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Durk Pearson and Sandy Shaw – 2
radical damage in the mitochondria. Dr. Denham Harman’s Free Radical Theory of Aging and Age-Related Diseases is holding up very well.
Sandy: But one thing that he actually realized quite early on was that most antioxidants do not get into the mitochondria–where the free radicals are generated. That’s actually where you have the most serious problem with free radicals–inside the mitochondria themselves.
Durk: Remember, the mitochondria are your little subcellular energy factories. They produce the universal energy molecule ATP by burning carbohydrates and fats, and they do this by a free radical mechanism. There’s single electron reactions going on there on purpose. That’s an essential part of the way it works, so you can’t just suck up all the free radicals. For example, cyanide will do a beautiful job of killing you–and the reason it does this is because it sucks up those single electrons in the mitochondria so you can’t make ATP and you die.
Sandy: Yeah, so it’s a perfect free radical quencher, which just goes to show that you have to be selective about free radical quenchers. Not just anything that prevents free radicals is going to be good for you.
Durk: A recent paper in Science reported that it is possible to stimulate biogenesis of new mitochondria in old cells.
Sandy: That means making new mitochondria. This is critically important when you consider that part of the aging process involves the decreasing numbers of mitochondria per cell, whereby you end up with less energy per cell, because the mitochondria are converting all the energy. But that’s what happens with aging–you end up with fewer and fewer mitochondria per cell. Also, a lot of the ones that still exist are damaged and not working too well.
Durk: And leaking a lot of free radicals.
Sandy: One way that you can make new mitochondria is through exercise. One of the beneficial effects of exercise is that it stimulates the biogenesis of mitochondria. So that’s one good reason to do exercise, but there’s other ways of doing it.
Durk: Arginine, particularly in conjunction with choline and vitamin B-5, that is pantothenate, is able to do this. This increased the production of endothelial-derived nitric oxide.
Sandy: Nitric oxide synthase is the enzyme that makes nitric oxide, and there are three forms of it. One of those forms of nitric oxide synthase is in the endothelial cells, which line blood vessels.
Durk: And it’s not only there, it’s in all other cells and organelles called caveolae, which are little sub-organs inside of the cells.
Sandy: This endothelial nitric oxide synthase is critically important for preventing cardiovascular disease, for example. A major factor in what happens to people when they get cardiovascular disease is that their endothelial nitric oxide synthase is no longer producing the nitric oxide that they need to keep the blood vessels open.
Durk: So the people end up hypertensive. But it’s a lot more than that. Without this endothelially-derived nitric oxide, which is made from arginine, what happens is you don’t get a bunch of new mitochondria. However, you can stimulate the biogenesis of mitochondria with compounds that either mimic nitric oxide or nitric oxide itself–and I think is a tremendously important finding in terms of life extension.
Sandy: Arginine is used by nitric oxide synthase to make nitric oxide.
Durk: And acetylcholine is what stimulates the endothelial caveolae synthesis of nitric oxide from arginine. You can make the acetylcholine from choline and pantothenate, that is vitamin B-5.
David: What are some of the new anti-aging treatments that you foresee coming along in the near future?
Durk: I think we’re going to see a lot more work on stimulating mitochondrial biogenesis. Just as an example, the erection drug Cialis works by inhibiting the enzyme that breaks down cyclic GMP. Now cyclic GMP is the second messenger for nitric oxide, and it’s in the pathway of mitochondrial biogenesis.
Sandy: In other words, the cyclic GMP actually takes the information that the nitric oxide release is providing and then transfers that to other parts of the metabolic pathways, which continue to pass down the message.
Durk: And long-acting, cyclic GMP-inducers–ones that work in things like skeletal muscle, and in neuronal tissue, as well as the smooth muscle in the penis–may increase longevity if they’re long-acting like Cialis, and they’re not too selective. I think that this could help with mitochondrial biogenesis, and they may be life extension drugs, although this hasn’t been tested. A lot of drugs have been developed for erectile dysfunction and have been thrown out because they weren’t sufficiently selective for the particular enzyme subtype that occurs in the smooth muscle in the penis. I think they need to go back and look at a lot of the drugs that have been thrown out, and examine their effect on lifespan in mice.
