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How Relevant Are Studies On Rodents?

Wilfrid

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Hi everyone,

It seems that long term pertubations of the pituitary-thyroid axis by various xenobiotics or physiologic alterations ( eg, iodine deficiency, partial thyroidectomy, PUFA, goitrogenic foods...) are more likely to predispose laboratory rodents than humans to a higher incidence of proliferative lesions in the thyroid.
" This appears to be particulary true in the male rat, which usually has higher circulating levels of TSH than the female rat.
The greater sensitivity of the rodent thyroid/metabolism to derangement by drugs, chemicals, herbs, foods and physiologic pertubations also is related to the shorter plasma half-life of T4 rodents than in humans due to considerable differences between species in the transport proteins for T4.
The plasma half-life of T4 in rats (12 -24 hours) is considerably shorter than in humans (5-9 days). This is related in part to differences between species in the transport proteins for T4 and T3. In humans and in monkeys, circulating T4 is bound primarily to thyroxine-binding globulin (TBG); however, this high-affinity binding protein for T4 is not present or is present in minute amounts in rodents, birds, amphibians, and fish. The binding affinity of TBG for T4 is about 1000 times higher than for T4-binding prealbumin or transthyretin. The percentage of unbound active T4 is lower in species with high levels of TBG than in animals in which T4 binding is limited to albumin and prealbumin.
T3 is transported bound to TBG and albumins in humans, monkeys, and dogs but only to albumin and transthyretin in mice, rats, and chickens." source: Werner and Ingbar's The Thyroid.

Keeping the statement made above in mind, I was wondering how relevant is to transpose studies (involving the thyroid, PUFA ect....) made on rodents to humans?
In most case, it seems that those studies probably reflect the worst scenario for humans.....and that our tolerance for any thyroid disturbing subtances are probably much higher than we think.
Any opinions?
 

Edward

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Because we also have cell studies that demonstrate decreased mitochondrial respiration with PUFA in the absence of thyroid. While thyroid controls overall metabolism, in the end, it is the ability of the mitochondria to respond to thyroid that determines how efficient cellular respiration is.

PUFA also causes changes in lipid membranes of mitochondria which increases the production of reactive oxygen species (ROS). When the mitochondria of cells are damaged from PUFA increasing thyroid will increase the generation of ROS which often will induce apoptosis of the cell. Almost literally the cells die of oxygen poisoning because the mitochondria can no longer use oxygen efficiently. This also causes Cythochrome c to leak which is involved with aromatic oxidation. Hello estrogen.

Further we have the cell organelle called peroxisomes which are essentially detoxifying organelles. In the presence of PUFA they up regulate trying to break down long chains of PUFA. In contrast saturated fats do not induce peroxisome proliferation.

As far as tolerating thyroid disturbing substances the threshold is usually different. For example green and black tea extracts can induce physiological changes in the thyroid in relatively small amounts in rats. I remember reading somewhere that about 5+ cups of tea would be the equivalent in humans to disrupt the thyroid.

The short answer is that PUFA with or without thyroid is problematic and in the case of goitrogenic substances it depends on how efficient the metabolism is at detoxifying substances and how quickly you saturate the body with those substances.

Because we have a propensity towards entropy I would say that if there is one substance to avoid that has the potential to benefit everybody it would be avoiding the polyunsaturates. And really that is quite easy to do. Even in grains most of the polyunsaturated fat is in the fiber. Remove the fiber and your left with essentially starch. 1 cup of white wheat flour has 277mg of saturated fat, 277mg of monounsaturated fat, and 771mg of polyunsaturated fat. Food allergies and the problematic nature of some plant proteins aside.

When people start asking about PUFA I usually get the impression that people are getting bored with drinking milk and orange juice. Who would want to eat that way for the rest of their life? You have teeth. Use them. But let me remind those of you who feel that way that nowhere does Dr. Peat recommend drinking milk and orange juice for the rest of your life. They are simple tools to emphasize at certain periods and in normal periods a welcome addition to a rational diet.

“Well the only foods I would suggest eliminating would be the grains and beans, and most of the nuts, and probably reducing most meats. Gelatin happens to be the part of the meat that doesn’t have so many of the disturbing acidic pro-inflammatory effects.” ~Ray Peat, March 16, 2012. Radio interview on Ask Your Herb Doctor.

There is exponential variety within Dr. Peat’s paradigm.
 

jyb

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What happens to the cell once one of its part is damaged? Let's say that, due to PUFA, high production of ROS affects the mitochondria. Is it a good thing that it then dies, thereby not affecting the tissue it belongs to with erratic functioning due to damaged apparatus and possibly spreading the damage through division? If damage is spread through division, then I don't see how a tissue can regenerate itself, as new cells are only getting worse over time. A mainstream idea is that depriving cells of energy, let's say by exercising intensely without providing energy, kills the less efficient cells which presumably would be the damaged ones thereby leaving the tissue with a higher proportion of efficient cells, but I'm sure that idea was opposed by RP in his articles.
 

