Secrets of longevity
A person does not age like a cart, but like a horse
The secret of a long life will be taught to us by a naked digger and a bat:
they reproduce all their lives and do not get cancerNadezhda Markina, Newspaper.
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About what aging is, about the role of genes in life expectancy "Newspaper.Ru" was told by Alexey Moskalev, Doctor of Biological Sciences, Head of the Laboratory of Molecular Radiobiology and Gerontology of the Institute of Biology of the Komi National Research Center of the Ural Branch of the Russian Academy of Sciences.
– Today there are many theories of the mechanisms of aging. Which one is closest to you?
– As you know, aging is a process of gradual suppression of the main functions of the body (regenerative, reproductive, etc.), as a result of which the body loses the ability to maintain internal constancy, resist stress, diseases and injuries, which makes death inevitable.
I believe that aging is one of the most complex biological phenomena, and any one theory is hardly applicable to it. At different levels (molecular, cellular, systemic), there are many destructive processes caused by different causes, and which of the causes will be the main one in a given tissue in a given individual will determine the spectrum of age-related diseases, their rate of occurrence, differences in life expectancy and causes of death.
However, I assign an important role to the decrease in the productivity of protection systems against various types of stress with age, in particular, repair of DNA and protein damage. At the organismal level, impaired regeneration is associated with changes in the levels of certain proteins – growth factors and hormones.
– What is known today about the role of genes in life expectancy?
– The analysis of the information available to us allows us to generalize the role of the genes of life expectancy as follows:
1. "Regulators" of life expectancy. Life expectancy programs play the role of switches between the mode of rapid growth and reproduction (with accelerated aging), on the one hand, and the mode of self–maintenance (and long life), on the other. For example, when living conditions are favorable, the body grows strenuously and leaves offspring, but it ages faster, it seems to transfer forces from stress resistance to more important processes. In conditions of moderate stress (lack of food, heat or cold), growth and abandonment of offspring are unprofitable, the body must "concentrate" on surviving an unfavorable period, resources flow to protect against stress, aging slows down. The switches of these two modes of life are genes whose products are responsible for the perception and transmission of external signals, synthesis, reception and transduction of hormones of the insulin pathway, secondary lipophilic hormones. Most of them promote growth and reproduction, but suppress stress resistance. Some hormone-like peptides, on the contrary, stimulate resistance to stress (for example, Klotho).
2. "Mediators" of longevity (various kinases, protein deacetylases, transcription factors). Under the action of regulators, they switch stress resistance programs in response to signals from the environment (food availability, hypoxia, temperature and light conditions, irradiation) or intracellular oxidative stress. In a tissue-specific way, the products of these genes regulate the activity of various effector genes or directly the activity or lifetime of effector proteins. In addition, the "mediators" interact with each other, suppressing or stimulating each other's effects.
3. "Effectors" of life expectancy. First of all, these are stress resistance genes: genes of heat shock proteins, antioxidant protection, protein and DNA repair, proteasome components, autophagy proteins, innate immunity, xenobiotic detoxification, metabolic regulators. In a certain sense, these are anti-aging genes, and their induction in the experiment, as a rule, increases the life expectancy of model animals. Often they act additively, that is, under the action of individual "mediators" several "effectors" are activated at once, which contributes to an increase in life expectancy under moderate stress. A number of "mediators", on the contrary, suppress the activity of "effectors".
4. Viability genes. They are also called "housekeeping genes". They function everywhere, at all stages of the life cycle, and provide cell structure, biosynthesis of amino acids, lipids and nucleotides, glycolysis, tricarboxylic acid cycle, etc. Their mutations are either lethal or lead to pathologies. Under stress, some of them can be temporarily repressed under the influence of "mediators", which allows you to save resources for the functioning of "effector genes" and increase life expectancy.
5. Genes involved in the functioning of mitochondria. These are components of the electron transport chain, the biosynthesis apparatus of mitochondrial proteins, and the decompression proteins. Regulate energy metabolism, the level of free radicals, and some of them – apoptosis.
6. Regulatory genes for replicative aging and apoptosis (p53, p21, p16, pRB). They are involved in the prevention of cancer, regulation of the cell cycle and the death of unnecessary or harmful cells in early ontogenesis and maturity. A side effect in old age is the cessation of division of old connective tissue cells or the loss of postmitotic cells (nervous and muscular systems).
– What are the genetic differences of long-lived animals?
– Currently, the most studied practically ageless mammal is the naked digger rodent, which has been living in captivity for more than 30 years. The animal practically does not lose its reproductive ability with age, does not get cancer. Its cells are difficult to kill with oxidant substances. They are able to quickly dispose of damaged proteins and are ten times more resistant than mouse cells to stressors (heavy metals, hydrogen peroxide).
– Tell us about your research on Brandt's moth. What makes her remarkable and what genetic features have she been able to detect?
– In Russia, there is an equally unique slowly aging animal – Brandt's bat moth. At the World Congress of Gerontologists in Paris in 2009, I attended a report by the American Stephen Ostad, who, in collaboration with Novosibirsk colleagues, found out that this small animal (on average weighs 7 g) is able to live up to 41 years in the wild.
Zoologists from Kirov and Syktyvkar were ready to catch several samples of this bat, and Harvard professor Vadim Gladyshev, who had already deciphered the genome of the naked digger by that time, agreed to take up the genome of the moth. Speaking about the mystery of the outstanding longevity of Brandt's moth, it is worth pointing out once again that this is one of the smallest mammals.
