Saturday, September 17, 2011

Back on line

Well that's me back from the AVA meeting in Liverpool. Highlights: Arterial blood gas sampling at the top of Everest, all rough quotes from memory:

"The peak was a bit 'peakier' that we had anticipated so we dropped down a few hundred feet to a more level patch before dropping out trousers in a 20 knot breeze at -24degC to stab each other's groins for arterial blood samples".

Getting to the top of Everest? "I never train" linked to "it's all mitochondrial" and "Ground level athletes really struggle on the big mountains, Ranulf Fiennes took three attempts to get to the top and it was very hard for him".

Reinhold Messner is STILL ALIVE (obviously he has remarkable mitochondria). OMG I thought he'd have made a single small mistake at some point before now. Having read some of his earlier achievements I'd never expected him to make old bones. But he must be older than me...

And the RN battlefield anaesthetist from Iraq/Afghanistan. "These guys come in needing one, two or even three amputations from an environmental temperature at up to 40 degC. One of the worst prognostic markers is hypothermia. We think it's mitochondrial".

A good friend (with an excellent brain, yes she has already read Power Sex and Suicide while moving from anaesthesia to obesity research) chatting about DMT2 in horses "It's all mitochondrial".

One of her co-workers on cartilage degeneration in arthritis "It's all mitochondrial".

I had a great meeting.



I got, without net access, to read through and analyse some of the implications of the downloaded papers on mitochondrial dysfunction in obesity from JS's page on metabolic flexibility. Needless to say these links are good but you HAVE to read the papers, follow the secondary links then read the methods. Needless to say there is a lot to say and I'm still not about to go carb loading.

Time to get the Baba-breakfast ready. I'll try to get to emails and read comments over the w/e, but life really is very busy.

Quote of the century: "It's all mitochondrial".

Oh, and it's not quite as simple as failure to burn fat.

Peter

32 comments:

Jane said...

Peter, you asked earlier 'Is it leptin which controls the mitochondria?'

Yes, I think it might be. Leptin-deficient mice have less manganese in liver and brown fat, and less copper in liver, suggesting leptin has something to do with absorption and/or utilisation of these metals. Manganese and copper are VERY important in mitochondria.

Strontium Pup said...

http://endo.endojournals.org/content/152/7/2609.abstract

::"Central Leptin Activates Mitochondrial Function and Increases Heat Production in Skeletal Muscle" (in sheep)

::"Leptin infusion increased the expression of UCP2 and UCP3 mRNA as well as UCP3 protein but not UCP1 mRNA in muscle. Leptin also increased substrate-driven, coupled (ADP-driven), and uncoupled (oligomycin) respiration but had no effect on the total respiratory capacity. The respiratory control ratio was lower in leptin-treated (vs. vehicle-treated) animals, indicating a predominant effect on uncoupled respiration. There was no effect of central leptin treatment on AMPK phosphorylation. ... In conclusion, leptin acts at the brain to increase heat production in muscle through altered mitochondrial function, indicative of adaptive thermogenesis."

http://diabetes.diabetesjournals.org/content/54/8/2343.full

::"Physiological Increases in Uncoupling Protein 3 Augment Fatty Acid Oxidation and Decrease Reactive Oxygen Species Production Without Uncoupling Respiration in Muscle Cells" (in rats)

JohnN said...

"It's all about mt" is a reasonable proposition. mtDNA mutate 4 orders of magnitude faster than nDNA that results in heteroplasmy, the cause of metabolic dysfunction.

Reading D C Wallace (*) I get the sense that one should set up a Darwinian situation within the cell. First, generate more mt (aerobic exercise). Kill off the mutated ones (via apoptosis) by intense exercise. And teach them to uncouple (ketogenic diet). That's how birds and bats do it and live 6 times longer than comparable mammals.

D C Wallace: Mitochondria as Chi" PMID: 18558648.
Also see Ted Hutchinson's recommendation on previous post - excellent read.

blogblog said...

@JohnN

That's how birds and bats do it and live 6 times longer than comparable mammals.

Not true.

Ground dwelling birds such as turkeys, chickens and quail typically have similar (sometimes shorter) maximum lifespans in captivity than similar sized ground dwelling mammals such as rodents or rabbits.

Arboreal and flying mammals typically have much longer lifespans in captivity than their ground dwelling relatives.

