Tuesday, November 11, 2008


Isoflavones block uptake of dietary cholesterol by macrophages in mice, but fail to cause a reduction of artherosclerosis.

"Soy protein containing isoflavones favorably influences macrophage lipoprotein metabolism but not the development of atherosclerosis in CETP transgenic mice."

How can they say that this had a favorable influence? If lowered uptake of cholesterol by macrophages had no benefit to the mice? ?

If you remove a mouse's ovaries, then feed her cholesterol, she gets artherosclerosis.

If you remove a dog's thyroid, and feed it cholesterol, artherosclerosis.

If you feed a bunny cholesterol, it gets artherosclerosis. This after all you did was add cholesterol to it's natural diet of corn starch cellulose and caseine protein. But if you make the rabbit type I diabetic by removing its pancreas, it fails to get artherosclerosis. Still in trouble, just no artherosclerosis. In other studies they avoided bunny heart disease by feeding them dessicated thyroid. In still other studies they just fed them iodine, and that worked against artherosclerosis.

A rabbit's natural diet is grass, bark, twigs. Grass is a rich source of vitamin k, beta carotene, and being a green vegetable, probably iodine. Did a multi-billion dollar statin industry grow out of studies on iodine-deficient rodents?

If you wanna avoid heart disease, get your hormones sorted out.

(The fact that women are less likely to get heart disease but more likely to get goiter--that's kind of suggestive, ain't it?)

Tuesday, November 4, 2008

I just found this book on Google Book Search; http://books.google.ca/books?id=taGpgaQ4Q7UC&pg=PA322&lpg=PA322&dq=fructose+carbohydrate+oxidation&source=web&ots=e8vxbZLWrW&sig=kfXOP6QMAY1JU1irZUApLifsqbE&hl=en&sa=X&oi=book_result&resnum=4&ct=result#PPA322,M1

The section I linked to talks about the effect of carb intake on carbohydrate oxidation; long story short, carb oxidation is maximized when glucose and fructose are taken together. Absorption rate is maximized with this mix, so there's just more to oxidize. (This is in humans for once.)

Calories taken in with an associated flavour can cause a preference for that flavour. Is that why glucose/fructose mixes, which would cause the quickest influx of carb calories, are the popular sugars? Fructose is sweeter; why don't they just put pure fructose in colas? Too sweet? Then why not use slightly less?

Potatoes were once sanctified for being complex carbs, the claim being that their structure caused a slow sustained absorption of carbohydrate. Then vilified for having a high glycemic index and just dumping glucose into the system. We're not back to saint status for spuds yet, but maybe the fact that they're mostly glucose limits the maximum rate of sugar absorption in the gut? As long as you don't eat them with honey?

I already posted about this study;


In which mice fed a high fructose (60 percent) became leptin-resistant. They were fed the fructose diet for 6 months, which didn't make them fat but increased their triglycerides. Then they were fed a high fat diet and this made them fat, but not control mice that never went through the fructose feeding. This went on for another two weeks. It would have been nice to see what happened on a longer high fat low fructose diet; whether the condition reversed itself.

As usual, kinda over my head. but does this relate to the failure of fructose to activate srebp's when compared to glucose?

The ability to regulate specific genes of energy metabolism in response to fasting and feeding is an important adaptation allowing survival of intermittent food supplies. However, little is known about transcription factors involved in such responses in higher organisms. We show here that gene expression in adipose tissue for adipocyte determination differentiation dependent factor (ADD) 1/sterol regulatory element binding protein (SREBP) 1, a basic-helix-loop-helix protein that has a dual DNA-binding specificity, is reduced dramatically upon fasting and elevated upon refeeding; this parallels closely the regulation of two adipose cell genes that are crucial in energy homeostasis, fatty acid synthetase (FAS) and leptin. This elevation of ADD1/SREBP1, leptin, and FAS that is induced by feeding in vivo is mimicked by exposure of cultured adipocytes to insulin, the classic hormone of the fed state. We also show that the promoters for both leptin and FAS are transactivated by ADD1/SREBP1. A mutation in the basic domain of ADD1/SREBP1 that allows E-box binding but destroys sterol regulatory element-1 binding prevents leptin gene transactivation but has no effect on the increase in FAS promoter function. Molecular dissection of the FAS promoter shows that most if not all of this action of ADD1/SREBP1 is through an E-box motif at -64 to -59, contained with a sequence identified previously as the major insulin response element of this gene. These results indicate that ADD1/SREBP1 is a key transcription factor linking changes in nutritional status and insulin levels to the expression of certain genes that regulate systemic energy metabolism.


