29 December 2014

Life extension: Unanswered questions

What will happen when we all live to be a hundred years old?

Elena Foer, Copper News based on The Atlantic: What Happens When We All Live to 100?For thousands of years, the duration of human life, by today's standards, was quite small – the forty-year milestone was perceived as a gift from the gods.

The situation began to change only in the XIX century. Since 1840, life expectancy has increased by three months annually. The average life expectancy of a woman in Sweden (where statistics were kept best) at this time was 45 years. Today – 83 years old. If this trend continues, the centennial milestone, according to American scientists, will be reached by the end of this century.

Speaking about the possible consequences of discoveries in this area, analysts consider two possible scenarios – optimistic and pessimistic. According to the pessimistic opinion, the share of pensioners in society, which is growing now, will increase even more significantly, which will mean a serious change in the structure of society, in which the interests of the elderly population will prevail, and the amounts allocated to the pension fund and healthcare will grow and grow. According to the optimistic scenario, not only life expectancy will increase, but also the period of working capacity – that is why most studies aim not just to lengthen life, but to increase the duration of a healthy life.

By leaps and boundsThe Buck Institute, created when research on the problem of aging was not yet taken fully seriously, today can be called one of the leading centers in this field.

Now about a hundred molecules are being studied here, which presumably can increase life expectancy. The role of model organisms is played by living beings with a very short life span – for example, yeast. At the same time, a third of their genes are the same as human ones. Removing some genes kills yeast, removing others allows you to live longer. Scientists do not yet know why this happens, but they suggest that, perhaps, this information will increase the life span of people.

The Buck Institute uses miniature electrocardiographs and CT scanners to study the internal organs of laboratory mice - after all, it is important not only how long they managed to live, but also what their health was.

Another model object is the roundworms Caenorhabditiselegans. Since 1999, the Institute's employees have managed to increase their life expectancy by five times. "Twenty years ago, increasing the life span of a worm was a really difficult task. Today, any young candidate of sciences can cope with it," says Simon Melov, a geneticist at the Institute. Now the institute can increase the life span of a mouse by a quarter and reverse the heart disorders that appear with age. As part of one of the projects, the institute's employees hope to collect 5-10 molecules that prolong the life of mice, and then proceed to the stage of testing them in human studies. However, these plans are still vague – in addition to the ethical difficulties and the high price of such a project, it would take decades.

What do whales know?Today's researchers had their predecessors, some of whom offered very dubious means.

A generation ago, Linus Pauling, a Nobel laureate in chemistry, suggested that megadoses of vitamin C could stop aging. But it turned out that such therapy is toxic to the body.

A decade ago, the organizers of a biotech startup called Sirtris were developing a drug that mimicked the supposed healing properties of red wine. Pharmaceutical giant GlaxoSmithKline bought Sirtris for 790 million in today's dollars and is still waiting for a return on investment: Sirtris experiments have not yet led to any result.

About 15 years ago, Bruce Ames, an employee of the University of California at Berkeley, suggested that the substance acetylcarnitine, which is important for the functioning of mitochondria in cells, in combination with an antioxidant can delay aging in the treatment of mild stages of Alzheimer's disease. Adding antioxidants to everything has long been a noticeable marketing trend, but the use of excessive amounts of antioxidants is harmful to the body, because the oxidative process is necessary for breathing. Ames decided that he had found a compound that safely slows down the rate of cell wear. He started taking acetylcarnitine himself and continued working at Berkeley at the age of 85 – who knows if he would have maintained the same performance without the substance. Pharmaceutical companies did not pay much attention to his research – since acetylcarnitine cannot be patented and, even worse, the substance itself is inexpensive.

Today, laboratory results demonstrate the relationship between a diet with a daily calorie restriction and life expectancy in mice. This is the most important discovery in the field of aging research today. The restriction in food brought the cells of mice into a state vaguely resembling hibernation. It is not yet known whether this method works in humans. The staff of the Baka Institute examined people who adhere to a low-calorie diet, and, according to them, "starving" do not look completely healthy.

