In search of a cure for old age
Telegraph "Around the World": Longevity of hedgehogs as an example to follow
The evolutionary advantages of Homo sapiens turned into the transience of life
Sergey Avilov
This year, a record number of residents over the age of one hundred years has been registered in the history of Japan — more than forty thousand people. About 86% of them are women. However, the United States leads the world in this indicator — in 2008, more than 96 thousand people lived in the country, celebrating the centenary.
Photo (Creative Commons license): Prakhar Amba
For centuries, religion and philosophy have taught us that aging of the body is as inevitable as the onset of winter or sunset. Only alchemists worked on the search for the elixir of eternal youth, for which they fell on the bonfire. In the XIX century, even physics joined the chorus of pessimists with the second law of thermodynamics, which states that the entropy (thermodynamic measure of disorder) of any system only grows over time, and the system itself only collapses. It turned out that the aging of the body is essentially the same as the dilapidation of a house or socks.
However, some meticulous biologists have noticed that not everything is so simple with the inevitable "dilapidation" of the body. There are animals that practically do not age or age much slower than their relatives. And it's not about body size or metabolic rate. It would seem that with a fast metabolism, the body should "wear out" faster — but, for example, bats live ten times longer than ordinary mice, despite the fact that their metabolic rate is about the same.
The explanation of such differences was proposed by Nobel laureate Peter Brian Medawar (1915-1987) in his theory of aging through the accumulation of mutations. In natural conditions, many animal species, even if they were "ageless", would not have a chance to live for a long time, dying from predators, infections and other "external" factors. The strategy of such species is to accelerate the change of generations. At the same time, mutations accumulate that harm the health of each individual in old age, but this does not matter much for the evolution of the species as a whole, since very few individuals survive to such an age.
Our effective blood clotting system is a "human" example of how natural selection ignores health in old age. Effective blood clotting is necessary to avoid death from blood loss due to injuries, which was critical for the caveman. This same effective clotting is "responsible" for blood clots, which sometimes kill quite young people, but it does not matter — there are already offspring.
On the contrary, those species that rarely die from predation and other external factors age slowly. The sea urchin Strongylocentrotus franciscanus and the roundworm Lamellibrachia live for more than two hundred years and show no signs of aging. There are no signs of aging in sturgeon fish and sharks, which grow all their lives. Many reptiles live for a long time without aging (although they stop growing), for example, the record for the Galapagos turtle is 177 years. Among the birds there are both "fast-aging" species and long-livers. Condor, for example, lives up to 75 years. Among mammals, "ageless" species are unknown, the Greenland whale, which can live up to 211 years, is considered the long-lived record holder. Long-lived species demonstrate that there are no insurmountable obstacles to slow aging.
Red sea urchins (Strongylocentrotus franciscanus) attracted the attention of scientists after a tag dated 1805 was found on one of the living individuals. The age of these invertebrates can exceed two hundred years.
Photo: Channel Islands NMS/NOAA
It turns out that for animals the second law of thermodynamics is "not written". If you think about it, the entire development of a living organism from a single egg to a complex ensemble of billions of cells is a monotonous decrease in entropy contrary to the second law. The decay and degradation of the body begin only after death. Physicists recognized that it was incorrect to apply the laws of equilibrium thermodynamics "head-on" to living organisms, and in the twentieth century concepts of nonequilibrium thermodynamics were developed, which "reconciled" the conclusion about the increase in entropy of systems in a state of thermodynamic equilibrium with the realities of living organisms.
Observations and experience of doctors, and in the twentieth century, systematic research allowed us to find a number of factors that slow down aging with greater or lesser effectiveness. In recent decades, one of the molecular mechanisms contributing to aging has been well studied — oxidative damage of biological molecules by free radicals. Prevent unwanted oxidation of substances-antioxidants. Many plant products are rich in them: from red wine to seaweed. The antioxidants were vitamins E and C, tea leaf polyphenols, components of marine animal fat and the amino acid cysteine. The problem is that the lack of antioxidants in the diet "accelerates" aging, but their excess does not stop this process: even if you eat only tea leaves, you will not stay young forever.
