— Updated: 9:01 am –>
Phys Ed: What Sort of Exercise Can Make You Smarter?
By Gretchen ReynoldsNick Veasey/Getty Images
Allow a laboratory mouse to run as much as it likes, and its brainpower improves. Force it to run harder than it otherwise might, and its thinking improves even more. This is the finding of an experiment led by researchers at National Cheng Kung University in Taiwan and placed online in May.
In the study, scientists had two groups of mice swim a water maze and in a separate trial had them endure an unpleasant stimulus to see how quickly they would learn to move away from it. For the next four weeks they allowed one group of mice to run inside their rodent wheels, an activity most mice enjoy, while requiring the other group to push harder on minitreadmills at a speed and duration controlled by the scientists. They then tested both groups again to track their learning skills and memory. Both groups of mice performed admirably in the water maze, bettering their performances from the earlier trial. But only the treadmill runners were better in the avoidance task, a skill that, according to brain scientists, demands a more complicated cognitive response.
The mice who raced on the treadmills showed evidence of molecular changes in several portions of their brains when viewed under a microscope, while the voluntary wheel-runners had changes in only one area. “Our results support the notion that different forms of exercise induce neuroplasticity changes in different brain regions,” Chauying J. Jen, a professor of physiology and an author of the study, says.
For some time, researchers have known that exercise changes the structure of the brain and affects thinking. Ten years ago scientists at the Salk Institute in California published the groundbreaking finding that exercise stimulates the creation of new brain cells. But fundamental questions remain, like whether exercise must be strenuous to be beneficial. Should it be aerobic? What about weight lifting? And are the cognitive improvements permanent or fleeting?
Other recent studies provide some preliminary answers. In an experiment published in the journal of the American College of Sports Medicine, 21 students at the University of Illinois were asked to memorize a string of letters and then pick them out from a list flashed at them. Then they were asked to do one of three things for 30 minutes — sit quietly, run on a treadmill or lift weights — before performing the letter test again. After an additional 30-minute cool down, they were tested once more. On subsequent days, the students returned to try the other two options. The students were noticeably quicker and more accurate on the retest after they ran compared with the other two options, and they continued to perform better when tested after the cool down. “There seems to be something different about aerobic exercise,” Charles Hillman, an associate professor in the department of kinesiology at the University of Illinois and an author of the study, says.
Similarly, in other work by scientists at the University of Illinois, elderly people were assigned a six-month program of either stretching exercises or brisk walking. The stretchers increased their flexibility but did not improve on tests of cognition. The brisk walkers did.
Why should exercise need to be aerobic to affect the brain? “It appears that various growth factors must be carried from the periphery of the body into the brain to start a molecular cascade there,” creating new neurons and brain connections, says Henriette van Praag, an investigator in the Laboratory of Neurosciences at the National Institute on Aging. For that to happen, “you need a fairly dramatic change in blood flow,” like the one that occurs when you run or cycle or swim. Weight lifting, on the other hand, stimulates the production of “growth factors in the muscles that stay in the muscles and aren’t transported to the brain,” van Praag says.
What then of the Taiwanese mice, all of which ran? According to the investigators, mice on a running wheel “usually show little improvements in the conventionally defined” measurements of fitness, like elevated muscle strength and improved aerobic capacity. They enjoy themselves; they don’t strain. Those on the treadmill, meanwhile, are forced to pant and puff. Jen says researchers suspect that treadmill running is more intense and leads to improvements in “muscle aerobic capacity,” and this increased aerobic capacity, in turn, affects the brain more than the wheel jogging.
Does this mean we should relinquish control of our workouts to a demanding coach? Jen cautions against assuming human bodies work exactly like those of rats. But there are lessons from his work. “It would be fair to say that any form of regular exercise,” he says, if it is aerobic, “should be able to maintain or even increase our brain functions.”
Phys Ed: What Sort of Exercise Can Make You Smarter? – Well Blog – NYTimes.com
Phys Ed: Does Exercise Boost Immunity? – Well Blog – NYTimes.com
— Updated: 3:14 pm –>
Phys Ed: Does Exercise Boost Immunity?
By Gretchen ReynoldsMarc Romanelli/Getty Images
Two recent experiments hit rather close to home at this time of year. In the first, published last year in the journal Brain, Behavior, and Immunity, researchers divided mice into two groups. One rested comfortably in their cages. The other ran on little treadmills until they were exhausted. This continued for three days. The mice were then exposed to an influenza virus. After a few days, more of the mice who’d exhausted themselves running came down with the flu than the control mice. They also had more severe symptoms.
In the second experiment, published in the same journal, scientists from the University of Illinois and other schools first infected laboratory mice with flu. One group then rested; a second group ran for a leisurely 20 or 30 minutes, an easy jog for a mouse; the third group ran for a taxing two and a half hours. Each group repeated this routine for three days, until they began to show flu symptoms. The flu bug used in this experiment is devastating to rodents, and more than half of the sedentary mice died. But only 12 percent of the gently jogging mice passed away. Meanwhile, an eye-popping 70 percent of the mice in the group that had run for hours died, and even those that survived were more debilitated and sick than the control group.