Sandy: One of the real problems right now in the development of life-extending substances is that nothing is going to be approved by the FDA for life extension–not prescription drugs, and certainly not dietary supplements. You can’t even provide information about how dietary supplements can be used in the treatment of disease. There’s still a large number of people that are fighting this in the courts, and by appealing to the political process. We’re involved in litigation and are a part of that. But until it is possible for people to provide truthful information concerning potential life-extending effects, then people aren’t going to be finding out about this research.
Look at what the NIH is getting now–some 40 billion a year that they’re spending on scientific research. Well, most of the biomedical research that’s done you never find out about. Unless you’re reading the journals like we do, the only way that you’re going to get that information is occasionally the media will cover something. But that’s a very short-term appearance. So you’re not going to get that information into a product that then can be sold to people on the basis that it does a certain thing, because you can’t provide that information.
Durk: Incidentally, we won in the U.S. Court of Appeals, for the district of D.C., in a case against the FDA called Pearson v. Shalala in 1999. They ruled three to zero that it was unconstitutional for the FDA to be prohibiting these four claims which we had brought–one of them was the fish oil claim.
Sandy: Yeah, one of them was that fish oil may reduce the risk of cardiovascular disease, and that it was unconstitutional for them to prohibit those claims.
Durk: The FDA asked for a rehearing, and that was turned down eleven to zero. Not only was it turned down eleven to zero, normally when that happens there’s just a note, a one-word note: refused. In this case they wrote another page and a half blasting the FDA for not getting it. In fact, the FDA had actually told a federal judge, the FDA lawyer, that they didn’t think the First Amendment applied to them. That was at a magistrate settlement hearing before a federal mandestrate. Now that’s really scary.
Sandy: It just goes to show where the FDA comes from. They didn’t think the First Amendment applied to them?
Durk: They didn’t appeal it to the Supreme Court, probably because realizing that if they did they’d lose on that, and they’d lose even more.
Sandy: That’s undoubtedly the reason they did it.
Durk: So what they did is they actually announced in the federal register that their regulations have been declared unconstitutional, but they also announced–and this takes your breath away–that they were going to continue to enforce them.
Sandy: That is, until they had developed a process and decided what they were going to do. So, in the meantime, until they decided what they were going to do about it, they were going to continue to enforce these unconstitutional regulations.
Durk: Now, our attorney Jonathan Emord said nothing like that had happened since the Civil War, when Lincoln tried to arrest Chief Justice Tawny and put him in prison. The executive branch of the government normally just does not ignore the courts–or I should say defy? They weren’t merely ignoring it, they were willfully defying the courts. So what we did is we asked the judge for a declaratory judgment.
Sandy: The judge at the district court level.
Durk: The Court of Appeals returned it to the district court for final action in terms of enforcing their ruling. She ordered the FDA to recind the regulations, and they published this thing–no, we’re not going to be withdrawing them, even though they’ve been declared unconstitutional. So we asked the judge for a declaratory judgment that the FDA decision makers were willfully and knowingly violating our constitutional rights. The response from the judge was quicker than anything we’ve ever seen from a federal court. It was just a few weeks, not six months or a year. The declaratory judgment comes back–they’re willfully and knowingly violating our constitutional rights. At that point, we warned them that we are going to sue them as individuals.
Sandy: And take their homes, their cars, everything!
Durk: Yeah, to impoverish them, and sue them for all the legal fees that we have paid to date. A couple of weeks later they decided, whoops, no, we’re not going to enforce these anymore.
Sandy: But it took two years. Our victory in Pearson v. Shalala occurred in January, 1999 but it took until 2001 before they