Uncoupling Mice Brain Mitochondria Extends Lifespan

ejalrp

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This study seems puzzling in light of what RP claims is one of the best indicators of general health. I'm trying to figure out how this study doesn't contradict RP but have not found an explanation yet. Anyone else?

Cool mice live longer : Nature News
 

haidut

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This study seems puzzling in light of what RP claims is one of the best indicators of general health. I'm trying to figure out how this study doesn't contradict RP but have not found an explanation yet. Anyone else?

Cool mice live longer : Nature News

This study title is misleading. Here is what they actually did.
"...Conti's team managed to cool down mice using genetic engineering. They used a gene called uncoupling protein 2, which diverts the cells' mitochondria from their usual task of making chemical energy, and instead prompts them to release energy as heat. They inserted this gene into a group of brain cells in the animals' hypothalamus and near to the region that senses and controls body temperature, much like a thermostat. The gene effectively heated up the thermostat and, as a result, tricked the rest of the body into cooling down by 0.3 to 0.5 °C."

So, they effectively uncoupled the animals' brain mitochondria. The real title of the study should have been "Uncoupling mice brain mitochondria extends lifespan". Uncoupling the metabolism is something Ray has written many times as a viable life extension strategy. Uncoupling mitochondria means higher metabolism, not lower. The lowering of the body temperatures was not shown in any way to be the actual cause for the extended lifespan.
This is actually pretty sneaky title picking. Unless the PR agency that prepared the article is really clueless about what uncoupling does, I am inclined to chalk this one off to deliberate misrepresentation.
 

ejalrp

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I see your point, but for the mice to be cooler, it seems by definition that metabolism of the body considered as a whole had to be slowed down (or their temps wouldn't have dropped). So even if a group of cells (mitochondria) in the brain were uncoupled, the bulk of the mouse's metabolism must have been slowed (again by definition). I suppose one can make the claim that the benefits of uncoupling some mitochondria in the brain somehow outweighed the negative aspects of slowing metabolism in the rest of the body but that would seem like a bit of a stretch.
 

Giraffe

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it seems by definition that metabolism of the body considered as a whole had to be slowed down (or their temps wouldn't have dropped).
Temperature alone is not a marker of metabolism. It's things like oxygen consumption, heat production that are used to determine metabolic rate. Heat production has not been measured in the experiment, but the the body temperature which is maintained through vasodilation or vasoconstriction in the skin and sweating, regulated by nerves and hormones.

"The mice inner thermostat was tricked into perceiving the temperature higher than it was. "
 

ejalrp

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Lower temperatures increase mitochondrial biogenesis.

So the higher body temperatures created by a RP approved healthy thyroid fueled metabolism actually simultaneously inhibits mitochondrial biogenesis because of the resultant higher body temps? Now I'm really confused!
 

Giraffe

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So the higher body temperatures created by a RP approved healthy thyroid fueled metabolism actually simultaneously inhibits mitochondrial biogenesis because of the resultant higher body temps? Now I'm really confused!
Mitochondrial biogenesis is an adaptive process, a reaction to stress or stimuli. Exposure to cold has been shown to stimulate mitochondrial biogenesis in brown fat to tolerate the cold better (in other words: keep up the body temperature).
 
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This is more like the opposite of ice baths, sensing a high temperature could be turning off adrenaline and brown fat, etc. it's basically similar to the reset from fixlowbodytemp.com
 

jb116

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Mitochondrial biogenesis is an adaptive process, a reaction to stress or stimuli. Exposure to cold has been shown to stimulate mitochondrial biogenesis in brown fat to tolerate the cold better (in other words: keep up the body temperature).
Yes, and more is not always better. Efficiency rules first and foremost. Incidentally, stressful cardio creates mitochondria and angiogenesis.
Those people do not always present as the healthiest people around.
 

PakPik

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So the higher body temperatures created by a RP approved healthy thyroid fueled metabolism actually simultaneously inhibits mitochondrial biogenesis because of the resultant higher body temps? Now I'm really confused!