Is this good news or bad? This is a particularly relevant question as two important human events converge: the peaking of the fall marathon and other sports seasons and the simultaneous onset of the winter cold and flu term. Scientists are diligently working to answer that question, perhaps because they are as interested as the rest of us in avoiding or lessening the severity of colds and the flu. The bulk of the new research, including the mouse studies mentioned, reinforce a theory that physiologists advanced some years ago, about what they call “a J-shaped curve” involving exercise and immunity. In this model, the risk both of catching a cold or the flu and of having a particularly severe form of the infection “drop if you exercise moderately,” says Mary P. Miles, PhD, an associate professor of exercise sciences at Montana State University and the author of an editorial about exercise and immunity published in the most recent edition of the journal Exercise and Sport Sciences Review. But the risk both of catching an illness and of becoming especially sick when you do “jump right back up” if you exercise intensely or for a prolonged period of time, surpassing the risks among the sedentary. (Although definitions of intense exercise vary among researchers, most define it as a workout or race of an hour or more during which your heart rate and respiration soar and you feel as if you are working hard.)
Why exercise should affect either your susceptibility to catching an illness or how badly a particular bug affects you is still unclear. But it does appear that intense workouts and racing suppress the body’s immune response for a period of time immediately after you’ve finished exercising and that “the longer the duration and the more intense” the exercise, “the longer the temporary period of immunosuppression lasts — anything from a few hours to a few days has been suggested,” says Nicolette Bishop, an associate professor of sport and exercise sciences at Loughborough University and the author of a review article about exercise and immunity published in January.
A telling new study, published in August in the Journal of Strength and Conditioning Research, looked at cellular markers of immune system activity in the saliva of twenty-four, Spanish, professional soccer players, before and after a strenuous, 70-minute match. Before play, the saliva of most of the players showed normal levels of immunoglobulins, substances that help to fight off infection. Afterward, concentrations of saliva immunoglobulins in many of them had fallen dramatically.
If scientists aren’t sure yet why intense exercise temporarily depresses the immune system, however, they seem to be closer to understanding why, once you’ve caught a bug, intense exercise can make the symptoms and severity worse. In work at the University of Illinois, reported last month in the journal Exercise and Sport Sciences Review, some of the same scientists who’d studied mice and flu looked at just what was going on inside the cells of the affected animals. They found that the leisurely jogging rodents showed signs of a very particular immune response to the flu. In general, and this is true in both mice and men, says Jeffrey A. Woods, a professor of kinesiology and community health at the University of Illinois and one of the scientists involved, viruses evoke an increase in what are called T1-type helper immune cells. These T1-helper cells induce inflammation and other changes in the body that represent a first line of defense against an invading virus. But if the inflammation, at first so helpful, continues for too long, it becomes counterproductive. The immune system needs, then, at some point to lessen the amount of T1-mediated inflammatory response, so that, in fighting the virus, it doesn’t accidentally harm its own host. The immune system does this by gradually increasing the amount of another kind of immune cell, T2-helper cells, which produce mostly an anti-inflammatory immune response. They’re water to the T1 fire. But the balance between the T1- and T2-helper cells must be exquisitely calibrated.
In the mice at the University of Illinois, moderate exercise subtly hastened the shift from a T1 response to a T2-style immune response — not by much, but by just enough, apparently, to have a positive impact against the flu. “Moderate exercise appears to suppress TH1 a little, increase TH2 a little,” Woods says.
On the other hand, intense or prolonged exercise “may suppress TH1 too much,” he says. Long, hard runs or other workouts may shut down that first line of defense before it has completed its work, which could lead, Woods says “to increased susceptibility to viral infection.” So, if you have just completed a strenuous 20-mile training run and have, in consequence, a depressed immune response, avoid colleagues who are sniffling. Wash your hands often. “I would recommend everyone get the annual influenza vaccination and the new H1N1 vaccination,” Woods says. But if all of that has been for naught and you now feel the early stirrings of sickness, “listen to your body and be prudent in your exercise decisions,” Woods says. In general, moderate exercise, such as a leisurely jog or walk, may prop up your immune response and lessen the duration and severity of a mild infection, but be honest about your condition. “If you don’t feel well, especially if you have fever or body aches, I would recommend stopping daily exercise until you are recovered,” Woods says. “It is okay to exercise if you have a simple head cold or congestion — in fact, it may improve the way you feel. I would avoid heavy, prolonged exercise with a head cold, though,” since it can unbalance that important T1 and T2-helper cell response.
And take comfort in the results of the most recent study to look at actual, practicing marathoners. In it, 1,694 runners at the 2000 Stockholm Marathon informed researchers about any colds or other infectious illness they developed in the three weeks before or three weeks after the race. Nearly one-fifth of the runners fell ill during that time period. That’s higher than the rates in people generally, but it still means that the overwhelming majority of runners didn’t get sick.
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Is your ab workout hurting your back?