Wilfrid

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The studies which involved PUFA and decreased mitochondrial respiration was probably made in vitro, right?
And even if it happens to be the case in vitro, how can we be sure that the same thing happen in vivo as much more variable are probably involved...
 

Edward

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jyb said:
What happens to the cell once one of its part is damaged? Let's say that, due to PUFA, high production of ROS affects the mitochondria. Is it a good thing that it then dies, thereby not affecting the tissue it belongs to with erratic functioning due to damaged apparatus and possibly spreading the damage through division? If damage is spread through division, then I don't see how a tissue can regenerate itself, as new cells are only getting worse over time. A mainstream idea is that depriving cells of energy, let's say by exercising intensely without providing energy, kills the less efficient cells which presumably would be the damaged ones thereby leaving the tissue with a higher proportion of efficient cells, but I'm sure that idea was opposed by RP in his articles.

It depends on the circumstance because not all stress is lethal to a cell, good nutrition and having adequate magnesium and sodium are protective among other things. If nutrition is adequate cells are able to generate enough energy to recover.

Cytochrome c release is proceeded by an influx of calcium, the influx of calcium is preceded by stress. When Cytochrome c is released or leaks, I'm not sure it is on purpose or not (because I view cells as structured gradients), because it seems like the mitochondrial membranes loose integrity from the intracellular uptake of calcium; but either way it is released and it continues to sustain uptake of calcium via release of other enzymes and because it can no longer function to catalyze the oxidation of estrogen, this causes estrogen to localize, which in this case it is good because it is a basic defense mechanism in the short term.

"The production of estrogen is a basic defensive reaction that is very easily misdirected. " ~Dr. Peat, Personal communication

Estrogen will cause a positive calcium balance in the cells. The sustained realease of Cytochrome c activates enzymes which essentially destroys the cell. Once the cell is destroyed healthy cells with intact Cytochrome c will metabolize the left over estrogen, and healthy cells will divide and fill in the gap.

PUFA is problematic because it makes respiration less efficient. It takes much longer for the cell to die. In the meantime ROS is going everywhere. Because the cells are stressed this probably is a factor that leads to estrogen dominance because this is essentially inflammation and this is what causes soft tissue to calcify because estrogen causes positive calcium balance. Your ability to deal with estrogen will depend greatly on PUFA intake and clearance which will be determined by thyroid status and how efficient respiration is i.e. the metabolism.

Still as we age PUFA collects and impacts cellular membranes which leads to less efficient metabolisms and calcium collects and we bite the dust. Usually those who have higher metabolisms compared to their peers seem to live longer.

Yet PUFA is not the only factor. You can eat a PUFA free liquid diet and die of boredom. There are other psychological factors at play. And interestingly psychology can greatly impact the generation of ROS and the handling of PUFA and other stress inducing compounds such as endotoxin.

Exercise probably does kill weaker cells, but at the expense of stressing other cells as well. I'm not in the business of telling people whether or not to exercise, by my opinion is that walking and weights is safe. I've never seen competitive endurance athletes that have been running all their life live long lives. There were a few that started when they were already old and I saw that one ran a marathon and a year or two later died. But he was already 99 or 100. I can't remember so he might have died anyway or he might have shortened his life. One exception is Ed Whitlock who is in his 80's and still runs marathons. But he trains quite a bit different from most runners and it is unlikely he will see 100. But I have seen examples of weight lifters who lived long and were still sturdy, and interestingly the gentleman who I'm thinking of was a big proponent of milk. Still having "explorative purpose" is probably even more energizing to physiology.

Interestingly red light stimulates Cytochrome c, that would be a good thing in intact mitochondria, because it would increase oxidation of estrogen.

I hope that answers your question jyb. Feel free to ask more if I missed something and I will try to answer.
 

Edward

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Wilfrid said:
The studies which involved PUFA and decreased mitochondrial respiration was probably made in vitro, right?
And even if it happens to be the case in vitro, how can we be sure that the same thing happen in vivo as much more variable are probably involved.

I will pull some papers for you Wilfrid.
 

jyb

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Edward said:
Still as we age PUFA collects and impacts cellular membranes which leads to less efficient metabolisms and calcium collects and we bite the dust. Usually those who have higher metabolisms compared to their peers seem to live longer.