Hi ejalrp, to answer this, Thyroid, and many other pro metabolic aspects stimulate mitochondria biogenesis:

“Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new mitochondria, and stimulate stem cell proliferation.” [RP]

As you probably know, the body is unimaginaby complex, and every "marker" must be analyzed in relation to the whole. Context, they call it. High temp/high pulse don't necessarily imply good metabolism, with bad metabolism you can be suffering from pathological "good"temp/pulse

"The basal metabolic rate, which is mainly governed by thyroid, roughly corresponds to the average body temperature. However, in hypothyroidism, there is an adaptive increase in the activity of the sympathetic nervous system, producing more adrenalin, which helps to maintain body temperature by causing vasoconstriction in the skin."


"While the early morning body temperature will sometimes be low in hypothyroidism, I have found many exceptions to this. In protein deficiency, sodium deficiency, in menopause with flushing symptoms, and in both phases of the manic depression cycle, and in some schizophrenics, the morning temperature is high, corresponding to very high levels of adrenalin and cortisol. Taking the temperature before and after breakfast will show a reduction of temperature, the opposite of what occurs in simple hypothyroidism, because raising the blood sugar permits the adrenalin and cortisol to fall."

"In old people, who lose heat easily during the day, their extreme increase in the compensatory nervous and hormonal adrenalin activity causes their night-time heat regulation (vasoconstriction in the extremities) to rise to normal."
(My comment: This probably is comparable to the old mice in the study, therefore the uncoupling calmed their nervous system via an improvement in metabolism, thus revealing the real core temp?)

Thyroid, insomnia, and the insanities: Commonalities in disease

And an example that I love a lot to show that pathological increase in temp can be detrimental:

"Since a sudden increase in temperature will release increased amounts of the pro-inflammatory fats, things should be changed gradually. Increased salt is thermogenic, but increased magnesium is protective against hyperthermia, so increased magnesium (epsom salts baths, for example, coffee, fruits, some vegetables and meats) would be helpful."

"Since aspirin lowers temperature, is antiinflammatory, in some situations antiestrogenic, and is a powerful antioxidant, it is likely that it would alleviate symptoms and prevent progression of MS, as it does in other degenerative diseases. "

"Temperature regulation apparently involves some nerve cells that sense temperature very accurately, and change their activity accordingly. Water has a remarkably high heat capacity, meaning that it takes a relatively large amount of heat to change its temperature. The "disappearing heat" is being consumed by structural changes in the water. Proteins have the same sort of structural complexity as water, and together they can make effective temperature transducers, "thermometers." (Other substances tend to undergo major structural changes only as they melt or vaporize. The famous "liquid crystals" have a few distinct structural phases, but cytoplasm is like a very subtle liquid crystal.) The "thermostat cells" are actually responding to a degree of internal structure, not to the temperature in the abstract. [my comment: this implies that the goal is to offer the body the temperature that is cellular "structure" needs to not melt, not too much, not to little. In the mice study, this old animals probably weren't regulating temp very well and the uncoupling of the brain brought the temp it to match the real structure] So things that change their internal structure will modify their temperature "set-point." "

"If this is the situation in the nerves in MS, it explains the strange behavior, in which warming the nerve reduces its function. The implication is that internal structure (and energy) must be restored to the nerves. In experiments that I have described in previous newsletters, increasing sodium, ATP, carbon dioxide, and progesterone, and increasing the ratio of magnesium to calcium, have been found to increase cellular energy and structure. The thyroid hormone is ultimately responsible for maintaining cells' energy and structure, and responsiveness, but if it is increased suddenly without allowing all the other factors to adjust, it will raise the temperature too suddenly. It needn't take a long time, but all the factors have to be present at the same time."

"Serotonin, melatonin, estrogen, and polyunsaturated fats all tend to lower body temperature. Since estrogen and the unsaturated fats are cellular excitants, the actual decrease in body temperature helps to offset their excitatory effects."
Multiple sclerosis, protein, fats, and progesterone

I find this topic fascinating :)

(Mr. @haidut et. al. invited to comment)
 
Last edited:

Mittir

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This study seems puzzling in light of what RP claims is one of the best indicators of general health. I'm trying to figure out how this study doesn't contradict RP but have not found an explanation yet. Anyone else?