Cellular Respiration
Cellular Respiration
| Index to this page |
Cellular respiration is the process of oxidizing food molecules, like glucose, to carbon dioxide and water. The energy released is trapped in the form of ATP for use by all the energy-consuming activities of the cell.
The process occurs in two phases:
- glycolysis, the breakdown of glucose to pyruvic acid
- the complete oxidation of pyruvic acid to carbon dioxide and water
In eukaryotes, glycolysis occurs in the cytosol. (Link to a discussion of glycolysis). The remaining processes take place in mitochondria.
Mitochondria
Mitochondria are membrane-enclosed organelles distributed through the cytosol of most eukaryotic cells. Their number within the cell ranges from a few hundred to, in very active cells, thousands. Their main function is the conversion of the potential energy of food molecules into ATP. 
Mitochondria have:
- an outer membrane that encloses the entire structure
- an inner membrane that encloses a fluid-filled matrix
- between the two is the intermembrane space
- the inner membrane is elaborately folded with shelflike cristae projecting into the matrix.
- a small number (some 5–10) circular molecules of DNA
The number of mitochondria in a cell can
- increase by their fission (e.g. following mitosis);
- decrease by their fusing together.
(Defects in either process can produce serious, even fatal, illness.)
The Outer Membrane
The outer membrane contains many complexes of integral membrane proteins that form channels through which a variety of molecules and ions move in and out of the mitochondrion.
The Inner Membrane
The inner membrane contains 5 complexes of integral membrane proteins:
- NADH dehydrogenase (Complex I)
- succinate dehydrogenase (Complex II)
- cytochrome c reductase (Complex III; also known as the cytochrome b-c1 complex)
- cytochrome c oxidase (Complex IV)
- ATP synthase (Complex V)
The Matrix
The matrix contains a complex mixture of soluble enzymes that catalyze the respiration of pyruvic acid and other small organic molecules.
Here pyruvic acid is
- oxidized by NAD+ producing NADH + H+
- decarboxylated producing a molecule of
- carbon dioxide (CO2) and
- a 2-carbon fragment of acetate bound to coenzyme A forming acetyl-CoA
The Citric Acid Cycle
- This 2-carbon fragment is donated to a molecule of oxaloacetic acid.
- The resulting molecule of citric acid (which gives its name to the process) undergoes the series of enzymatic steps shown in the diagram.
- The final step regenerates a molecule of oxaloacetic acid and the cycle is ready to turn again.
Summary:
- Each of the 3 carbon atoms present in the pyruvate that entered the mitochondrion leaves as a molecule of carbon dioxide (CO2).
- At 4 steps, a pair of electrons (2e-) is removed and transferred to NAD+ reducing it to NADH + H+.
- At one step, a pair of electrons is removed from succinic acid and reduces FAD to FADH2.
The electrons of NADH and FADH2 are transferred to the electron transport chain.
The Electron Transport Chain
The electron transport chain consists of 3 complexes of integral membrane proteins
- the NADH dehydrogenase complex (I)
- the cytochrome c reductase complex (III)
- the cytochrome c oxidase complex (IV)
and two freely-diffusible molecules
- ubiquinone
- cytochrome c
that shuttle electrons from one complex to the next.
The electron transport chain accomplishes:
- the stepwise transfer of electrons from NADH (and FADH2) to oxygen molecules to form (with the aid of protons) water molecules (H2O);
(Cytochrome c can only transfer one electron at a time, so cytochrome c oxidase must wait until it has accumulated 4 of them before it can react with oxygen.)
- harnessing the energy released by this transfer to the pumping of protons (H+) from the matrix to the intermembrane space.
- Approximately 20 protons are pumped into the intermembrane space as the 4 electrons needed to reduce oxygen to water pass through the respiratory chain.
- The gradient of protons formed across the inner membrane by this process of active transport forms a miniature battery.
- The protons can flow back down this gradient, reentering the matrix, only through another complex of integral proteins in the inner membrane, the ATP synthase complex (as we shall now see).
Chemiosmosis in mitochondria
The energy released as electrons pass down the gradient from NADH to oxygen is harnessed by three enzyme complexes of the respiratory chain (I, III, and IV) to pump protons (H+) against their concentration gradient from the matrix of the mitochondrion into the intermembrane space (an example of active transport).
As their concentration increases there (which is the same as saying that the pH decreases), a strong diffusion gradient is set up. The only exit for these protons is through the ATP synthase complex. As in chloroplasts, the energy released as these protons flow down their gradient is harnessed to the synthesis of ATP. The process is called chemiosmosis and is an example of facilitated diffusion.
One-half of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their discovery of how ATP synthase works. Link to some of the details.
| External Link |
| Animations of the electron transport chain and the workings of ATP synthase |
| Please let me know by e-mail if you find a broken link in my pages.) |
How many ATPs?
It is tempting to try to view the synthesis of ATP as a simple matter of stoichiometry (the fixed ratios of reactants to products in a chemical reaction). But (with 3 exceptions) it is not.
