20 February 2008

Hot spots of modern gerontology

V.N. Anisimov, "Nature" No. 2-2007.

Vladimir Nikolaevich Anisimov, MD, Professor, Head of the Department of Carcinogenesis and Oncogerontology of the N.N.Petrov Research Institute of Oncology, St. Petersburg

Perspectives of biology:
from false knowledge –
to true ignorance.

V.Ya. Alexandrov

Over the past 160 years, life expectancy in economically developed countries has been steadily increasing at an average rate of 3 months/year, and there is no reason to believe that this trend will change in the near future [1]. Moreover, the number of people who have lived for 100 years or more is growing rapidly. In some European countries, their number doubles every 10 years. The number of centenarians in Russia is also growing. For example, in St. Petersburg in 1979 there were 92 residents who crossed the 100-year milestone, in 1996 - 150, and in 2001 – already 369 [2]. According to the UN, the fastest growing segment of the senile population is people 80 years and older. Such a global aging of the population is associated with the problem of quality of life in old age. All this determines the increased interest in gerontology, and above all – in the study of the primary mechanisms of aging of organisms and populations, as well as factors determining life expectancy.

To date, the question is being discussed whether it is possible to separate normal or physiological aging (without diseases) and pathological aging, directly related to diseases such as cancer, heart and vascular diseases, osteoporosis, osteoarthritis, diabetes mellitus and some neurodegenerative diseases – Alzheimer's disease, Parkinson's disease, etc. (The terms used to describe aging are rather inaccurate, since there is no generally accepted definition of the process itself. In English–language literature there are two terms - aging and senescence, and although both are translated into Russian by the word aging, but in Russian literature aging usually corresponds to normal or physiological aging, and senescence is defined as pathological aging.)

This problem has been dealt with for more than 40 years by the Baltimore Longitudinal Study on Aging (BCLA) of the US National Institute of Aging, which monitors groups of healthy people throughout their lives. Since the age dynamics of indicators varies greatly from person to person, it is almost impossible to assess the degree of aging of an individual based on the measurement of one or more biochemical, physiological or physical characteristics. Therefore, there are still no universal tests for determining biological age comparable in reliability to chronological age.

Thanks to the work of BCLA, it turned out that most of the measured indicators change gradually with age, whereas abrupt changes are more characteristic of age-associated pathology. There are diseases associated with aging (aging-dependent), or with age (age-dependent). Thus, some genetically determined diseases (for example, Huntington's disease) depend on age, since they manifest themselves in predictable years. Changes associated with normal aging can play a significant role in the development of a particular pathology. Therefore, it is very important to distinguish non-pathological age-related changes (for example, graying of hair) from contributing to the development of one or more pathological processes (for example, the accumulation of oxidative damage) and causing or indicating disease (for example, the formation of amyloid plaques in the brain as a risk factor for Alzheimer's disease). Such a distinction is necessary for the choice of preventive measures against premature aging and age-related pathology.

In a short journal article, it is impossible to cover even briefly the main directions of research in modern fundamental gerontology, so we will refer the reader to the relevant literature [3, 4]. We will touch only on the most “hot spots” in this area, which, according to the journal "Science", will become one of the most priority scientific disciplines in the next 25 years.

Search for aging and longevity genes

How did you manage to live so long, beard?
How did you get to be that old?

Lewis Carroll. Alice through the Looking Glass

The life expectancy of animals and humans differs significantly in different species. This indicator varies by 1 million times among all types and from 10 to 50 times within groups with the same level of organization. Among mammals, the record of longevity belongs to one of the whale breeds (over 200 years), laboratory rodents live no more than two or three years, and many other rodents of the same size - up to 5-10 years or more. Since species maximum life expectancy correlates with the rate of development, there is reason to believe that there are similar mechanisms of development and aging that are species-specific and genetically programmed. The genetic code of humans and chimpanzees is 98% similar, but humans live up to 122 years, and chimpanzees up to 56 years. A very small number of genes can determine the differences between them in the development strategy and the rate of physiological aging [5].