I came across SREBP when I was digging around reading about leptin; they did a study a while ago where they fed mice a leptin-free diet, and the mice lost all of their body fat within a few weeks. Leucine is more famous for it's anti-catabolic effect, promoting protein synthesis in muscles.

Leucine is a keto-protein; it can be made into fat, but not sugar. Fat can be used to synthesize cholesterol and steroids and stuff, and so can leucine. The presence of certain sterols is important in the synthesis of fatty acids. (Just don't ask me which sterols!) You can see how a very low fat diet that is also low in leucine might lower the production of fat cholesterol and sterols, and might thus make it hard to produce the very elements necessary to synthesize fats that might be used in turn to produce fat cholesterol and sterols... That is, if I'm at all following the plot here.

Maybe the catabolic effect of marathon-type exercise is related to this as well? But this time in muscle instead of fat?

Heres another one;


Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver.
Horton JD, Shimomura I, Ikemoto S, Bashmakov Y, Hammer RE.
Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA. Jay.horton@utsouthwestern.edu
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from adipocytes led, in turn, to a fatty liver. Overexpression of the alternative SREBP-1 isoform, nSREBP-1c, in adipose tissue inhibits adipocyte differentiation; as a result, the transgenic nSREBP-1c mice develop a syndrome resembling human lipodystrophy, which includes a loss of peripheral white adipose tissue, diabetes, and fatty livers (Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., and Brown, M. S. (1998) Genes Dev. 12, 3182-3194). In striking contrast, nSREBP-1a overexpression in fat resulted in the hypertrophy of fully differentiated adipocytes, no diabetes, and mild hepatic steatosis. These results suggest that nSREBP-1a and nSREBP-1c have distinct roles in adipocyte fat metabolism in vivo.
PMID: 12855691 [PubMed - indexed for MEDLINE]


One more study, quoted near the end of the last study;

Vol. 12, No. 20, pp. 3182-3194, October 15, 1998
RESEARCH PAPERInsulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy Iichiro Shimomura,1,4 Robert E. Hammer,2,4 James A. Richardson,3 Shinji Ikemoto,1 Yuriy Bashmakov,1 Joseph L. Goldstein,1,5 and Michael S. Brown1
1 Department of Molecular Genetics, 2 Department of Biochemistry and Howard Hughes Medical Institute, 3 Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235 USA
Overexpression of the nuclear form of sterol regulatory element-binding protein-1c (nSREBP-1c/ADD1) in cultured 3T3-L1 preadipocytes was shown previously to promote adipocyte differentiation. Here, we produced transgenic mice that overexpress nSREBP-1c in adipose tissue under the control of the adipocyte-specific aP2 enhancer/promoter. A syndrome with the following features was observed: (1) Disordered differentiation of adipose tissue. White fat failed to differentiate fully, and the size of white fat depots was markedly decreased. Brown fat was hypertrophic and contained fat-laden cells resembling immature white fat. Levels of mRNA encoding adipocyte differentiation markers (C/EBP, PPAR, adipsin, leptin, UCP1) were reduced, but levels of Pref-1 and TNF were increased. (2) Marked insulin resistance with 60-fold elevation in plasma insulin. (3) Diabetes mellitus with elevated blood glucose (>300 mg/dl) that failed to decline when insulin was injected. (4) Fatty liver from birth and elevated plasma triglyceride levels later in life. These mice exhibit many of the features of congenital generalized lipodystrophy (CGL), an autosomal recessive disorder in humans. http://www.ncbi.nlm.nih.gov/pubmed/12855691?ordinalpos=64&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

In the study itself, they mention that the plasma free fatty acids were not elevated; so they were not the source of the elevated triglycerides, and they suggest that free fatty acids synthesized in the liver itself went into those triglycerides. Do free fatty acids produced in the liver itself promote the production of glycogen and it's release? If the liver's ability to produce free fatty acids outstrips it's ability to produce triglycerides and this leads to increased blood sugar... Uh oh.

Sunday, November 2, 2008


This is an article about a study on type II diabetes treatment with a vegan diet. Neal Barnard of the Physicians Committee for Responsible Medicine was involved. The vegan diet improved blood glucose control and HBA1C levels when compared to the American Diabetic Association Diet.


