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,

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

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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





http://www.cbc.ca/health/story/2008/07/03/wine-aging.html





lists positive effects of resveratrol;


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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


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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?






2 comments:

John said...

Hi Donny,

If calorie-restricted mice (or any animal) end up in a higher energy state [once adapted], why would they heal more slowly?

john said...

They seem to eat more per g of mass but not more per g of lean mass--maybe. Of course, fat does use some energy, but not much. I'll do some simple calculations to adjust for fat mass.