One of the few factors that absolutely reliably lengthens the life of some laboratory animals is a "starvation ration": a significant reduction in the caloric content of the diet is about half compared to the calories that animals with an excess of food eat. The mechanisms of action of a lack of calories are unknown, as well as the presence of a similar relationship in humans. And is it a great pleasure to suffer from hunger for 120 years?
Keys to the mechanisms of agingFrom the point of view of molecular biology, aging occurs when cells stop dividing and renewing.
In connection with the problem of cancer, one of the most popular and funded issues has become the control of the cell cycle — the mechanisms that determine the "decision" of the cell: to divide, specialize or die. Similar mechanisms regulate the aging of the body, at least some of its aspects. Modern approaches of molecular biology have allowed us to get closer to understanding these mechanisms.
One of the fundamental causes of aging of various organisms is the damage to the DNA molecule, the material carrier of hereditary information, accumulating with age. For several decades, scientists have been developing the problem of prolonging life "from the opposite" — studying hereditary syndromes of premature aging (for example, progeria and Huntington's syndrome). It turned out that the molecular causes of such syndromes are defects in DNA repair systems.
DNA is needed not only for the transmission of hereditary information to daughter cells during division. In any physiologically active cell, DNA is intensively used — short-lived "copies" of RNA are read from it, which are necessary for protein synthesis, and ultimately for all biochemical reactions. Long polymer DNA molecules are chemically relatively unstable and are in an "aggressive environment". We are exposed to ultraviolet radiation and ionizing radiation, and some products of our own metabolism can spontaneously enter into chemical reactions with DNA and other biopolymers. Especially dangerous are free radicals (superoxide, peroxide) — payback for the rapid intracellular metabolism.
Moreover, the genetic information is recorded "linearly", as on a magnetic tape: if it breaks in one place, the whole cassette is no good, it must be "glued together". Our DNA would very quickly become unsuitable as a carrier of genetic information if it were not for complex complexes of enzymes that recognize various types of damage and correct them — with greater or lesser efficiency. For example, they cut out damaged sections of DNA and fill the gaps with "correct" sections, or cut "extra" covalent bonds that interfere with the normal functioning of DNA.
In humans and animals suffering from premature aging syndromes, the repair systems themselves are damaged. As a result, DNA damage accumulates very quickly and cells lose their ability to function normally. "Normal" aging occurs (in part) because the repair systems are not perfect, and DNA damage accumulates with age, which the "repair teams" could not cope with. It turns out that "normal" aging can be slowed down to some extent if we increase the efficiency of systems that maintain the integrity of DNA.
One of the processes that contribute to aging is an "incorrect" gene expression profile. The expression of different genes (that is, the intensity of protein production, which determines the manifestation of a particular trait) varies greatly. In a young organism, many unwanted genes are "silent". Recently, American scientist David Sinclair and his colleagues found out that this happens partly because the sirtuin protein prevents these genes from "turning on". Another function of sirtuin is to "repair" DNA damage. When there is a lot of damage, which is observed in old age, sirtuin is "busy repairing" and cannot control the expression of unwanted genes.
In 2007, an article about a line of mice called Klotho was published in the journal Nature Reviews Molecular Cell Biology. The line is genetically identical individuals, which were crossed only among themselves, something like a breed. Klotho mice differ from normal ones by a single mutation, which is responsible for many manifestations of aging at the cellular level, in particular for a reduction in the proportion of stem cells in various tissues. Stem cells are non—specialized cells capable of dividing and turning into specialized cells of different types, that is, to "rejuvenate" tissues. It is believed that the non-mutant Klotho protein, which is present in normal mice, blocks the transmission of a signal into the cell via the so-called Wnp3 pathway, which inhibits the ability of cells to divide, which means the ability of tissues to recover. It turns out that some aspects of aging are not manifestations of inexorable thermodynamics, but regulated biological phenomena, like cell division or immune response. The Wnp protein is an example of a specific "trigger" of tissue aging, the effect of which can theoretically be suspended.