There's also a 'cure' for diabetes video going the rounds, which has even found it's way deep into carnivore territory.

The video's about a raw vegan program, and makes more spectacular claims than the PCRM study--PCRM is talking improved blood glucose control, while Gabriel Cousens and others are talking cure--actual reversal of type II diabetes.

If you poke around on some raw vegan sites, you'll find some people with spectacular results.

Increased energy, spectacular weight loss, control of bipolar disorders. The list goes on and on.

Lots of good things to say about this diet, even if you don't necessarily buy into the explanation of the benefits given by those who enjoy them. Detox? I don't really follow you. Enzymes? The usual answer in carnivore (or just cooked food) circles seems to be that enzymes from the diet are broken down into amino acids in the stomach, and do the consumer no good as enzymes. But we release enzymes in our saliva, don't we? So it must be possible to benefit from enzymes, pre-stomach. And if dietary enzymes don't do anything, are just broken down into their component amino acids, then why are there studies that show benefits from consuming the pineapple derived enzyme, bromelain?

These people are eating food that belongs in the human diet, even if it's often lower in protein than most would consider desirable. Some of them may have serious honey or agave nectar habits, but I get the impression, mostly, from the blogosphere, that it is more common for raw whole foods to be the focus, whether fatty or carby, precluding most refined sugars from the diet.

There's another, non-vegan cure for Type II diabetes. It goes like this; feed mice or rats a choline-deficient diet. The rodents get fatty liver disease; excess buildup of triglycerides in the liver. This decreases free fatty acids in the liver. Free fatty acids encourage glucogenesis; which makes sense. When glucose is high, fat cells tend to synthesize glycerol, which acts sort of like a lynchpin to keep fatty acids in the cell. Glucose gets low, and less glycerol is synthesized, so that the breakdown of triglycerides predominates over synthesis; so that free fatty acids serve as a signal that glucose levels are low.

I got a lot of that from Wikipedia; I think most of it still stands, although I think that the increase in blood glucose from high free fatty acids in the liver is probably because of increased glycogen breakdown, because of a post Michael Eades did a while back about a colleague who traced glucogenesis in the liver and found that before finding it's way into the general circulation, newly formed glucose was formed into glycogen. I wonder if that's true of fats, too--are they first stored as triglycerides in the liver, before being released packaged as VLDL? Since there's such a thing as fatty liver disease, I guess that's probably true. If glucose isn't the proper endpoint, I guess we should probably just call it glycogenesis as well. So this must not just be a problem of glucose synthesis, but of glycogen breakdown, as well.

This also explains why rodents with visceral fat removed fail to get type 2 diabetes, even when genetically susceptible or when fed a diet that would normally give them type 2 (high fructose, for example.) And why it works also in humans, although they can't go to the extremes they go to with animals. Visceral fat is kind of close to the liver, and enjoys more blood flow than most fat tissue. It's a ready source of free fatty acids, and thus a steady source of encouragement to the liver to push blood sugar up.

Back to the mice; they get fatty liver from the choline-deficient diet. But no type 2 diabetes. Hooray.

Here's an interesting study that ties into this choline, fatty liver thing;


Mice that are fed a diet that is both choline and methionine free (and high in sugar) enjoy some curious therapeutic benefits; increased metabolism, weight loss (largely fat), increased fatty acid oxidation, and of course a nice fatty liver.

Not to put too fine a point on this, but it wouldn't be too hard to design a vegan diet that was low in both methionine and choline, would it? (Please don't start an online fat-loss clinic called fattyliverkins. Seriously.)

What we need isn't a diet that keeps visceral fat and liver fat from breaking down; we need something that reverses and prevents its excess accumulation.

Saturated fat protects against fatty liver disease, especially that caused by alcohol. Polyunsaturated fats don't, so you could imagine studies where saturated fat worsened blood sugar control when compared to polyunsaturated fat.

Saturday, November 1, 2008

This is cool. Ammonia is poisonous. Yeast in a potassium poor medium are poisoned by ammonia in that medium; nitrogen and potassium being similar enough for nitrogen to slip through a potassium channel if potassium isn't there to block it.


Wednesday, October 29, 2008

Fructose raises the blood glucose threshold at which epiniphrine (adrenaline) will be released. This causes the liver to catabolize glycogen to sugar, and also signals fat cells to release fatty acids. I got that from this study.

/type one/9 .