Most of the ATP is generated by the proton gradient that develops across the inner mitochondrial membrane. The number of protons pumped out as electrons drop from NADH through the respiratory chain to oxygen is theoretically large enough to generate, as they return through ATP synthase, 3 ATPs per electron pair (but only 2 ATPs for each pair donated by FADH2).
With 12 pairs of electrons removed from each glucose molecule,
- 10 by NAD+ (so 10×3=30); and
- 2 by FADH2 (so 2×2=4),
this could generate 34 ATPs.
Add to this the 4 ATPs that are generated by the 3 exceptions and one arrives at 38.
But
- The energy stored in the proton gradient is also used for the active transport of several molecules and ions through the inner mitochondrial membrane into the matrix.
- NADH is also used as reducing agent for many cellular reactions.
So the actual yield of ATP as mitochondria respire varies with conditions. It probably seldom exceeds 30.
The three exceptions
A stoichiometric production of ATP does occur at:
- one step in the citric acid cycle yielding 2 ATPs for each glucose molecule. This step is the conversion of alpha-ketoglutaric acid to succinic acid.
- at two steps in glycolysis yielding 2 ATPs for each glucose molecule.
Mitochondrial DNA (mtDNA)
The human mitochondrion contains 5–10 identical, circular molecules of DNA. Each consists of 16,569 base pairs carrying the information for 37 genes which encode:
- 2 different molecules of ribosomal RNA (rRNA)
- 22 different molecules of transfer RNA (tRNA) (at least one for each amino acid)
- 13 polypeptides
The rRNA and tRNA molecules are used in the machinery that synthesizes the 13 polypeptides.
The 13 polypeptides participate in building several protein complexes embedded in the inner mitochondrial membrane.
- 7 subunits that make up the mitochondrial NADH dehydrogenase
- 3 subunits of cytochrome c oxidase
- 2 subunits of ATP synthase
- cytochrome b
Each of these protein complexes also requires subunits that are encoded by nuclear genes, synthesized in the cytosol, and imported from the cytosol into the mitochondrion. Nuclear genes also encode ~900 other proteins that must be imported into the mitochondrion. [More]
Mutations in mtDNA cause human diseases.
A number of human diseases are caused by mutations in genes in our mitochondria:
- cytochrome b
- 12S rRNA
- ATP synthase
- subunits of NADH dehydrogenase
- several tRNA genes
Although many different organs may be affected, disorders of the muscles and brain are the most common. Perhaps this reflects the great demand for energy of both these organs. (Although representing only ~2% of our body weight, the brain consumes ~20% of the energy produced when we are at rest.)
Some of these disorders are inherited in the germline. In every case, the mutant gene is received from the mother because none of the mitochondria in sperm survives in the fertilized egg. Other disorders are somatic; that is, the mutation occurs in the somatic tissues of the individual.
Example: exercise intolerance
A number of humans who suffer from easily-fatigued muscles turn out to have a mutations in their cytochrome b gene. Curiously, only the mitochondria in their muscles have the mutation; the mtDNA of their other tissues is normal. Presumably, very early in their embryonic development, a mutation occurred in a cytochrome b gene in the mitochondrion of a cell destined to produce their muscles.
The severity of mitochondrial diseases varies greatly. The reason for this is probably the extensive mixing of mutant DNA and normal DNA in the mitochondria as they fuse with one another. A mixture of both is called heteroplasmy. The higher the ratio of mutant to normal, the greater the severity of the disease. In fact by chance alone, cells can on occasion end up with all their mitochondria carrying all-mutant genomes — a condition called homoplasmy (a phenomenon resembling genetic drift).
Why do mitochondria have their own genome?
Many of the features of the mitochondrial genetic system resemble those found in bacteria. This has strengthened the theory that mitochondria are the evolutionary descendants of a bacterium that established an
Lipoic Acid Basics : Interview with Dr. Jim Clark
Interviewed By Richard A. Passwater Ph.D.
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In several recent articles, Dr. Lester Packer and I have discussed the merits of alpha-lipoic acid as an unique antioxidant that is critical to the antioxidant network involving vitamin C, vitamin E and glutathione. Last month we discussed how alpha-lipoic acid protects nuclear factor-kappa-B which has a role in gene expression and control. These articles have resulted in readers requesting more information about the basic properties of alpha-lipoic acid.