In July 2009, very significant data were published in the journal Nature: the biologically active substance rapamycin (a product of the bacterium Streptomyces hygroscopicus, which was first isolated from the soils of Rapa Nui Island in the Pacific Ocean) significantly lengthens the average life expectancy of experimental mice: from 1094 to 1245 days for females, from 1078 to 1179 for males. Moreover, rapamycin began to be added to the diet of already quite "elderly" mice, whose biological age approximately corresponded to sixty years in humans. The result was obtained as part of The US National Institute on Aging's Interventions Testing Program (ITP), which studies the effects of a variety of substances on aging. The substances taken in ITP are tested in three independent centers, so there is no doubt about the reliability of the results.
It was previously known that rapamycin blocks the function of the so—called TOR protein - a link in one of the "chains" of intracellular signal transmission, which "causes" the cells of worms, flies and yeast to age. These results could mean nothing in relation to a person. But now it has been proven that rapamycin also affects mammals. Moreover, rapamycin has already been approved for clinical use — as an immunosuppressant. On the one hand, this means that it does not cause severe side effects, and on the other hand, the suppression of already weak immunity in elderly patients may not prolong, but shorten life. Scientists hope to create a modified rapamycin molecule that would prolong life, but not depress the immune system.
The concept of aging as a disease that can be "cured" with pills certainly has some scientific basis, but we should not forget that such a concept is beneficial to pharmaceutical companies. If scientists recognize that an "old age pill" is possible, then it will be possible to produce and sell it.
The Hunt for Longevity GenesA group of American scientists led by Eric Topol from the Scripps Research Institute are going to search for new genetic "keys" to longevity methodically and systematically.
It is planned to analyze up to 500 genes of a large group of people (about 2000) who have lived to at least 80 years, hoping to find gene variants that occur more often in them than in "short-lived", which means they may be responsible for an increased life expectancy. As a control group, the genes of people who died before the age of 80 from typical "diseases of old age" will be taken. The work will be large—scale — less than 10 years ago, scientists with pomp completed the largest project in the history of biology — the "Human Genome" - that is, the genome of one "average" person. Now it will be necessary to compare the genomes of thousands of people. The strategy resembles a well-known joke about the scientific method of catching lions in the desert: you need to sift the entire desert through a sieve, then the sand will wake up, and the lions will remain. But the modern level of automation of molecular biological methods and computer analysis of genetic information make the project feasible in principle. As long as 80-year-old research objects don't die before their turn comes.
Renowned cardiologist and geneticist Eric Topol and his assistant study the genes of octogenarians to find which ones are responsible for longevity. Photo: TSRI
Gerontologists from the Leiden University Medical Center are also looking for "longevity genes", but in people over 90 years old. The Dutch criticize Topol and his colleagues for studying too young. Ideally, the test subjects should also come from "long—lived" families - then it is more likely that their long life is due to genetic factors. In response, Dr. Topol replies that just super-old age is not yet a sign of the presence of "long—lived" genes: maybe these people were just lucky to survive three heart attacks and cancer. Therefore, scientists from the United States are looking for people who have not just lived to 80, but also are not seriously ill, have not a very large "physiological" age.
Currently, there is no effective "cure for aging". And I really want to live for a long time. Therefore, firms have appeared that offer deep freezing of the client's sick body until better times — when they invent ways to treat his illness, as well as ways to safely defrost. While the technology is working at 50%: scientists can freeze, but they have not yet learned how to bring it back to life after this procedure. The last hope is a unique product for which you can give everything. However, at present, for example, only the legal status of the cemetery is recognized for the well-known freezing firm "Cryonics Institute".
Portal "Eternal youth" http://vechnayamolodost.ru14.09.2009