Cool mice live longer : Nature News
It does not look puzzling to me. The problem with this article is there is no description of
result, method and protocols, especially diet for control and cold mice.

RP often quotes the George Burr's PUFA free rat experiment where mice
developed skin disease and died quickly. But PUFA free rat had 50 percent
higher metabolism. Source : Fats and degeneration
Later study showed those mice had nutritional deficiency from higher metabolism
and B vitamins, B6 or zinc corrected that disease. I do not think they measured
body temperature of the rats, but it is expected that PUFA free high metabolic
rats had higher body temperature.

There is another study RP quote on fat free diet preventing cancer/tumor.
In that experiment rats on fat free died quickly too but were quite
resistant to implanted tumor/ cancer.

Rat with low body temperature would require less energy, thus lower
energy production and lower nutritional requirement of some vitamins.

A good experiment should have different diet for low and high temp group
that support their metabolic state.
 

haidut

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Hi ejalrp, to answer this, Thyroid, and many other pro metabolic aspects stimulate mitochondria biogenesis:

“Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new mitochondria, and stimulate stem cell proliferation.” [RP]

As you probably know, the body is unimaginaby complex, and every "marker" must be analyzed in relation to the whole. Context, they call it. High temp/high pulse don't necessarily imply good metabolism, with bad metabolism you can be suffering from pathological "good"temp/pulse

"The basal metabolic rate, which is mainly governed by thyroid, roughly corresponds to the average body temperature. However, in hypothyroidism, there is an adaptive increase in the activity of the sympathetic nervous system, producing more adrenalin, which helps to maintain body temperature by causing vasoconstriction in the skin."


"While the early morning body temperature will sometimes be low in hypothyroidism, I have found many exceptions to this. In protein deficiency, sodium deficiency, in menopause with flushing symptoms, and in both phases of the manic depression cycle, and in some schizophrenics, the morning temperature is high, corresponding to very high levels of adrenalin and cortisol. Taking the temperature before and after breakfast will show a reduction of temperature, the opposite of what occurs in simple hypothyroidism, because raising the blood sugar permits the adrenalin and cortisol to fall."

"In old people, who lose heat easily during the day, their extreme increase in the compensatory nervous and hormonal adrenalin activity causes their night-time heat regulation (vasoconstriction in the extremities) to rise to normal."
(My comment: This probably is comparable to the old mice in the study, therefore the uncoupling calmed their nervous system via an improvement in metabolism, thus revealing the real core temp?)

Thyroid, insomnia, and the insanities: Commonalities in disease

And an example that I love a lot to show that pathological increase in temp can be detrimental:

"Since a sudden increase in temperature will release increased amounts of the pro-inflammatory fats, things should be changed gradually. Increased salt is thermogenic, but increased magnesium is protective against hyperthermia, so increased magnesium (epsom salts baths, for example, coffee, fruits, some vegetables and meats) would be helpful."

"Since aspirin lowers temperature, is antiinflammatory, in some situations antiestrogenic, and is a powerful antioxidant, it is likely that it would alleviate symptoms and prevent progression of MS, as it does in other degenerative diseases. "

"Temperature regulation apparently involves some nerve cells that sense temperature very accurately, and change their activity accordingly. Water has a remarkably high heat capacity, meaning that it takes a relatively large amount of heat to change its temperature. The "disappearing heat" is being consumed by structural changes in the water. Proteins have the same sort of structural complexity as water, and together they can make effective temperature transducers, "thermometers." (Other substances tend to undergo major structural changes only as they melt or vaporize. The famous "liquid crystals" have a few distinct structural phases, but cytoplasm is like a very subtle liquid crystal.) The "thermostat cells" are actually responding to a degree of internal structure, not to the temperature in the abstract. [my comment: this implies that the goal is to offer the body the temperature that is cellular "structure" needs to not melt, not too much, not to little. In the mice study, this old animals probably weren't regulating temp very well and the uncoupling of the brain brought the temp it to match the real structure] So things that change their internal structure will modify their temperature "set-point." "

"If this is the situation in the nerves in MS, it explains the strange behavior, in which warming the nerve reduces its function. The implication is that internal structure (and energy) must be restored to the nerves. In experiments that I have described in previous newsletters, increasing sodium, ATP, carbon dioxide, and progesterone, and increasing the ratio of magnesium to calcium, have been found to increase cellular energy and structure. The thyroid hormone is ultimately responsible for maintaining cells' energy and structure, and responsiveness, but if it is increased suddenly without allowing all the other factors to adjust, it will raise the temperature too suddenly. It needn't take a long time, but all the factors have to be present at the same time."