I have always found Dr. Jim Clark, Director of Technology Development of the Henkel Corporation to be an invaluable resource for information regarding the biochemistry of the antioxidant nutrients. Readers may remember the discussion on carotenoids with Dr. Clark and Lance Schlipalius in the September 1993 issue. In this issue, Dr. Clark and I will discuss some of the basic properties of this important antioxidant. Well, actually it is more than an antioxidant as Dr. Clark will explain. Passwater: Let's start at the beginning for the benefit of those readers who have not heard very much about alpha-lipoic acid. What is alpha-lipoic acid and what does it do? Clark: Alpha-lipoic acid is often referred to as the metabolic antioxidant. It really has two functions in the human body. First, it plays a role in the metabolism of the food that we eat to convert it into energy. The second role, and this is more recently discovered, is that of an antioxidant where it prevents oxidative damage to body components. The chemical structure of alpha-lipoic acid gives it very unique capabilities. It consists of a relatively small, eight-carbon atom chain having two attached sulfur atoms, one attached to the sixth carbon atom and the other sulfur atom attached to the eighth carbon atom, with the sulfur atoms also linked to each other. Passwater: The sulfur atoms are what make this unique compound so versatile, but let's talk some more about the benefits of alpha-lipoic acid before we discuss more about its structure. Do we make optimal amounts of alpha-lipoic acid in the body or is it "conditionally essential?" Clark: That's difficult to answer because no one has determined the optimal level of alpha-lipoic acid. Certainly the optimal level will vary from individual to individual depending upon their lifestyle and especially how much exercise and oxidative stress they experience. There is no doubt at all but what the body does synthesize alpha-lipoic acid. There is a lot of evidence that the synthesized alpha-lipoic acid is only adequate for the metabolic function and that additional alpha-lipoic acid that is needed for the antioxidant function comes from dietary sources including supplements. Passwater: Let's look at the converse of that. If it is such that the body makes barely enough for metabolic purposes if we are well-nourished and environmental factors and everything else is going right, and then we encounter oxidative stress due to free radicals or other reactive oxygen species, is some of the alpha-lipoic acid consumed in the battle against free radicals? Clark: That is not well understood. It is certainly conceivable that severe oxidative stress could deplete the level of alpha-lipoic acid needed to fulfill its metabolic function. However, the control mechanisms for synthesis of alpha-lipoic acid aren't well enough understood yet so that we could unambiguously say that the body would or would not replenish the consumed alpha-lipoic acid. Passwater: In essence, alpha-lipoic acid is converting food carbohydrates and fats into blood sugar (glucose) and fatty acids which then go through a process that leads to the extraction of energy. What is alpha-lipoic acid helping the body do? Clark: The body needs to "burn" blood sugar to produce energy, but instead of using high temperatures like we have in fire, the body has special biological catalysts called enzymes which extract the energy from sugars and fatty acids at normal body temperatures. Catalysts are atoms or molecules that facilitate reactions that either, as in the body, would not occur to any significant degree without their help, or in the case of chemical plant productions, need to be sped up to be commercially feasible. Catalysts are not consumed in these reactions, and a small amount can facilitate many reaction cycles. Enzymes act as catalysts and are not consumed in the process. They are present to facilitate the process along the way. In essence, the multi-enzyme complex involving alpha-lipoic acid is breaking down the molecules produced in earlier metabolism, pyruvate, into a slightly smaller molecules called acetyl-coenzyme A. This results in molecules that can enter into a series of reactions called the citric acid cycle or Kreb's cycle which finishes the conversion of food into energy. Sugars and fats are first partially oxidized in the body by other enzymes that combine them with oxygen that we have respired through our lungs. These products such as pyruvate, must then be acted upon by the alpha-lipoic enzyme complex in order for the process to continue into the citric acid cycle. A shortage of alpha-lipoic acid would be a critical bottleneck slowing down the energy-production process. Alpha-Lipoic acid is involved in what is called a "decarboxylation" which simply means that it cleaves off carbon dioxide. In the process excess energy is liberated which the body captures as ATP (adenosine triphosphate) and then uses that to provide the energy for muscle contraction. The carbon dioxide is then expired in our breath and the energy is used for body functions including everything from thinking to exercising. So we're converting food into carbon dioxide, water and energy. Passwater: How does lipoic acid work as a coenzyme? Clark: Alpha-lipoic acid is a co-factor in what is called a multi-enzyme complex that catalyzes what biochemists like to call "oxidative decarboxylation of alpha-keto acids" such as pyruvic acid. Forget the jargon and just remember that pyruvic acid is a product of a process called glycolysis, which is the first step in converting blood sugar (glucose) into energy that the body can use. The alpha-lipoic acid itself is bound to a very complex enzyme which is a high molecular weight protein and is not consumed when it is serving as a metabolic co-factor but it is continually regenerated. Passwater: Does this process wherein alpha-lipoic acid facilitates the conversion of blood sugar into energy have an effect on blood sugar level? Clark: Normally it doesn't, because this entire process is subject to other types of enzymatic control. However, there is strong evidence that very high intake of alpha-lipoic acid does influence glucose metabolism. It appears to increase the absorption of glucose into muscle tissue in non-insulin dependent diabetes ("Type II diabetes," also called "adult onset diabetes.") Passwater: Very high intake — this implies a level that the body normally doesn't produce. This would be an effect of either diet or supplementation. Is that correct? Clark: That is correct. It would take consumption of let's say more than 1,500 milligrams per day before any effect would be seen on glucose metabolism. Passwater: Do alpha-lipoic acid supplements reduce glycation? Clark: Yes. Glycation is the process where proteins react with excess glucose. This sugar damage to protein is just as detrimental as oxygen damage to proteins. There is strong evidence that alpha-lipoic acid reduces glycation. Passwater: That is important. You have explained how alpha-lipoic acid is critical to energy production and reduces glycation. How does lipoic acid work as an antioxidant? Clark: It works in many different ways. The first thing that we have to realize is that when we talk about alpha-lipoic acid there are actually two molecules that we have to consider. The first is alpha-lipoic acid itself and the second is a reduced form called dihydrolipoic acid. In the reduced form, two atoms of hydrogen have been added to alpha-lipoic acid, one hydrogen attached to each of the sulfur atoms. Passwater: What effect does having the sulfur-sulfur linkages split and hydrogen added to them have on the function of the molecule. Why does this change make the two molecules so different and what is the significance of this? Clark: They are different because you now have different chemical functionalities and they can react in different ways with other materials. Compounds that supply hydrogen atoms or electrons in chemical reactions are called reducing agents. Oxidizing agents are compounds that receive hydrogen atoms or electrons. The primary difference is the fact that the reduced form –the dihydrolipoic acid– is a much stronger reducing agent and it is capable of regenerating vitamin C and vitamin E from their oxidized forms. Both dihydrolipoic acid and alpha-lipoic acid can form strong chelates. These are complexes with transition metal ions such as iron and copper. Passwater: The chelation role of alpha-lipoic acid is also very important, and I want to follow up on that point later. But let's continue with the transport and interconversion of alpha-lipoic acid and dihydrolipoic acid. Is there evidence that the alpha-lipoic acid is taken up into cells then? Clark: Normally dihydrolipoic acid is formed in the cells. Cells tend to absorb the alpha-lipoic acid, reduce it and then secrete the dihydrolipoic acid back into the bloodstream. Passwater: We have mentioned how lipoic acid gets into the cell. Is there an active transport mechanism through the membrane? Does it have receptors or is it a chemical process or diffusion?. Just how does it get into the cells? Clark: No one knows that for sure. There is some indication that there may be a specific transporter for alpha-lipoic acid but it has not been pinned down yet. Passwater: Alpha-lipoic acid can be converted into dihydrolipoic acid inside of cells. Can dihydrolipoic acid be converted back into alpha-lipoic acid in the cells? Clark: Definitely. Most of that evidence comes from animal studies and from cell culture studies . But it is quite clear that under those conditions alpha-lipoic acid is taken up by cells and of course the metabolic function of alpha-lipoic acid occurs inside cells. The processes that it catalyzes actually occur in the mitochondria. Mitochondria are sometimes called the "powerhouse" of the cell where food is converted into energy. Passwater: What is "redox cycling" and what is the advantage of a compound that undergoes redox cycling? Clark: Redox cycling is simply the interconversion of an oxidized form of the material to a reduced form and back again. In some materials, the oxidation or reduction is irreversible. But the reduction and oxidation of alpha-lipoic acid is quite reversible. So since it is quite reversible, it can sit there and switch from one to the other. This is a real advantage because it allows it to act as a carrier, as a transfer agent for electrons from one compound to another. One of the earlier discoveries concerning alpha-lipoic acid was that it could prevent the symptoms of scurvy and also vitamin E deficiency in animals. It appears to be very clear that what it is doing is regenerating vitamin E and vitamin C from their oxidized form back to their active reduced forms. Passwater: So we have evidence that lipoic acid is carried from the bloodstream through the cell membrane into the cell interior, the cytosol, and then we also know it can go from the cell interior through another membrane that surrounds mitochondria. Do we know if it goes through any other of the cellular structures components? Clark: Since mitochondria are reconstructed every ten days, alpha-lipoic acid must get into them. It probably penetrates other cellular components also. The remaining question is: Is there a specific alpha-lipoic acid transporter? Unfortunately, we don't have an answer for that question yet. Passwater: Now we have discussed the fact that it's transported very well into cell and critical cell components like the mitochondria, that as dihydrolipoic acid, it regenerates vitamin C which in turn can regenerate vitamin E. It's a pretty universal antioxidant. Can it get into various compartments of the body, both lipid-based areas and water-based areas? Clark: Yes, that is one of the reasons why it is sometimes referred to as a universal antioxidant, as well as the metabolic antioxidant. Not only does it react with many different free radicals and oxidizing species including singlet oxygen, but it also, because of the size and functionality of the molecule is soluble in both water-based and fat-based areas of tissues. It is not as water-soluble as vitamin C, but it is much more water-soluble than vitamin E. This degree of water-solubility and fat-solubility will allow alpha-lipoic acid into all body systems. The main reason for this dual solubility is the size of the molecule. It is larger than ascorbic acid but it is much smaller than vitamin E. The other factor is the functionality of the molecule. It does contain a carboxylic acid end-group, and that has a tendency to make it more soluble