They explain it like this; 'We hypothesized that this effect was due to the interaction of a "catalytic" dose of fructose with the regulatory protein for glucokinase in glucose-sensing cells that drive counterregulation. '

When a sugar molecule is phosphorylated, it makes it harder for that sugar to leave the cell. Fructose that is absorbed and then finds it's way to the liver, for example, is phosphorylated by fructokinase, and sort of stays put to be converted into glucose or fat or glycerine.

From the discussion;

"In concert with the augmentation of epinephrine release during hypoglycemia, the fructose studies were accompanied by significantly higher rates of EGP during the 3.9- and 3.3-mmol/l glucose steps and corresponding decreases in glucose infusion rates. Moreover, because of this enhanced counterregulatory response in the fructose studies, we were unable to lower the plasma glucose levels below 3.9 mmol/l."

Monday, October 27, 2008

Lyle Macdonald writes about increased blood to fat cells helping in fat loss.

This guy here http://www.sns-web.org/pages/advances/01/article.asp is doing work investigating the idea that rather than being just a symptom of insulin resistance and metabolic syndrome in general, high blood pressure might also be a cause of insulin resistance, making it harder to get nutrients and insulin to muscle and other cells.

Dr William Davis writes about wheat belly, suggesting that cutting wheat out of the diet will help to reduce central obesity--or visceral fat.

Removing visceral fat from rats and then feeding them a diet that would normally induce type 2 diabetes fails to do so. They've done the same to a lesser degree with humans. I don't think they can remove the whole organ from a human being; it probably has legitimate functions in the body.

This study http://hyper.ahajournals.org/cgi/content/abstract/27/1/125 looks at a possible connection between loss of visceral fat and lowered blood pressure. If you read a lot of low carb books and spend some time on some blogs and forums, you'll see that a decreased waist circumference is claimed very often, as well as decreased blood pressure.

My sister sent me an article at work today. Hydrogen Sulfide, a chemical produced by some gut bacteria and present in farts, lowers blood pressure. An enzyme the article called "CSE" was needed for production of the hydrogen sulfide.

Devil of a time finding out what the heck CSE was. Seems like every researcher has their own name for it. I'm pretty sure Cystathionine gamma-lyase is our baby though. (mostly because I found an article clearly stating that this is so.)

Homocysteine is associated with heart disease. Various b vitamins, b12, folic acid, b6, choline, tend to normalize homocysteine levels. Most of the b vitamins are used by the body in various cycles to transform homocysteine into methionine. B6 is instrumental in a pathway that produces cysteine instead of methionine. It seems Cystathionine gamma-lyase is one of the enzymes necessary for the production of cysteine in this manner.

CSE can also be used in a reverse process that takes cysteine apart.

Check this out; http://www.ionchannels.org/showabstract.php?pmid=15497768&redirect=yes&terms=cystathionine+gamma+lyase+cysteine+hydrogen+sulfide


" The H2S produced from cysteine functions as a neuromodulator and smooth muscle relaxant. In glutamatergic neurons, the production of H2S by cystathionine beta-synthase enhances N-methyl-D-aspartate (NMDA) receptor-mediated currents. In smooth muscle cells, H2S produced by cystathionine gamma-lyase enhances the outward flux of potassium by opening potassium channels, leading to hyperpolarization of membrane potential and smooth muscle relaxation"


So a lack of an enzyme that helps produce cysteine from homocysteine, can also cleave cysteine and produce hydrogen sulfide, which could
dilate blood vessels, relieving high blood pressure and maybe improving insulin sensitivity,
relax other smooth muscle cells, like the ones in your lungs for instance. I read a study a while back where researchers were surprised at the high cysteine levels they found in asthma sufferers. They thought they'd be lower. Glycine levels were found to be lowest in the worst cases of asthma in that study. Dimethylglycine and Trimethylglycine (that second one's betaine) both lower homocysteine. Giving rats too much methionine raises homocysteine levels. Glycine reverses this affect of methionine.

Sunday, October 26, 2008

is this how you spell luxuskonsumption?

In grade school health class I was taught that there were three kinds of people; ectomorphs, endomorphs, and mesomorphs. Ectomorphs tended to be lean and have smaller muscles, endomorphs had more muscle but also more fat, and mesomorphs had lots of muscle and more fat than the ectomorph but less than the endomorph.