More recently, at the same time at Harvard, Stanford and the University of California, researchers came to the conclusion that transfusion of blood from young mice to old ones has a rejuvenating effect on the latter. The purpose of this work, of course, is not to organize similar transfusions in people in the future, but to find out which specific chemicals in the blood of young people positively affect mature tissues. Perhaps the fact is that "young blood" affects dormant stem cells, and it is possible to develop a drug that will do the same without transfusions.

The Buck Institute and other laboratories are also looking for genes that are associated with an increase in healthy life expectancy in other mammals. Whales, for example, are much less likely to get cancer. Polar bears eat much more fatty foods, and yet they do not develop thrombosis. If the mechanisms behind these biological features are found, it will be possible to create a drug that recreates these effects in humans.

In addition, scientists are trying to change the "suspicious" genes of animals in order to achieve life extension. For example, the daf-2 and daf-16 genes in worms can be changed in such a way that animals will live twice as long and remain healthy until death. Molecular biologist Cynthia Kenyon made this discovery two decades ago while working at the University of California, San Francisco. Mice in which Kenyon modified the same genes lived longer and were less likely to get cancer than animals from the control group. The daf-16 gene is similar to the human foxo3 gene, a variant of which is associated with exceptional longevity. The biotech company Calico, created by Google Corporation, hired Kenyon and, according to rumors, she is now developing a cure for aging based on her results. However, so far she has not been able to prove that changes in the same genes in humans will have the same effect.

The Buck Institute is optimistic about the results of research on the drug rapamycin. This is the most promising substance of all the means developed at the Institute for delaying the aging of the body. Designed to prevent rejection of transplanted organs, rapamycin appears to alter some cellular processes associated with aging. Laboratory mice treated with this drug aged more slowly and remained healthy and energetic for longer. If it turns out that it exhibits the same properties in humans, it will be the greatest pharmaceutical discovery. However, it is still too early to run to the doctor for the appointment of rapamycin – not only the effectiveness of the drug in humans, but also possible dangerous side effects have not been studied.

Smoking, eating red meat, living up to a hundred yearsWith the exception of the development of infectious diseases, it is often difficult to track cause-and-effect relationships in medicine.

Coffee, salt, oil – do they harm the body and do they affect it in any way at all? There is still no definite answer. Why do some people develop heart disease, while others with the same habits do not? The Framingham Heart Study, a global project in which doctors have been observing residents of the American town of Framingham since 1948 (already their third generation), has not answered this question for 66 years. Keeping track of weight, eating more vegetables and less sugar, exercising and getting a good night's sleep – all these are tips based only on common sense, and not evidence of their effectiveness in terms of prolonging life.

The uncertainty inherent in medicine in general only increases when longevity becomes the object of research, since decades must pass before an unambiguous conclusion that this drug or practice leads to an increase in life expectancy. Conducting research with centenarians has not become a gold mine, as many scientists expected. "Studies of the lifestyle of people who have lived to be a hundred years old look puzzling," says Brian Kennedy, executive director of the Buck Institute. – They smoke a lot and drink less than we would have guessed. There are few vegetarians among them. Nothing indicates the exact reason for their longevity."

One of the first large-scale projects in the field of gerontology was the Baltimore Long-term Study of Aging, which began in 1958 and continues to this day. The current head of the project, Luigi Ferrucci, says that they still do not have clear answers to the question of what longevity is more related to: genes or the environment. The study of twins showed that in about 30% of cases longevity is an inherited characteristic. This inspires scientists with optimism – perhaps in the future it will be possible to reproduce the mechanism that leads to the inheritance of life expectancy.