in water than vitamin E. At the same time it has more carbon atoms than vitamin C and that makes it more soluble in lipid compartments. Passwater: Already it is apparent that alpha-lipoic acid is a versatile antioxidant. However, there is still more to its antioxidant protective actions. Let's discuss the ability of dihydrolipoic acid to chelate transition metals. If iron and copper are present in excess as free, unbound ions, they can be oxidants. Any compound that would chelate free ions of iron and copper would thus indirectly reduce oxidation and be considered an antioxidant. Clark: In most cases in the body, iron and copper are complexed with other proteins so the concentration of free metal ions is quite low, but under some conditions of trauma, you can have these metal ions released and under those conditions, the ability to complex is very important because that prevents these ions catalyzing oxidative processes. There is experimental evidence that both alpha-lipoic acid and dihydrolipoic acid can form chelation complexes, but dihydrolipoic acid is probably more effective in this role. Passwater: Would lipoic acid be of use for someone with iron overload disease? Clark: Alpha-lipoic acid has been used to treat individuals with heavy metal poisoning. Passwater: Is the ability to chelate due to the presence of both sulfhydryl and carboxylic groups in the molecule? Clark: The chelation ability is due to both sulfur atoms and the carboxyl functionality with mixed results. This property still needs investigation. Passwater: Are there other roles for the sulfur atoms in the ring? Here we have a simple molecule having a "backbone" of eight carbon atoms and nature, instead of adding a hydroxyl group to form a monophenol nutrient like vitamin E, or adding several hydroxyl groups similar to bioflavonoids, adds two sulfur atoms and links them together. What do the sulfur atoms have to do with alpha-lipoic acid's function as a coenzyme in the bonding of this multi-enzyme complex system? Clark: It gets rather complex, but when alpha-lipoic acid is in its role of a metabolic coenzyme, the carboxylic acid end-group anchors it to the enzyme through formation of a chemical bond called an "amide linkage" or a "peptide linkage." The sulfur groups on the other end of the alpha-lipoic acid molecule then actually undergo chemical reactions and bond to the carbonyl group on the keto acid which is undergoing the oxidative decarboxylation. Also the sulfur atoms are essential for the antioxidant activity and for the chelation properties. The oxidation potential between the sulfur-sulfur bond and the sulfur-hydrogen bond is such that it allows easy interconversion under physiological conditions. Consequently, the tissues can quite easily convert alpha-lipoic acid which has a sulfur-sulfur bond to dihydrolipoic acid which has cleaved that sulfur-sulfur bond and replaced it with two sulfur- hydrogen bonds. Passwater: That helps explains why alpha-lipoic acid is such a powerful and versatile antioxidant. How does the body make alpha-lipoic acid and what are the limiting factors for its biosynthesis? Clark: We believe it is synthesized from an eight-carbon carboxylic acid called octanoic acid. It is also believed that the sulfur comes from cysteine, a sulfur-containing amino acid, but the exact chemical mechanism and the factors that control the synthesis are not known yet. Passwater: Are there are any dietary conditions or disease conditions that you can think of that might limit one's production of lipoic acid? Clark: I suppose if you had a deficiency of sulfur-containing amino acids. Certainly cysteine is an essential amino acid and if your dietary consumption of that were inadequate, then you would not have one of the building blocks for alpha-lipoic acid. Passwater: Since dietary lipoic acid is so important to so many people, what are some good dietary sources? Clark: Again this is an area where science doesn't fully understand. If you look in the literature, you don't find very much about the lipoic acid content of various foods. What does seem clear is that is present in mitochondria. So you would think foods that are rich in mitochondria should be good sources. Of course the most common foods rich in mitochondria would be red meat because they are some of the richest mitochondria sources. Also, alpha-lipoic acid is present in chloroplasts which are the "mitochondria" of plants. Passwater: But we have a problem today where people today are de-emphasizing red meat in their diet and other sources in the scientific literature mentioned are yeast, which is not a staple of a typical American diet. Do you think that our emphasis on controlling dietary factors like the amount of fat are also possibly inadvertently putting a limiting factor on the amount of the dietary alpha-lipoic acid and its precursors like the sulfur-containing amino acid cysteine. Could you foresee this as a problem? Clark: It certainly could be, particularly individuals who don't eat red meat could well benefit from supplementation of lipoic acid. Passwater: How well is alpha-lipoic acid absorbed and is it absorbed intact? Clark: There is a lot of evidence from animal studies that it is absorbed intact and absorption appears to be pretty efficient as you would expect for something that is fairly water soluble. I have seen figures as high as 80% for animal studies, but no one has really quantitated that with human trials. Passwater: Once it is absorbed from the diet, can the body transport this in a form that can be utilized or is it degraded or somehow not made available to the body? Clark: It is quite clear that cells do take up alpha-lipoic acid and some is retained, some is secreted. Some is secreted as dihydrolipoic acid. There is also metabolism of alpha-lipoic acid in the liver. Passwater: What research has been conducted into possible therapeutic uses for alpha-lipoic acid in relation to its role in metabolism? It must be of value to diabetic patients who have oxidative stress as well as glycation problems. This seems like a nutrient that would have an influence on both, reducing oxidative stress and reducing glycation. Clark: It certainly does. This is one of the earliest areas that has been explored with alpha-lipoic acid. In Europe it is actually used