The most plasible explanation is that low rates of predation in flying and tree dwelling animals has selected for slow reproduction and longevity.

Unknown said...

Hey, Peter,

I don't really have the chops to completely understand all of your posts (or even the posts of your commenters -- you attract an illustrious crew), but I thought I'd throw out an odd observation from a trip to Nepal.

I was part of a group that was hiking up to the Makalu basecamp (5250 m), and we had Sherpa guides who were every bit as comfortable at altitude as fabled.

Some of them were with us when we returned to Kathmandu (1,300 m above sea level.) Interestingly, the Sherpas got sick at 1,300 m -- really under the weather! Several of us noticed it, but couldn't imagine why they would do worse at lower altitude.

Anyway, a very unscientific observation, but unexpected...thought you might find it interesting.

Thanks for finding the time to blog again.

Peter said...

Hi Jane and Strontium Pup,

Thanks, I'd guessed this was the lie of the land.

JohnN, I would agree, this is very much the way I am thinking. However, we only get one population of mts. If that has been pre mutated to semifunctional dross we have our work cut out to find a sub-population of functional mts to breed up a decent population from. But this would explain a great deal of the familiality of obesity.

blogblog, I'm definitely thinking mitochondria at the moment. If needs must I'll change, but currently they are very easy to slot in to my world view.

Hi Unknown,

That certainly is fascinating. The Everest group didn't have ethics board approval to study the Sherpas (that's the next trip). But the possibility of a flip in the adaptability to low oxygen concentrations would be potentially fascinating at the oxygen utilisation level. We anaesthetists work so hard at oxygen delivery. Life or death appears to be determined by oxygen utilisation once delivery is optimised. That will be part nuclear genomic and part mt genomic. Or adaptation.

Current thinking inclines towards signaling issues in nitrites and peroxynitrites. There was a standing joke amongst anaesthesia exam victims in the 1990s that if stumped by a deep question from an external examiner you should just answer "nitric oxide". If superficially incorrect, it would get a laugh anyway. As Blair said, just say "NO". The bstard couldn't be wrong ALL of the time.

Interestingly I was at another ICU presentation many, many years ago (pre nitric oxide days) on surviving the un-survivable. Who lives and who dies in the ICU. It had relatively little to do with macrovascular response to all of those maneuvers we use to deliver oxygen to the tissues. The clinician threw in the tidbit that it looked to be NO signaling that mattered and that might be a simple basic gene. Scary thought. Do you geneotype ICU patients and pull the plug sooner on those with bad NO processing genes????? Or work harder with them when you know you are more likely to fail? Don't even go there! That's why people are looking for tools and the switch. I do wonder about ketones, mitochondria and free radicals...

Peter

JohnN said...

@blogblog
There are 10,000 other species of birds whose power of flight also correlates with longevity and a finely tuned army of mitochondria thanks to the exquisite management of uncoupling and ROS. Why quibble about these flightless avian mammals?

I would hate to point out one glaring exception to my confirmed bias toward fat metabolism. The hummingbird weighs a mere 5g and lives for 4 yrs while consuming 40% of its weight in sugar daily. But then this is an exception that proves the rule. The bird can hover more than 100 times a day for a total of more than 30 minutes - the pinnacle of aerobic fitness.

G Taubes should stop ruminating about the value of exercise. I know it's fashionable to bash aerobic conditioning but the birds know better.

JohnN said...

Peter - it's the original population of mt that mutates over time. Nick Lane did say in his fine little red book that middle age is not too late to recover. I don't know the basis for that statement but it's better late than never.

Unknown said...

Peter, glad you found the Nepal thing interesting.

I've been carrying the observation of the exhausted Sherpas around with me for twenty years. I just always had a hunch it signified something important...still do.

Thanks again.

Peter said...

JohnN, My concern is that we eat a diet which, by breeding age of 30+ chronological years, gives us a population of mitochondria in the oocyst of 60+ mitochondria "years". Fine if some mts still have a mitochondrial age of 20 years, but if none of them do then we're not getting them back from anywhere..... All offspring are then ****ed.

Am I being too pessimistic here? Do we have a reserve? Is the size of the reserve what determines time to adaptation to a ketogenic diet? How rapidly to mts breed?

Peter

Hee hee Unknown, struggling Sherpas in a sea level lab would be very, very interesting to look at.

Strontium Pup said...
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Strontium Pup said...

