26 June 2013

An old age pill: the search continues

"They were forever young"

Nadezhda Markina, Newspaper.Roo

How scientists manage to prolong the life of a living organism by 10 times, which drugs to slow down aging will be used in the future, "the newspaper.En" tells one of the most famous scientists in the world in the field of aging and life expectancy, professor at the University of Medical Sciences of Arkansas (Little Rock, USA) Robert Schmuckler Fig.

Photo from the personal archive

– Tell us about your experiments with extending the life of the nematode. What genetic manipulations have managed to achieve this?

– We drew attention to the studies of two laboratories that worked with nematodes. And they realized that they had missed the possibility of a serious increase in life expectancy. In these laboratories, mutations of a gene that is necessary for reproduction were studied. But if a worm has only one copy of the gene bad, and the other good, then such heterozygous worms can have offspring. Among their offspring, a quarter of individuals will carry two copies of bad genes, this is the first generation of homozygotes. It was this first generation that those two laboratories were engaged in, but these worms lived only twice as long. At the same time, despite defective genes, they could still lay eggs. We assumed that they received RNA or protein itself from their mothers through the cytoplasm of the egg, which allowed them to have offspring.

 So nematodes of the second generation of homozygotes were obtained, and now they could not reproduce at all. The researchers did not look at how long these worms would live, because they thought that they would never be able to develop into a full-fledged individual. But the word "never" is determined by your patience. We had everything in order with patience, we began to observe these worms and found that they have a slow development: they do not develop to adulthood in two days, as usual, but from 8 to 16 days. Nematodes are cold–blooded, and the speed of their development is affected by temperature. Usually the development occurs faster at a temperature of 25 degrees. But these worms did not develop at all at 25 degrees, and they developed only at temperatures from 16 to 20 degrees. Most likely, this was because DNA replication was slow due to the lack of a gene and could not keep up with other molecular mechanisms. Normal development occurs when all systems work synchronously.

We decided to look at the health of nematodes of the second generation. And it turned out that they always looked a tenth of their age, were forever young. In addition, it turned out that they experienced oxidative and chemical stress very well. As for life expectancy, these nematodes lived ten times longer than usual, namely 190 days.

– What gene were they deprived of?

– In nematodes, this gene is called Age-1. In mammals, the analog of this gene is the phosphainositol-3-kinase (PI3K) gene.

– Have you recognized the mechanism of action of this gene on life expectancy?

– We're working on it. We don't know for sure, but we think that in the absence of this gene, many signaling pathways are turned off. We see a significant difference in transcriptional activity in the second generation compared to the first. That is, very few proteins are synthesized in the second generation.

– Were the long-lived nematodes of normal size or small?

– At first they were small, as they grew very slowly, but then they acquired normal sizes.

– In mammals, an increase in life expectancy is often accompanied by a decrease in body size and a decrease in metabolism. Is this a pattern?

– There are several examples in which long-lived mice do not shrink in size. One example is mice in which the PEPCK gene does not work. The second is mice that have no PI3K gene activity. Three years ago, Japanese researchers published a paper in which they turned off the PI1K gene in the heart of mice. They did not look at life expectancy, but assessed the health of the heart in mice. The animals were offered tests like patients at a cardiologist: a treadmill test and a chemical stress test. Only the size of the treadmill was smaller than for people. Ordinary mice at the age of 20 months did not tolerate such tests well, and knockouts coped with them much better.

In the second work, which was published two months ago, scientists selected one copy of this gene from mice, but in the whole body. At first, these mice looked like diabetics, but after 20 months, instead of insulin resistance, they developed insulin sensitivity. And life expectancy as a result increased by 17-18%.

– Do nematodes and humans have common aging mechanisms?

– Yes, of course. The signaling pathways that we know about for mammals, including humans, were first discovered in simple model animals. All signaling pathways that play a role in aging are evolutionarily conservative.

– Is the cure for aging still just an idea or specific developments?

– Today it has been shown that there are several substances that increase life expectancy. These are aspirin, which prolongs the life of mice by 8-12%, and rapamycin, which prolongs the life of mice by 14%.

– What explains the effect of aspirin?

– In a third of people, aspirin causes irritation of the gastrointestinal tract, but at the same time it reduces the frequency of several age-dependent diseases - primarily heart attacks and strokes.

– Due to the fact that it dilutes the blood?

– Large–scale studies have been conducted to understand what ultimately outweighs the positive effects of aspirin or possible negative effects. As a result, it turned out that the positive ones outweigh. In addition to reducing the risk of cardiovascular diseases, other positive effects of aspirin were found.

The biggest is a decrease in the incidence of Alzheimer's disease (from 22% to 28%) and a decrease in insulin resistance and the incidence of type II diabetes. The incidence of some cancers characteristic of late life is also decreasing.

Scientists are always looking for a simpler answer – in accordance with the principle of Occam's razor. And in this case, the answer is that aspirin slows down aging. Human studies have shown that taking aspirin reduces mortality from all causes by 6-8%. And studies on mice have shown that mice live longer. After studying the mechanism of action of aspirin on nematodes, we realized that it blocks the work of the insulin-like signaling pathway and reduces the level of oxidative stress. We are continuing our research, and we have inspiring results.

– And what are the prospects of your medicine with a genetic mechanism of action?

– Our goal is to create a pharmacological drug that would block the activity of phosphainositol–3-kinase, but it should be taken only in adulthood. This is a joke, but it could be advertised as a life-prolonging pill "in one bottle" with a contraceptive. Although it does not completely block reproduction, it all depends on the reception mode. We investigated the PI3K inhibitor and saw that it has a positive effect on health and increases insulin sensitivity in mice. But – I want to emphasize this – it is premature to run to the pharmacy and buy the drug. I am sure that in a large dose it can be fatal!

An important fact that we have shown is that a substance in a small dose can repeat the effect of genetic intervention. This is, in fact, what pharmaceutical companies do: first you study the genetic effect, and then you look for a substance that will repeat it. The only problem: pharmaceutical companies do not track the effect of the drug for long enough.

– Can you give a forecast when your drug will appear?

– We are conducting research in collaboration with the Russian company Quantum Pharmaceuticals. I can predict quite accurately when the drug will be tested on animal models. We already have the first generation of candidate substances that will lead to the emergence of a second generation of even better candidates, and all this may take less than a year. And then you will need to start the standard process of taking the drug to clinical trials, and it will take much longer. I can't predict how much.

Portal "Eternal youth" http://vechnayamolodost.ru26.06.2013

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