as a pharmacological agent to prevent some of the side effects of diabetes and oxidative stress. Large clinical trials have shown a clinically meaningful reduction in diabetic polyneuropathy, one of the complications of diabetes. Passwater: How about other long-term uses such as detoxification. You mentioned earlier that it chelates transition metals. Has this been used for purposes such as this? Clark: It has been used for detoxification of heavy metal poisoning in Europe. This is taking advantage of its ability as a chelator instead of its antioxidant function, but there is fairly decent evidence showing its beneficial effects against cadmium and mercury poisoning. Passwater: What are some of the latest areas of research interest in lipoic acid? Clark: Alpha-lipoic acid is being looked at in many of the areas where oxidative stress is believed to be a causative agent. One of these is cataracts. The interior of the eye is a very aqueous environment and many of the common antioxidants such as vitamin E and beta-carotene are not very soluble in water. Alpha-lipoic acid, because of its water solubility, may exert a protective effect against the formation of cataracts. This has been demonstrated in some animal models but there is not yet solid data for human trials. Another area that is being investigated is atherosclerosis. As we learn more and more about atherosclerosis, there is strong evidence indicating that oxidation plays a key role in some of the early steps in depositing of cholesterol plaques in arterial walls. There is a strong possibility that alpha-lipoic acid will be protective against this. I think those are the two most exciting area of new research with alpha-lipoic acid. Passwater: Dr. Clark, thank you for reviewing the scientific literature on the basic properties of alpha-lipoic acid with us. All rights, including electronic and print media, to this article are copyrighted to © Richard A. Passwater, Ph.D. and Whole Foods magazine (WFC Inc.). http://www.healthy.net/scr/interview.asp?ID=160![[hal.jpg]](http://1.bp.blogspot.com/_VyTCyizqrHs/SeOP2FW3akI/AAAAAAAADcY/qFksO_k1NcA/s1600/hal.jpg)
Can You Get Fit in Six Minutes a Week? – Well Blog – NYTimes.com
Can You Get Fit in Six Minutes a Week?
By Gretchen Reynolds
The potency of interval training is nothing new. Many athletes have been straining through interval sessions once or twice a week along with their regular workout for years. But what researchers have been looking at recently is whether humans, like that second group of rats, can increase endurance with only a few minutes of strenuous exercise, instead of hours? Could it be that most of us are spending more time than we need to trying to get fit?
The answer, a growing number of these sports scientists believe, may be yes.
“There was a time when the scientific literature suggested that the only way to achieve endurance was through endurance-type activities,” such as long runs or bike rides or, perhaps, six-hour swims, says Martin Gibala, PhD, chairman of the Department of Kinesiology at McMaster University in Ontario, Canada. But ongoing research from Gibala’s lab is turning that idea on its head. In one of the group’s recent studies, Gibala and his colleagues had a group of college students, who were healthy but not athletes, ride a stationary bike at a sustainable pace for between 90 and 120 minutes. Another set of students grunted through a series of short, strenuous intervals: 20 to 30 seconds of cycling at the highest intensity the riders could stand. After resting for four minutes, the students pedaled hard again for another 20 to 30 seconds, repeating the cycle four to six times (depending on how much each person could stand), “for a total of two to three minutes of very intense exercise per training session,” Gibala says.
Each of the two groups exercised three times a week. After two weeks, both groups showed almost identical increases in their endurance (as measured in a stationary bicycle time trial), even though the one group had exercised for six to nine minutes per week, and the other about five hours. Additionally, molecular changes that signal increased fitness were evident equally in both groups. “The number and size of the mitochondria within the muscles” of the students had increased significantly, Gibala says, a change that, before this work, had been associated almost exclusively with prolonged endurance training. Since mitochondria enable muscle cells to use oxygen to create energy, “changes in the volume of the mitochondria can have a big impact on endurance performance.” In other words, six minutes or so a week of hard exercise (plus the time spent warming up, cooling down, and resting between the bouts of intense work) had proven to be as good as multiple hours of working out for achieving fitness. The short, intense workouts aided in weight loss, too, although Gibala hadn’t been studying that effect. “The rate of energy expenditure remains higher longer into recovery” after brief, high-intensity exercise than after longer, easier workouts, Gibala says. Other researchers have found that similar, intense, brief sessions of exercise improve cardiac health, even among people with heart disease.
There’s a catch, though. Those six minutes, if they’re to be effective, must hurt. “We describe it as an ‘all-out’ effort,” Gibala says. You’ll be straying “well out of your comfort zone.” That level of discomfort makes some activities better-suited to intense training than others. “We haven’t studied runners,” Gibala says. The pounding involved in repeated sprinting could lead to injuries, depending on a runner’s experience and stride mechanics. But cycling and swimming work well. “I’m a terrible swimmer,” Gibala says, “so every session for me is intense, just because my technique is so awful.”
Meanwhile, his lab is studying whether people could telescope their workouts into even less time. Could a single, two- to three-minute bout of intense exercise confer the same endurance and health benefits as those six minutes of multiple intervals? Gibala is hopeful. “I’m 41, with two young children,” he says. “I don’t have time to go out and exercise for hours.” The results should be available this fall.
http://well.blogs.nytimes.com/2009/06/24/can-you-get-fit-in-six-minutes-a-week/
