by the Institute of Medicine of the US National Academy of Sciences recommends that the current intake of linoleate in the USA is ‘adequate’, i.e. 17 g/day for men or about 5% of energy based on an overall energy intake of 3000 kcal/day. (http://www.iom.edu/IOM/IOMHome.nsf/Pages/Whats+New). An ‘adequate intake’ sidesteps the issue of determining requirement. Continuing to cloak linoleate as ‘essential’ in the USA where a-linolenate is still not given equivalent status makes a mockery of this terminology. More importantly, such a distinction still insidiously allows promotion of linoleate as ‘the EFA’. Certain representatives of the food industry with a vested interest in promoting linoleate intake have already begun representing this ‘adequate’ linoleate intake as appropriate and desirable even though it exceeds what is needed by at least 5 fold. Experimental evidence indicates that a more reasonable linoleate requirement would be about 3–4 g/day on a 3000 kcal/day diet.”

“…Few intervention studies to test the risks or benefits of high linoleate intake have been done that have assessed long term health outcomes and mortality. While some have shown that linoleate is innocuous and perhaps even beneficial to reduce serum cholesterol [46], others looking at cancer risk and overall mortality disagree [45]. I believe this issue needs conscientious attention and that it will not be solved unless a new paradigm is adopted when referring to nutritional requirements for PUFA.”

“…It arises from the fact that healthy adults generally have at least 1 kg of linoleate in body stores, more if they have more than 20% body fat. If the true linoleate requirement of a healthy adult human is about 5 g/day, there is a store of linoleate in body fat alone that would last 200 days; even if it is 10 g/day, there is a 100 day (>3 month) store.”

“…Despite very good reasons to promote the consumption of dietary sources of eicosapentaenoate and docosahexaenoate, these two PUFA have been classified as conditionally dispensable because many populations have relatively low risk of chronic degenerative diseases, especially heart disease and cancer, while consuming negligible amounts of these fatty acids. Again, in geographical areas or with lifestyles in which heart disease risk is elevated, eicosapentaenoate and/or docosahexaenoate may well be beneficial and, indeed, would be classified as conditionally indispensable.”



4. http://www.ncbi.nlm.nih.gov/pubmed/18990554

“…The objective of this session was to address this fundamental question, ‘‘What would be the impact on health if an individual modified their typical intake of LA (linoleic acid), either up or down?’’ So, if the public chose to consume less LA, would their risk for chronic disease go down because they were consuming less n-6 polyunsaturated fatty acids (PUFA), and would their risk increase if they were to increase their consumption?”

“…AA is arguably the most important cell signaling PUFA associated with membrane phospholipids. It is this ability of LA to be potentially converted to AA-derived eicosanoids that is so troubling to scientists. Following the release of AA from membrane phospholipids by a variety of phospholipases, AA can be enzymatically oxidized to prostaglandins (PGs) by the two cyclooxygenase (COX) isoforms (COX-1 and -2), the committed step in the biosynthetic pathway. AA is a preferential substrate for PG biosynthesis [6]. Chronic and elevated levels of PGs, such as PGE2 are linked to the promotion and progression of cancers [7]. Likewise, other AA-derived eicosanoids such as leukotrienes (LT) (i.e., LTB4 and cysteinyl-LT) are linked to inflammation [8] and asthma [9], and thromboxane formation has been linked to platelet function and cardiovascular disease risk.”

“…The implications of this would be important. For example, with cancer it has been proposed that while AA is a protumorigenic fatty acid because it can be converted to bioactive PGs, there appears to be a threshold for this effect and any benefit appears to be observed only when tissue levels of AA drop below this threshold [17]. This would suggest that alterations in LA intake needed to impact tissue AA levels and subsequent cancer risk would require drastic changes in food consumption patterns, i.e., elimination of animal products (meats) because they all contain preformed AA [18], in addition to a reduction of LA intake below 2% energy. A review of the cancer literature appears to bear this out.”



5. http://www.ncbi.nlm.nih.gov/pubmed/23900039

“…Because the physiological requirement of linoleic acid appears to have been overestimated due to methodological bias during early investigations performed in the 1920’s, the hypothesis that the current intake of linoleic acid could contribute to the development and increase of inflammation and metabolic diseases has gained momentum[6].”

“…These works pointed out all physiological symptoms of linoleic acid deficiency (growth rate, fertility and skin symptoms) and histological changes in organs (liver, kidney and lung). These studies led to the widely admitted linoleic acid requirement in animals at about 1% of the dietary energy intake [11].”

“…Moreover, several studies have shown that a minimal of 0.5% energy intake of a linolenic acid is required for normal reproduction and development [12,16,20]. Two recent studies have also shown that dietary a linolenic acid is able to diminish the symptoms of n-6 PUFA deficiency.”