I notice you never mention degradation of genetic information as part of the ageing process, where information received by a new cell is of equal or lower integrity than its parents, which would inevitably lead to ageing. Instead, you describe it in terms of PUFA and calcium accumulation, which seems more reversible: if one ate healthy but absolutely no PUFA (which may impossible in practice), then eventually cells and stored fats renew, then PUFA would exit and ageing would stop? If the renewed cells are healthy (perfect membrane composition), surely the tissue would remain damaged (I mean aged) to some extent, so something is irreversible.

Edward said:
Yet PUFA is not the only factor. You can eat a PUFA free liquid diet and die of boredom. There are other psychological factors at play. And interestingly psychology can greatly impact the generation of ROS and the handling of PUFA and other stress inducing compounds such as endotoxin.

Can't boredom be interpreted in terms of PUFA and usual culprits? It would be easy to imagine how boredom eventually creates psychological, and then physiological stress, reduced metabolic rate and PUFA accumulation. You seem to think that psychology acts by a different and unexplained mechanism.
 

Edward

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jyb said:
I notice you never mention degradation of genetic information as part of the ageing process, where information received by a new cell is of equal or lower integrity than its parents, which would inevitably lead to ageing. Instead, you describe it in terms of PUFA and calcium accumulation, which seems more reversible: if one ate healthy but absolutely no PUFA (which may impossible in practice), then eventually cells and stored fats renew, then PUFA would exit and ageing would stop? If the renewed cells are healthy (perfect membrane composition), surely the tissue would remain damaged (I mean aged) to some extent, so something is irreversible.

Correct. Because I view it as secondary. If a cell is stress resistant, replication of DNA will be accurate. When stress is overwhelming this is what causes inaccurate DNA replication. Essentially because we are exposed to stress everyday it is inevitable that DNA replication will be interfered with, I prefer to deal with primary stressors that an individual has practical control over. Even then, it is not always bad. I think it depends on the stress, outright damage is probably unwanted. But a cell adapting to stress—well—Dr. Peat believes that it is the stress of the adaptation process that is a central cause of ageing—I disagree—I can understand how one can come to that conclusion but I disagree. I view aging in mainly two contexts. It can be a positive adaptive process or negative adaptive process. We age because we fail to adapt not because of the actual stress (excluding lethal stresses, surprisingly though individual lethal stress can be a positive adaption for the species in some circumstances). I very lightly touched on this in my fetal programming essay. I’m not sure I would consider it desirable for “aging” to stop. “Irreversible” changes can be positive or negative. Positive changes allow continual adaptation and negative changes stall adaptation. Because the nature of stress is always evolving, I think it is desirable to have “experienced” cells, not quote-unquote “healthy” cells.

jyb said:
Can't boredom be interpreted in terms of PUFA and usual culprits? It would be easy to imagine how boredom eventually creates psychological, and then physiological stress, reduced metabolic rate and PUFA accumulation. You seem to think that psychology acts by a different and unexplained mechanism.

In a certain contexts, yes, in others, no. The biggest piece of evidence I have in my favor is the placebo effect. And that is a big piece of evidence. I think psychology is an intelligent feedback loop. I think that nutrition plays a role in “aging” but I think psychology is a primary factor and nutrition secondary. I am writing a book about this idea titled: “Your Ideas on Nutrition are Superstitious”; the book will be free when it is finished. In a vacuum the PUFA theory works well. In the real world it fails to explain certain phenomena in a satisfying way. I think it is perfectly logical and rational for Wilfrid to be skeptical, there is reason to be skeptical. Now, although that is somewhat paradoxical, I'm not endorsing drinking a bottle of corn oil nor am I implying that you shouldn't avoid PUFA. I think it is extremely beneficial to humanely avoid PUFA. That's not what I'm saying. I discuss in detail these things and give good examples of this in my book.

The idea that there is an optimal diet is extremely mechanical thought. And again, that is not to say some ways of eating aren't better than others, merely, the outcome of such ideas is problematic.
 

pboy

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I agree, your mindset literally directs your DNA and hormones, and with enough healthy hormones flowing through your body, especially testosterone, you can overcome nearly any
potential infection or stress response that could damage cells. Technically, everything is reversible, its just a matter of how difficult it is for each person, and the fact that yes, most of the changes would require mental, psychosomatic, relationship, lifestyle...possibly full makeover changes to your life....something that after a certain point in their lives most people are just too resistant to. The idea is that being 'rigid', or stuck, or inflexible leads to calcification of joints, organs, muscles...thereby permanently inefficient metabolism, and the likelihood for calcium, PUFA's, arterial plack, estrogen, ect to accumulate. With less PUFA in your diet, you are more likely to be operating in a faster metabolic state, therefore more likely to be able to thwart any potential infections (mental and physical) as they occur in real time, but I agree with Edward...its ultimately the mindset that determines whether or not things 'stick' per se. Being able to forgive yourself and move on is huge
 

DaveFoster

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