An Interview With Durk Pearson & Sandy Shaw®
Life Extension Developments
By David Jay Brown
Durk Pearson and Sandy Shaw are clearly two of the most well-informed people on the planet regarding the biochemical mechanisms of aging. In conversation, they symbiotically bounce back and forth off one another, and their high-energy brains seem to perform at super-luminal speeds. I spoke with them about the latest developments in antioxidant research, how mitochondrial DNA grows defective as we age, and the benefits of heat-shock proteins.
DAVID: Can you talk a little bit about some of the latest developments in antioxidant research?
DURK: There's a lot of work that's being done in this area. It's getting so broad sometimes that it's a little bit difficult to tell whether you should call this antioxidant research or something else - for example, the relationship of the amino acid homocystine to heart attacks, strokes, and arteriosclerosis. Certainly, homocystine increases the level of free radical activity, but that may not be the only mechanism that's involved. You can bring down homocystine levels with Vitamin B6, which can act as an antioxidant. You can also do it with folic acid and Vitamin B12, which in and of themselves aren't antioxidants, but are involved in making some endogenous antioxidants.
SANDY: Homocystine is a neurotoxin too. Now, whether that is because of free radical activity I don't know. It might be a different mechanism.
DURK: I think one of the more interesting things is the continued research on green tea polyphenols. The number of papers is just exploding in that area. One of the most interesting things that was found recently is that a green tea polyphenol - epigallocatechin gallate - has a very interesting biphasic effect on genetically-damaged cells that are exposed to free radical stress, such as ionizing radiation in cancer therapy, compared to normal cells. Namely, this polyphenol protects the normal cells from free radical stress, such as ionizing radiation, but promotes apoptosis [cell death] in the genetically-damaged cells.
That's exactly what you're trying to do with that radiation when you are radiating cancer. So, unlike some antioxidants that you wouldn't want to take while undergoing radiation therapy because they could increase the resistance of the tumor, it looks as if the green tea polyphenols seem to have an opposite effect - which is just what you're looking for. Now, I must point out that these experiments were done in vitro, and the type of cancer a particular person has may not have that type of effect on it from the green tea polyphenols, but things are certainly looking interesting in that area.
Let me give another example of something where you really don't know whether you want to call it specifically free radical research or not, but free radicals are certainly involved. One of the things that happens as an animal ages is that you end up with relatively stable long-lived proteins, such as collagen or connective tissue becoming glycosylated. That is, glucose reacts with it, and it forms a Schiff base. That rearranges to an Amidori product, and eventually you end up with a terminal irreversible reaction between the glucose and the connective tissue.
SANDY: The glucose actually forms chemical bonds with amino acids.
DURK: And when this occurs, it's a free-radical-mediated mechanism.
SANDY: Exactly. And what you end up with is defective proteins, because they're connected to sugars, and they're not in the proper molecular configuration anymore.
DURK: Now, in the case of a diabetic, one way of measuring the severity of their diabetes is by measuring their amount of glycosylated hemoglobin. The hemoglobin has a rather fast turnover. You make a considerable amount of it every day. A year from now, you're not going to have a significant amount of the same hemoglobin molecules in you then, that you have in you now. On the other hand, there are other tissues which are not replaced, such as the basement membrane in the kidney. Diabetics very frequently die of kidney failure. The process is caused by glycosylation of the basement membrane. The basement membrane gets thicker and thicker, and eventually the kidneys just can't filter anymore.
SANDY: You can duplicate the same thing in experimental animals, like rodents, by either taking ones that are diabetic and have high levels of blood sugar, or just giving the animals a very high carbohydrate diet that results in high blood sugar levels.
DURK: Or by taking a regular animal and damaging its ability to release insulin, or damaging its insulin receptors in such a way it becomes hyperglycemic.
SANDY: But you end up with a lot of glycosylation, and the kidney basement membranes get thickened.
DURK: Now, there's a good rodent model for human glycosylation damage to the kidneys. Just as many adult-onset diabetics end up dying of kidney damage caused by glycosylation (due to the thickening of the basement membrane), the same thing happens to these rodents. It was reported that if you gave them an amount of arginine added to their diet, equivalent to only about three grams a day for a human being, it completely abolished this age-related basement membrane glycosylation-induced thickening. I mean, we're not talking about staggeringly large amounts of arginine.