Peter,

There are some profound and alarming implications in what you are saying that I'm only just beginning to appreciate.

Are we witnessing an epidemic some large fraction of which had a thirty-year lead time? If so, are those who have pointed to a supposed recent reduction in carbohydrate consumption in the US wide of the mark by thirty years?

More alarming, what is the "gain" in the intergenerational feedback loop? Is there a stage at which sufficient mitochondrial damage in one generation is always going to lead to more of the same in the next? That would be scary.

Is carbohydrate restriction, or fructose restriction, etc., a way of modulating the gain?

Fascinating stuff! Keep it coming!

blogblog said...
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blogblog said...

@JohnN,

The scientific literature states quite clearly that mortality from predation is very important with regards to evolved longevity.

Animals that have low rates of predation as adults generally have low reproduction rates and long lives.

Animals that have high rates of predation have evolved to reproduce rapidly because there is very little likelihood of surviving a long time.

Living in trees and/or having the ability to fly massively reduces the risk of predation.

Flying birds and bats have evolved to live a long time because they have very low rates of predation due to flock behaviour, roosting in high places and flying ability rather any alleged metabolic advantage over ground dwelling mammals.

Arboreal mammals always live considerably longer than closely related ground dwelling species. The only known exceptions are tree kangaroos (they really exist) which have a similar lifespan to regular kangaroos.

Arboreal mammals typically have considerably longer lifespans in captivity than ground dwelling birds. This is despite these birds having a supposed metabolic advantage.

Mice have just as impressive aerobic capacity as hummingbirds. A mouse can effortlessly run at high speed for up to 90 minutes.

john said...
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john said...

blogblog,

I think the point is that they don't live long only because they escape predators; they age slowly, and it's helpful to learn about their physiology and compare to other animals'.

JohnN said...

Peter - we just have to rely on selective pressure - externally applied (*) - and the mt's fast mutation rate and hope for the best.

I am a little more optimistic since: (a) the goal is arresting and/or reversing the decline and not to recreate Reinhold Messner-like performance and (b) there is always some mt in a more pristine condition in a given population (quantum mechanics would allow this). Mutation is a two-way street. It can degrade or it can improve.

*: here we enter the realm of speculation. What are the exact training conditions, the exact diet and its cycling period to create that selective pressure to force the mitochondria to adapt? If one eats [and fasts] like a predator (full credit to J Stanton) one might as well train like a decathlete and apply power law to everything we do.

JohnN said...

@John - thanks for your comment.

@blogblog - we are not disagreeing. I invite you to look beyond the abstract concept of taking flight as an adaptive strategy to avoid predation. Regardless of the motive flying confers the successfully adapted species physiological benefits.

OTOH, this rare accomplishment is noted by recognizing that only insects, pterosaurs, birds and bats have managed to do it. It clearly does not help one to live longer and another did become extinct.

Best regards. John

Gladina said...

Mitochondrial function seems very intuitive. Let's explore the mechanisms which affect mit functioning.

Does anyone see the cyclical nature of this?

As Peter says: I'm pretty sure I'm not about to carb load.

blogblog said...

@John and JohnN
saying that animals have long or short lifespans is being anthropocentric. It is far more realistic to say they "fast" or "slow" lives. A mouse does just as much "living" in two years as a human does in 80 years. The mouse simply goes through each stage much more quickly.

Longevity may benefit the individual but it is often disastrous for the species. Longevity is always associated with low reproductive rates. Whales and African elephants barely survived a few decades of low level hunting by humans. Australian rabbits have easily survived 150 years of determined attempts to exterminate them. This includes the use of the myxoma virus that had an initial mortality rate of 98%.

blogblog said...
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blogblog said...

@Unknown.
there is a very simple non-physiological explanation to the Sherpa mystery.

Most of the "Sherpas" used on treks in Nepal are actually extremely poor lowland farmers recruited as pack animals. They are not properly acclimated to high altitudes. They are often inadequately clothed and poorly fed. However they know if they fail in their task they will simply be abandoned on the side of the track with some money stuffed into their pockets (and a real possibility of death).

Once the porters reach Kathmandu their ordeal has ended. They have been paid. They no longer have to pretend they are feeling well and collapse.

8:32 AM

Jane said...