As it turned out, there are mutations in her genome that reduce the effectiveness of growth hormones (growth hormone and insulin-like growth factor) that accelerate the growth and aging of the body.
By the way, the combination of diet and a mutation that reduces the effectiveness of growth hormone allowed other researchers, Miller and Bartke, to extend the life of ordinary mice from 2 to 4 years. At least three more features have been found in the bat genome that could potentially explain its longevity, but testing these assumptions is a matter of further research.
– What is the relationship between the incidence of cancer and life expectancy?
Ordinary mice almost all die from cancer. In humans, cancer mortality reaches 25% with age. Together with cardiovascular pathologies, cancer is the most common age-dependent disease.
Long-lived mammals (a naked digger, an ordinary blind man, most likely, and Brandt's moth) do not suffer from cancer. The big mystery is why. Having a unique opportunity to study the blind and moth living in our country, together with colleagues from the University of Rochester in the USA, we applied for a mega-grant from the Russian government, explaining the need for such unique research, but we did not receive the support of the authorities, now we are thinking about how to do this work abroad.
– Many studies show that an increase in the life expectancy of some animals is accompanied by dwarfism. What is the mechanism of this connection?
– Cell growth and division compete for energy and plastic resources with stress resistance, the cell always has to choose: either grow or fight damage. Growth hormone and the insulin-like growth factor regulated by it trigger a cascade of reactions in cells leading to cell growth and division while simultaneously disabling cellular mechanisms of stress resistance. A decrease in sensitivity to these hormones leads to dwarfism when cellular systems are unblocked to counteract stress, as a result, life expectancy increases.
– What kind of stress accelerates aging?
– Significant deviations of external and internal parameters of cell life from optimal ones (nutrient concentrations, pH, oxygen level, temperature) lead to stress. Oxidative, genotoxic stress, mitochondrial stress, endoplasmic network stress are different types of complex intracellular processes that lead to the accumulation of damage to cellular structures. The damaged cell copes with its tasks worse, is not able to participate in physiological functions and tissue regeneration.
Gerontologists often talk about the fundamental difference between the aging of a "cart" and the aging of a "horse". The "cart" accumulates breakdowns and ceases to perform its function. The "horse" actively resists internal breakdowns at the level of each cell until the mechanisms of dealing with breakdowns themselves, which are called stress resistance, break down.
The mechanisms of response to damage to DNA, proteins, membrane lipids, detoxification of toxins with age either decrease their effectiveness or begin to work inadequately. Therefore, the real cause of aging is not the actual accumulation of cell damage, but the loss of damage control mechanisms. Artificial induction of the activity of at least one of the stress resistance genes, GADD45, in the nervous system of flies allowed us to extend the life of these model animals by 70%.
– You talked about the found association of smell and life expectancy. In which animals is this found? How can this connection be explained?
– Surprisingly, some long-lived mammals, in particular the naked digger, Brandt's moth and man, have reduced olfactory sensitivity. In addition, model genetic experiments on worms, flies, and now mice have shown that mutations of olfactory receptor genes prolong life.
The reason seems to be in the same regulatory genes that, in response to the smell of food, activate an insulin-like signaling pathway of growth and development. By the way, experiments on flies have shown that if the factor of a low-calorie diet that prolongs life is combined with the smell of their favorite food (yeast), the aging slowdown practically disappears.
– What is aging – a stage of development? Illness? Can it be canceled or pushed back?
– Many diseases are characterized by exponential growth with increasing age, which indicates their direct connection with aging. This suggests that aging is the cause of most of these diseases (many types of tumors, cardiovascular diseases, retinopathy, cataracts, type II diabetes, etc.) and an important risk factor for other causes of death (viral diseases, accidents, etc.). Some authors, in particular the editor-in-chief of the journal Aging Mikhail Blagoslonny, they believe that it's time to talk about aging itself as a disease, and age-dependent pathologies are its manifestations or biomarkers. Adopting this approach could change modern medicine.
Struggling with specific manifestations (individual age–dependent pathologies) of a single disease - aging, doctors achieve only short-term success. Suppressing the causes of aging, in particular the age-dependent decrease in the activity of stress resistance genes, it is possible to expect a much greater prolongation of life and an improvement in the quality of life.
– You run a laboratory at the Institute of Biology in Syktyvkar and at the same time the laboratory of aging and life expectancy at MIPT. Why MIPT? What kind of research is being conducted there?
– MIPT is one of the leading scientific and educational centers of the country, there is a concentration of talented youth in this university like nowhere else, biotechnological developments are funded at a high level. My laboratory at MIPT has been in existence for only a month, and a grant search is currently underway. I would like to introduce innovative research approaches on the basis of MIPT – a comprehensive analysis of biomarkers of human aging (a combination of analysis of the metabolome, transcriptome and proteome), the identification of new longevity genes and geroprotector drugs on a unique model - short–lived (lives only 6-7 months) fish notobranche.
– In your opinion, will there be medicines in the near future that prolong life or slow down human aging?
– There are no fundamental reasons that make the task of slowing down human aging impossible. This is evidenced by studies on model animals that have managed to extend life expectancy from about two times (mice) to 10 times (nematodes). These successes have been achieved by genetic methods, but since these genes encode proteins, it is likely to find low-molecular substances that will regulate the function of these proteins and slow down aging.
Portal "Eternal youth" http://vechnayamolodost.ru30.05.2013