Seen from a Taubesian cellular starvation angle, something suggests itself. There's could be a very simple difference between these three types of people;

Ectomorphs don't store much energy in their fat cells. Therefore, when in the fasting state, they are forced to metabolize lean tissue for energy. Go to Bodybuilding.com and dig around in the forum and you'll find no shortage of very lean teenage boys claiming to have a very hard time building lean mass, even when eating at very high calorie levels.

Endomorphs tend to store too much energy in fat cells, or perhaps have trouble getting out of the fed glucose-burning state and back into the fasting state. So instead of those fatty acids locked up in their fat cells, they turn to lean tissue for fuel.

Mesomorphs have excellent metabolisms. If they eat lots of food, they have no trouble at all storing away both protein and fat. They also have little trouble accessing that fat, probably switching readily between the fed and fasted state. So their muscles get lots of energy when they eat, and lots of energy when they're asleep. Sparing lean tissue.

Taubes writes about adolescent hogs, who, when fed a low-protein diet, simply eat more of it to support growth, and burn the extra calories off. He also mentions research in the late nineteenth century by Carl von Voit and Max Rubner of something like this happening in humans, with overfeeding failing to cause weight gain. This effect is termed luxusconsumption.

Do a search for more recent studies on luxusconsumption, and you get stuff like this 9

with abstracts starting with lines like this;

"In this paper, we redefine the term luxus consumption to mean food waste and overconsumption leading to storage of body fat, health problems, and excess resource utilization."

So what's changed between the late 19th century and today? The usual line is that the measurements have gotten better. We got fancy metabolic chambers, we can measure oxygen utilization and calculate RQ, (respiratory quotient. By measuring oxygen consumption, researchers can calculate how much of a person's energy use is coming from carbs, fat, protein, etc.) Blah blah blah.

It's nice that we have a fancier yardstick. But late nineteenth century researchers were perfectly capable of calculating and tabulating how much food was being consumed, and the composition of that food, and whether or not the subject consuming that food was gaining fat mass. So I don't think we just measure stuff better now really cuts it.

So the charge against Carl von Voit and Max Rubner becomes one of incompetence or of dishonesty. Always possible; but these are serious charges. Especially for a scientist.

But what if it's not the yardstick that changed? What if it was the nature of the thing being measured?

The thing being measured was the effect of overconsumption of food on human fat stores.

Is there anything that can change the effect of food on an organism?

Maybe fructose?

Peter at Hyperlipid posted this article someone sent him in an email; I'm yoinking it here for my own foul purposes;

Florida Researchers Find Consuming Fructose Can Suppress Leptin Hormone, Lead l

Fat cells put out leptin to signal that they're full to overflowing; it's sort of a signal that they have energy to spare and wish to share it. The signal is "heard" at various places in the body, but of particular importance is the hypothalamus. Triglycerides interfere with leptin's ability to send a signal prompting the hypothalamus to respond by sending it's own messengers to sort of redirect that energy. Fructose supplementation is an excellent way to up triglyceride production. Almost any carbohydrate source will do the same, but fructose really does the job.

In the study fructose interfered with the action of leptin not just while the mice ate fructose, but later on when they switched to what they called a high-fat diet, but was probably a high corn starch and high (or even just medium) fat diet.

How else have we changed?

Much is made of inactivity as a cause of childhood weight gain. Tv, computers, video games. One obvious alternative to any association of these activities to weight gain in children is that these are all indoor activities, which might affect vitamin d levels. And it's been shown that vitamin d affects all kinds of things in the body, one of them being thyroid stimulating hormone, which can affect the thyroid which has a rather obvious connection to the availability of stored fat.

I spent my pre-teen years in the 70s, and was lean. Anyone remember The Kroft Supershow? HR Puff 'n Stuff? Gilligans Island, The Addams Family, Scooby Doo, The Flintstones, The Jetsons, Captain Caveman, Bewitched, The Munsters, Happy Days, Laverne and Shirley, All in the Family, Star Trek, Rocket Robin Hood, Looney Tunes, Trouble with Tracy, Definition (some are Canadian, so you might not.) Uncle Bobby The Friendly Giant Sesame Street, Get Smart, Hogan's Heroes, Maude, I Dream of Jeanie, The Brady Bunch, Batman, I think I got in some old Superman reruns, Ponderosa, Little House on the Prairie, The Electric Company, Romper Room, the list just doesn't end. Which doesn't really back up the idea that TV is keeping kids from getting enough sun, compared to my own youth. But I do remember having a pretty dark tan by the end of every summer.