It all depends on whether your maintenance and repair systems are working well. If they are, you can munch up any malfunctioning mitochondria and make new ones from the ones that do work properly. I suspect you won't survive long enough even to be born if all your mitochondria are dodgy.

The prevailing view among scientists and doctors is that maintenance and repair systems don't really exist. This is why they give you drugs to control symptoms: the disease is incurable.

But things are changing. Scientists are waking up to the following. Maintenance and repair systems are dependent on a family of enzymes called PI3kinase-like kinases (PIKKs), all of which are activated by manganese or magnesium. These two metals are largely or completely removed from white flour, white rice and white sugar.

PIKKs include mTOR which controls protein synthesis, Vps34 which controls autophagy, and ATM, ATR and DNA-PK which control DNA repair. They are said to be dependent on manganese rather than magnesium to an unusual degree, and up till now this was a puzzle because the concentration of manganese needed to activate them in vitro is very high. But we know know these enzymes all work in cellular compartments that concentrate manganese (mitochondria, nucleus, lysosomes), so it could be true.

For instance it was found a year ago by Sabatini that mTOR moves to lysosomes when it's activated. This means that protein synthesis and autophagic breakdown are controlled together at lysosomes, possibly by the manganese concentrated there. This coordinate regulation means that faulty cell components won't be degraded unless the machinery is in place to make new ones. Clever, isn't it?

JohnN said...

@blogblog:
"saying that animals have long or short lifespans is being anthropocentric."
Being anthropocentric was not my intent just as the way this discussion is going.

Gladina said...

@Jane,I'm just curious how much manganese you would recommend? Also, you recommend in combination with magnesium. Do you recommend this regardless of a whole foods diet?

I am aware of toxic levels such as those persons employed in the production or processing of manganese alloys, patients receiving total parenteral nutrition, workers exposed to manganese-containing fungicides such as maneb, and abusers of drugs such as methcathinone made with potassium permanganate. (Source: Wikipedia...ya I know).

So I was not aware that there could be a deficiency in this metal.

gwarm said...

Mitochondial theory of aging (video) Are all of these plants rusting us or is it good to boost superoxide enzyme?

PDFs

Unknown said...

blogblog,

Beg your pardon, but your "simple explanation" is nonsense.

I'd like to see you pretend your way up to 18,000 feet above sea level, carrying heavy loads, with a spring in your step, for five straight weeks.

Jane said...

Hi Gladina, good question. Manganese is supposed to cause parkinsonism. But have a look at this paper, whose authors found to their surprise that manganese completely PREVENTS parkinsonism in rats caused by excess iron:

http://www.ncbi.nlm.nih.gov/pubmed/9681949

This suggests that the absolute amount of manganese isn't as important as the ratio with iron. I would only consider taking extra manganese if I were addicted to meat, which many years ago I was.

Yes, I'd want to take extra magnesium too. And copper. But I don't think supplements are a good idea on the whole.

blogblog said...
This comment has been removed by the author.
blogblog said...

@Unknown,

The indisputable fact is that most Nepalese porters are lowland farmers who are not adapted to high altitude. They actually suffer much higher rates of altitude sickness and frostbite than the Westerners they accompany.

If the porters had a spring in their step for five weeks it was only because they were drugged to the eyeballs. Drug use including cannabis, heroin (smoked), benzodiazapines and hallucinogens is rampant in Nepal.

In the Andes the stimulant of choice for porters is coca leaf.

No one is highly energetic at 18,000 feet unless they are using stimulant drugs. There are no exceptions

The early polar explorers were only able to perform their superhuman only feats because they used large quantities of "marching powder" a mixture of cocaine and caffeine. This was perfectly legal in the early 20th century.

There is absolutely no plausible physiological mechanism for healthy porters to suddenly become exhausted at low altitude. The only logical explanation is that they were already exhausted well beyond volitional fatigue and only kept moving by taking stimulants. When the stimulants wear off they crash.

Unknown said...

blah blah blah yammer yammer yammer

You can't think of a 'plausible explanation', so it obviously couldn't be.

Enjoy being right -- Peter was the only one I wanted to communicate with.

blogblog said...

@Unknown,
you are perfectly willing to assume that some bizarre and mysterious physiological process suddenly hits Nepali porters at low altitude. However you can't accept the far more likely explanation that the porters may have been relying on stimulants for weeks and were suffering from extreme exhaustion. Logic certainly isn't your strongest asset.