The key to such a mechanism is being actively sought now, studying the processes of cellular aging. Just as tissues and organs are subject to disorders and malfunctions, the cells of the body are also subject to them. In such cases, the cells transmit chemical signals that initiate the restoration of damaged cells or the destruction of those that cannot be repaired. At least that's how it works for young people. But when the body ages, the cells begin to send false signals, as a result of which constant inflammatory processes develop in the body, which cause heart disease, Alzheimer's disease, arthritis and other chronic age-related diseases. Judith Campisi, who is leading work in this area at the Buck Institute, believes that finding a way to stop the aging of cells or turn off the signals they transmit may be the answer to the question of how to prevent many chronic diseases associated with aging.

Disputes about stabilityThe increase in life expectancy for the last two hundred years has been going at a rate of about three months per year, despite wars, epidemics and advances in pharmacology.

There is no clear answer to the question whether this process will continue, but there are two opposing points of view on this. According to one of them, the increase in life expectancy is the result of progress and general improvement of living conditions and, consequently, the process will only accelerate in the future. Adherents of the opposite point of view believe that the growth was associated with a sharp drop in child mortality in the past and, therefore, the life span will not continue to grow. If cancer is ever defeated, on average humanity will win another three years of life, after which other deadly diseases will take its place. Thus, pessimistic experts say, we will not be able to win more than ten years in the future for sure.

One way or another, the ongoing changes in lifestyle and social institutions are likely to lead to a decrease in mortality. The number of murders is falling, water and atmospheric pollution is also decreasing in the long run. Changes in social institutions also lead to an increase in life expectancy – sanitary conditions are improving, health care opportunities are growing. Of course, the picture is not so rosy everywhere and not for everyone – the average life expectancy in developed and developing countries varies significantly, in addition, people with higher education, with a family and constantly maintained social ties live longer.

Guided evolutionAn improved understanding of the evolutionary biology of aging may also play a role in prolonging life.

Evolutionists have talked a lot about the idea of programmed death – the assumption that natural selection "wants" old animals to die and not waste resources that may be useful to young ones. Today's point of view boils down rather to the fact that natural selection simply does not have mechanisms to reward longevity.

Felipe Sierra, a researcher at the National Institute of Aging, says: "Evolution does not care about individuals who have passed the reproductive age. From the point of view of natural selection, an animal that has finished with reproduction and the necessary care for its offspring can easily be eaten, since the genetic material has already been transferred."

A generation ago, theorists assumed that menopause is an adaptive mechanism peculiar only to humans – women stop wasting energy on bearing children and can take care of those already born as mothers and grandmothers. This was supposed to increase the offspring's chances of survival and allow the family's genes to be passed on. Modern research, however, suggests that some animals, including lions and baboons, are also going through menopause, which is increasingly similar to a disorder associated with aging, rather than a special mechanism gifted by natural selection.

The key conclusion boils down to the following: if life expectancy does not affect the ability to transmit genes to offspring, then nature is not interested in centenarians in any way. Evolution "encourages" strength, intelligence, reflexes, sexual attractiveness, but not the ability to keep the body healthy for a long time. Here again we can recall the aging of cells. Natural selection, apparently, helped us to develop mechanisms that prevent the development of cancer, since cancer can also begin in young people of reproductive age. However, cell aging occurs when evolution goes out of play, and natural selection is no longer interested in the transformation of mammalian bodies with their defects leading to aging and death.

If cell aging could be slowed down, humans would hardly become immortal. Violence, accidents, infectious diseases would continue to kill us. Even free from chronic diseases, our bodies can break down.

But the assumption that drugs and even gene therapy can change the human body in such a way that the life span will increase cannot be called absolutely ridiculous futurism. Brian Kennedy of the Buck Institute observes: "Although natural selection has not protected us from aging, we have a chance to win. The latest BMW model is close to perfection. How can it be improved further? But the old cheap Ford is now easy to improve. While we are young, genetically we are all BMW. As we get older, we become an old Ford. Evolutionary improvements have not yet begun."

Portal "Eternal youth" http://vechnayamolodost.ru29.12.2014

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