“…These linoleic acid metabolites have been reported to promote a strong pro-inflammatory response in rats [42,43]. For the first time in humans, a recent study showed that reducing dietary linoleic acid from 6.8 to 2.4% of energy intake, decreased the concentrations of Oxlams in plasmas.”

“…To conclude, Oxlams are pleiotropic bioactive derivatives of linoleic acid. They seem to be implicated in a variety of pathological conditions. Oxlams are reported to play a key role in foam cell formation and pathogenesis of atherosclerosis [50,51]. Some studies have also shown an elevated circulating level of Oxlams in Alzheimer’s disease [45] and steatohepatitis [52].”

“…Previous reports suggested that elevated intakes of linoleic acid during early stages of development may be related to the development of obesity [58,59]. Ailhaud et al. suggested that an excess of n-6 fatty acid could contribute to excessive adipose tissue development. In piglets, arachidonic acid supplementation (0.5% of total fat) caused a 27% increase in body weight, probably due to increased fat mass [60]. A significant positive correlation between plasma arachidonic acid levels and human infant body weight was also reported [47]. Moreover, among long chain fatty acids, arachidonic acid is the main adipogenic component because it is the precursor of prostacyclin.”

“…Additionally, arachidonic acid metabolites (prostaglandins and leukotrienes) seem to have other implications in tissue growth. Several in vitro studies investigating on breast cancer showed a high activity of COX2 in tumor [63]. An inhibition of COX 2 reduced the synthesis of pro-angiogenic prostaglandins whereas COX 2 was positively associated with lymphoangiogenesis, which is a key step of metastatic progression [64,65]. To conclude, arachidonic acid metabolites have a potent role in angiogenesis and tumor growth.”

“…Endocannabinoids could be considered as linoleic acid derivatives. Nevertheless, few studies have investigated the effect of dietary linoleic acid on the endocannabinoid system [70]. Animal obesity seems to be associated with an elevated endocannabinoid concentration [71] and probably via a downregulation of adiponectin release, probably due to CB1 receptor activation. Moreover, the CB1 receptor stimulates adipocyte proliferation [69], and participates in the preadipocyte differentiation into mature adipocytes, which induces the accumulation of lipid droplets and stimulates the fatty acid synthesis both in adipose tissue and the liver [72]. Using diets with 8% linoleic acid as energy intake, Alvheim et al., have shown a correlation between the level of linoleic acid and endocannabinoid synthesis [70]. Indeed, this study has demonstrated a significant increase in endocannabinoids when increasing the percentage of dietary linoleic acid (from 1% to 8% energy intake).”

“…In conclusion, this part summarizes the major metabolic pathways where an excess of linoleic acid intake could have an impact. It may have implications in metabolic diseases like obesity which could be considered as a component of atherosclerosis and also in tumor growth.”

“…This new approach of SDHS coupled with the use of modern statistical analysis showed a higher total mortality in the group receiving the high linoleic acid diet. Moreover, this study highlighted the increased risks of death from coronary heart disease with an increase in linoleic acid in the diet.”


6. http://www.ncbi.nlm.nih.gov/pubmed/25787691

“…Although LA is described as an essential fatty acid in the literature, the deficiency symptoms (reduction of growth and scaliness) could not be completely and specifically attributed to a sole LA deficiency since the conditions in the previous studies included both LA and ALA deficiency in lipidoprive conditions.”

“…We are aware that beyond the necessity to redefine the dietary requirement of LA, many questions concerning the consequences of its excessive consumption on human health arise. Indeed, in human health, the precautionary principle has to be applied since the LA requirement was already over evaluated. Although many authors claim that this minimal requirement could be overtaken without risk for health (The American Heart Association for example) (37), the literature points out the deleterious effects of a LA excess and of a high LA:ALA ratio as well.”

“…Indeed, in vitro LA studies had already demonstrated the inflammatory properties of both LA oxidized metabolites and 20 : 4n-6 derivatives (i.e. PG and thromboxane).In human studies, a first meta-analysis led by Ramsden et al., including results from Oslo Diet Heart and Lyon Diet Heart Studies, detailed the specific n-6 PUFA effects in increasing CVD. Moreover, a very recent meta-analysis has completed the previous cited meta-analysis results and put forward the hypothesis that an excess of LA (by extension the n-6 fatty acid family) could play a non-negligible role in CHD. Actually this new approach of Sydney Diet Heart Study coupled with the use of a modern statistical analysis showed a higher total mortality in the group receiving the high LA diet. Moreover, the present study highlighted the increased risks of death from CHD and CVD with an increase in LA in the diet. Obviously, more studies are needed to confirm these previous results.”
 
Last edited by a moderator:
OP
P

PeatThemAll

Member
Joined
Oct 3, 2015
Messages
280
Thanks to everybody!

Further to feedback, this series will be continued in a different post (same idea, diferent format: sticky links, bonus: always mirrors any updates/edits):

Best of Haidut

Thank you for your understanding.
 

Similar threads

Back
Top Bottom