I mentioned vitamin d's connection to the thyroid. (One of them, at least.) How about other nutrients that affect the thyroid? The most obvious one is iodine. I have no idea what the iodine or the thyroid status of the people in the original luxuskonsumption studies might have been, but it's just one more thing modern researchers might need to know before dismissing the results of those studies out of hand. Table salt is iodized, by law. The salt used in industry when producing corn and potato chips or frozen dinners doesn't necessarily have any iodine supplemented. Much of the US and Canada has iodine-deficient soil. Avoiding egg yolks and whole milk (removing the whey from milk removes much of the iodine) wouldn't help any.

Thyroid disorders do seem to be more common than they probably should be. Treatment of choice seems to very rarely involve iodine supplementation, at least from what I can tell from bopping around on the web. The discussions mostly seem to revolve around supplementation of t3 and t4. It's hard to believe that iodine's never the answer. One problem with supplementing iodine in an actual case of iodine deficiency is that it can sometimes cause goiter.

http://www.ajcn.org/cgi/content/full/86/4/1040 This study, "Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate."

seems to show that vitamin a protects against goiter in iodine deficient areas, even in the absence of iodine supplementation. In the study, vitamin A supplementation decreased thyroid stimulating hormone levels without reducing t4 levels, and the authors suggest that this might show an effect of vitamin a of improving thyroid hormone sensitivity. (Vitamin D, on the other hand, has the reverse effect, increasing output of tsh from the pituitary gland. Which doesn't mean vitamin d bad--it just means you'd better not be vitamin a deficient, is all. It could just be that Vitamin D helps the metabolism notice a need for thyroid hormone, while vitamin A makes your body use the stuff better, in which case the two vitamins wouldn't be antagonist here at all, but rather complementary.)

I don't know if vitamin a would have this anti-goiter effect in those cases where too much iodine precedes the goiter, but it wouldn't be surprising if something involving the balance of vitamin a and d were involved there.

Okay, I wandered all over the place with this. My point was that there are any number of differences in different groups of subjects separated by nutrient status, time, country, what have you. A failure to measure something in one group of people doesn't prove that it doesn't exist in another.

Saturday, October 25, 2008

Cellular starvation and longevity

In Good Calories Bad Calories, Gary Taubes writes about cellular starvation. The basic idea is that overweight people, while they have plenty of energy in storage, can't actually access that energy. I've been rereading the book lately, and what Taubes has to say, along with some poking around on the net, has gotten me to thinking about some of the ramifications of this idea.

Calorie-restricted mice live longer than ad-lib fed mice. One peculiarity of these mice is that while they eat less on a food per mouse basis, they actually eat more on a calorie per gram of mouse basis, at least once they've adapted to the diet. So that by eating less, they're sort of in an increased energy state.

Researchers have increased the lifespans of mice in another way, by manipulating a gene, causing the mice to overexpress an enzyme called phosphoenolypyruvate carboxykinases (PEPCK-C). The mice live sixty percent longer, while eating more. They also have more endurance, and the some of the females have the ability to breed at two and a half years, while fertility usually ends at a year for most mice.

One thing that ties these two types of mice together, besides longevity, is that they both enjoy a high availability of energy on a cellular level. One type is calorie restricted, the other is high calorie, but both enjoy longer lives. But, to repeat myself, on a cellular level both enjoy higher energy utility than the usual mouse.

A third example of increased lifespan for mice is the Snell Dwarf Mouse. The name of this study here http://www.jbc.org/cgi/reprint/282/48/35069 "Low Utilization of Circulating Glucose after Food Withdrawal in Snell Dwarf Mice" in itself kind of suggests a link of one more type of long-lived mouse to energy levels. Burning less glucose in the fasted state? What does this mean? One thing it could mean is that these mice are better at switching fuels. When you eat carbs, your body switches over primarily to burning carbohydrate for energy. This is mediated by insulin and various other hormones. You eat carbs, your pancreas puts out insulin, your liver starts repackaging free fatty acids as triglycerides, and meanwhile your major source of energy is carbohydrate. All fine and dandy; once you've burned or stored all the carbs you've eaten, and your blood sugar's returned to normal, you return to your basal, fasted-state energy source, which is primarily fat.

I'd think the better you were at switching back to burning fat, the more continuous the available supply of burnable energy would be to most of the cells in your body.