"Serotonin, melatonin, estrogen, and polyunsaturated fats all tend to lower body temperature. Since estrogen and the unsaturated fats are cellular excitants, the actual decrease in body temperature helps to offset their excitatory effects."
Multiple sclerosis, protein, fats, and progesterone

I find this topic fascinating :)

(Mr. @haidut et. al. invited to comment)

I also think it is fascinating. Body temperature by itself can be very misleading. For instance, people with serotonin syndrome have very high fever and we would certainly not count them as hypermetabolic. High histamine will create very high surface temps but core temp will not change or even be lower. The facial flush is an example of histamine doing that. Estrogen does the same - lowers core temp and raises surface. In those people, aspirin will lower temperature, so I think this is the context Peat is writing about. In normal folks, higher doses of aspirin raises core body temp. Just ask anybody with rheumatoid arthritis who is self-medicating with high dose aspirin - i.e. they often go out shirtless in the winter. I have tested it myself - 3g single dose aspirin gets me (and most of the people I know) sweating profusely and ear temps rise to 100 degrees. Caffeine does the same.
So, I think, like the other posts pointed out, there are a few extra factors that need to be measured. These include oxygen consumption, especially in the brain, lactate, urine output (as a biomarker of metabolism), blood CO2 levels, etc.
 
Last edited:

ejalrp

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I also think it is fascinating. Body temperature by itself can be very misleading. For instance, people with serotonin syndrome have very high fever and we would certainly not count them as hypermetabolic. High histamine will create very high surface temps but core temp will not change or even be lower. In those people, aspirin will lower temperature, so I think this is the context Peat is writing about. In normal folks, higher doses of aspirin raises core body temp. Just ask anybody with rheumatoid arthritis who is self-medicating with high dose aspirin - i.e. they often go out shirtless in the winter. I have tested it myself - 3g single dose aspirin gets me (and most of the people I know) sweating profusely and ear temps rise to 100 degrees. Caffeine does the same.
So, I think, like the other posts pointed out, there are a few extra factors that need to be measured. These include oxygen consumption, especially in the brain, lactate, urine output (as a biomarker of metabolism), blood CO2 levels, etc.

So aspirin is like the mighty thermos in reverse. Turns cold sick bodies warm and hot sick bodies cool. Nice.
 

misery guts

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This is more like the opposite of ice baths, sensing a high temperature could be turning off adrenaline and brown fat, etc. it's basically similar to the reset from fixlowbodytemp.com

Erm, is there a link describing this guys protocol/instructions somewhere on that site? The forum link seems to be down :(
 

jaguar43

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The uncoupling "genes" were probably the biggest factor in longevity. But the core temperature doesn't necessarily mean low metabolic rate. Ray Peat has said that people are low metabolic when their hands, feet, and nose are cold. I don't think he has referred to core temperature though.
 

ejalrp

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Now that's a pretty gruesome experiment. Let's guillotine a cat and see what aspirin does to the fresh headless corpse! Must admit it's an interesting and surprising finding that I may use if I ever decide to get away with murder. "Your honor, the body temperature of the corpse proves that my client couldn't have killed Mr. Smith because when it was found it was still 98.5 and my client was 100 miles away".
 

haidut

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Aspirin has an inverted U-shape curve on uncoupling. The optimal concentration for uncoupling is about 0.5mM, which is achievable by taking 1g - 1.5g aspirin. In higher and lower doses it may be an anti-pyrogen.
Aspirin comparable to DNP as mitochondrial uncoupler
 
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