SANDY: So the kidneys in the old rodents were actually functioning as well as the kidneys in the young rodents, because what generally causes the decline is thickening of the basement membrane.
DURK: Arginine is an outstanding sacrificial target for this activated form of sugar, which causes the glycosylation. If you have some extra arginine running around in your bloodstream, it is much more reactive toward the glucose in this glycosylation reaction than, say, your collagen is. And, of course, it's real easy to get rid of glycosylation product, for the arginine is not part of a protein. It is floating around as a free amino acid. You are able to dispose of that because it's water soluble.
DAVID: What other developments in longevity research currently look promising?
SANDY: One of the most exciting areas in life extension that's taking place is the study of the genes that are involved in controlling aging. But you have to keep in mind that even there free radicals are important, because the genetic changes take place over a lifetime, and we know there's a lot of free-radical-induced genetic changes. For example, you have a dramatically different mitochondrial situation when you get to be old. Then most of the mitochondrial DNA in muscles, for example, ends up defective. It's not working like the young mitochondrial DNA. Ninety-five percent of the mitochondrial DNA in somebody who is 90-years old is defective. Only 5% is full-length mitochondrial DNA. All the rest of it is defective. There are things missing in it, and it's got damage.
DURK: It's really remarkable that people are able to actually continue to walk around under those conditions. All of a sudden it becomes very obvious why most people that age are very weak.
As more and more sequences of different organisms are developed and found, we're going to find out a great deal very rapidly. There's a tremendous amount of conservatism in the protection mechanisms that you have in, say, a yeast cell and a human cell. Perkin-Elmer [a genetics company] is doing a great job of sequencing DNA in the private sector, without using tax money. They're also doing it far cheaper, and far faster, than the government-funded human genome project.
SANDY: Yeah, it's amazing. By studying the genes that are involved in aging in bacteria, yeast, and other simple organisms, you get information that can be directly used in studying the human genetics of aging.
DURK: For example, heat-shock proteins are released when cells are stressed by heat or cold, ionizing radiation, or heavy metals. Almost anything that's capable of causing damage to the genome of the cell can cause an increase in the production of the heat-shock proteins, which are, in fact, protective factors. Some of these heat-shock proteins are actually honest-to-God little nanomachines with moving parts. What they do is, they'll go up to a protein, unfold it, and then refold it. Then they'll check to see whether the thing is in the proper three-dimensional configuration. And if it's not, they'll take it for destruction and replacement. The heat-shock proteins in yeast are almost identical to those in human beings, in spite of the fact that we split off from the yeast line probably a lot more than a billion years ago.
Now, it's been found recently that when you induce mild heat shock repetitively during the lifespan of human fibroblasts (that are growing in tissue culture), you do not get the normal phenotype - that is, the appearance of cells.
SANDY: The cells look a lot different as they age. In this particular study there was no increase in lifespan. However, there was a dramatic slowing of the aging in the cells. The old cells in the heat-treated cultures still had the characteristics of young cells, as compared to the cells that were in the culture and weren't given heat treatment.
DURK: The heat-treated cells looked like young cells under the microscope. Old fibroblasts in terminal cultures look a lot different from the young fibroblasts. These continue to look like young fibroblasts, and they also had a much lower expression of an enzyme that's common in very old terminally-divided cells, but not in the younger cells. The amount of heat shock that was required was really quite mild, about 30 minutes of about 105 degrees Fahrenheit. That, incidentally, is something that's quite achievable in a home hot tub.
SANDY: It's about 105.8 degrees Fahrenheit. This temperature is not at all uncomfortable. It's quite a nice temperature for a hot tub.
DURK: Now, of course you're not going to heat your core body temperature up to that. I wouldn't recommend exposing your brain to 105.8. But the part of your body where you have rapidly-dividing cells is where you have a lot of problems with things like cancer. The outer skin is something you can very easily heat up to that temperature simply by settling yourself down in a hot tub for 30 minutes. It's been said for a long time by Scandinavians that their use of saunas and hot tubs is beneficial to the appearance of the skin, and that keeps it more youthful looking. It looks like there's an actual basis for that under the microscope. The cells that are treated this way look a lot more youthful.
SANDY: Now, it's interesting to note that when you improve the resistance of an organism or cell to one type of stressor, like heat, you very frequently also improve the resistance to other stresses, like free radicals for example. So improving the heat resistance of these cells doesn't mean that's all the improvement they got. They very probably were more resistant to a wide variety of stressors.
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