Intermittent fasting, eating every other day, has also increased rodent lifespan. In the past I've given more attention to the fasting side of the equation, and it makes sense in the context of this post that if a creature switches between the fed and fasted states poorly, then that creature might actually have more energy in the fasting state if that state is prolonged, that creature spending less time in the, for it, low energy "switchover" state. So the prolonged fasted state might be a higher-energy state. If you look at the fed state as well, if the mouse is eating enough on the feeding day to make up for what it didn't eat on the fasting day, then we have a mouse that might have more energy available to its organs and muscles and body in general on it's feeding days as well. So this mouse would get it coming and going; more energy when it ate, more energy than it might normally have between meals given a shorter fasting period.

If the availability of certain enzymes or nutrients was instrumental in the process of switching over from the fed to the fasting state, actually switching over less often between the glucose dominant and the fat dominant energy use states might spare some of those nutrients and further improve general energy availability. L-carnitine comes to mind. The carnitine shuttle helps to make triglycerides available for the production of energy. Free fatty acids seem to sort of wander around at will, triglycerides need a hall pass. L-carnitine is an important part of that hall pass. During the (carb) fed state, triglycerides go up, free fatty acids go down. If tissues can still take in triglycerides during the fed state, it seems obvious that their supply of nutrients would be more constant, and that the supply to those same tissues might be jerkier, lacking l-carnitine. According to this, http://conditioningresearch.blogspot.com/2008_02_03_archive.html, intermittent fasting and calorie restriction both increase levels of l-carnitine.

According to this study http://if,


I had a quote in here but I lost it and I'm tired. Check out the link.


carnitine improves certain markers that worsen with aging.

Resveratrol has been shown to extend life in mice, but only if they're overweight, or at least eating a diet that would otherwise make a mouse overweight. This CBC article


lists positive effects of resveratrol;


Mice that consumed resveratrol on a daily basis had better bones, with increased thickness, volume, mineral content and density than mice fed a standard high-calorie diet.

At 30 months, mice that had resveratrol daily had fewer cataracts than mice fed the high-calorie diet.

Mice on resveratrol had better balance and co-ordination at 21 and 24 months than untreated mice.

Resveratrol had a similar effect to cutting calories in terms of improving liver and muscle function, and reducing fatty deposits in the body.

Mice fed a high-calorie diet but also given resveratrol lived longer than mice only consuming a high-calorie diet, suggesting the compound may improve longevity copyright cbc 2008


After reading Taubes, the reduced fatty deposits in the body don't suggest lost weight as a cause of the benefits to muscle and liver function and to bone mass and reduced cataracts and improved brain and central nervous system function (or you just could say balance and coordination like they did.) Anymore than body fat was a cause of those ills in the first place. It suggests the possibility that at least some of these ills happen because the muscles, the liver, the bones, etc., aren't getting enough calories to maintain proper function.

The stuff you're made of isn't static; protein in your muscles constantly is broken down and synthesized, bone is broken down and reworked (they use the words resorption and formation), the triglycerides in your fat cells are broken down into free fatty acids and fatty acids are sythesized into triglycerides again. And so on through the body. And these processes of breakdown and synthesis go on simultaneously, and continuously, although one or the other may be dominant at any one moment.

When triglycerides are broken down into free fatty acids, it's easier for the fat to escape the fat cell and be available to the body's other tissues as fuel. When protein is broken down into amino acids, it's easier for the amino acids to escape the (muscle, bone, whatever) cell and be available to the body's other tissues as fuel.

What if, say, a muscle cell is going along, in a high energy state, taking proteins apart, putting them back together, again and again, and suddenly--crash! It lacks an external source of energy. So it ends up feeding on itself; it wastes away. If this happens too often, it may end up unviable.

If the same thing happens with bones, the more rigid nature of bone structure might lead to somewhat porous bones.

Back to the resveratrol, the mice in the study didn't eat more minerals, but they ended up with more minerals in their bones. What changed was not mineral availability, but the body's ability to do the work necessary to put those minerals where they'd do the most good.

Growth hormone increases breakdown of fat. And it increases (or at least protects) muscle mass and bone mass. Men have more muscle than women. Testosterone decreases body fat--but is that what's important here? I'd rather say again, it keeps energy from being locked away, that is, it increases energy availability to bone and muscle tissue.

Weight training has been shown to be effective against both sarcopenia and osteoporosis. The body responds to weight training by releasing certain hormones (growth hormone, testosterone, um and stuff) that encourage the release of fatty acids from the fat cells. More energy=stronger bones, bigger muscles. Longer life?