It is possible to assess the heritability of longevity in a person by observing members of the same family, including foster children (to take into account the role of environmental conditions). The results of most studies of longevity in twins show that the heritability of life expectancy in humans does not exceed 50%. According to Swedish gerontologists who studied a large group of twins raised in different families, one third of the variability in total mortality is due to genetic factors. The life expectancy of twins can be influenced by specific genes, for example, determining a predisposition to obesity or atherosclerosis. At the same time, data have been obtained indicating a greater heritability of longevity. Thus, the descendants of centenarians were four times more likely to live 85 years or more than the children of those who died before the age of 73 [4].

Today, the point of view is quite common, according to which the genetic development program is exhausted by reproductive success (i.e., the birth of offspring), and the survival of the organism after the completion of reproductive function, if mediated by the genome, then very indirectly [4]. A number of recent publications concerning the relationship between the age of birth of children and the life expectancy of parents have attracted close attention to this problem. It has been shown that women who lived 100 years or more were four times more likely to give birth to children after the age of 40 than those who lived no more than 73 years [6]. According to the authors, late menopause may be a factor contributing to longevity.

Analysis of data on the number of children and the age of their parents in the families of British aristocrats revealed that these indicators correlate with life expectancy [7]. Among those who died at a young age (under 20 years) two out of every three women were childless, and among those who lived more than 80 years, there were less than a third. Early childbirth and a large number of children had a negative impact on a woman's life expectancy. The age of the first birth was the lowest for those who died early and the highest for those who lived more than 80 years. Those who gave birth to their first child after 40 had more chances to live up to 100 years. Interestingly, husbands also lived longer if the number of children they produced was not too large (and fruit flies lived longer if they were not allowed to reproduce). The life expectancy of daughters is more related to the life expectancy of the mother than the father; in sons, this dependence is much less pronounced and is not determined by the gender of the parents.

In recent years, significant progress in the study of aging genetics has been due to work on invertebrates. The nematode (Caenorhabditis elegans), which lives for about 20 days, has become a popular model. Worms reproduce by hermaphroditic self-fertilization, which ensures the formation of genetically similar populations. With the help of chemical mutagens or genetic engineering methods, worms with a 50% higher average and twice as long maximum lifespan than their predecessors were obtained. The presence of such populations of nematodes strongly indicates the genetic control of the rate of aging. The age-1 gene has been identified, modification or suppression of the product of which increases life expectancy [4]. This gene controls a whole group of genes related to life expectancy (daf-2, daf-23, spe-26, clk-1). Thus, a decrease in the activity of the daf-2 gene (homologue of the insulin receptor gene) doubles the lifespan of nematodes.

Another good model for gerontologists is the fruit fly Drosophila melanogaster. As in the case of the nematode, drosophila mutants with different life spans were obtained. Individuals with an increased number of copies of the genes of superoxide dismutase (sod1) and catalase enzymes lived 20-37% longer than usual, and flies with excess copies of the genes of only one of these enzymes did not have such an effect of antioxidant protection [8]. Transgenic fruit flies with overexpression of the sod1 gene in motor neurons lived 40% longer and were significantly more resistant to oxidative stress than flies without this gene [9].

In drosophila, as in nematodes, the signal transmission system from insulin and insulin-like factor-1 (IGF-1) also regulates body size and lifespan (Fig.1). Thus, mutations in the regulatory region of the insulin receptor homologue gene (chico) increased the lifespan of flies by 45%. Flies heterozygous for two different mutations in this gene lived 85% longer than wild-type fruit flies [10]. Both types of mutations in this gene were also accompanied by increased activity of the enzyme superoxide dismutase.

In drosophila, as in nematodes, the signal transmission system from insulin and insulin-like factor-1 (IGF-1) also regulates body size and lifespan (Fig.1). Thus, mutations in the regulatory region of the insulin receptor homologue gene (chico) increased the lifespan of flies by 45%. Flies heterozygous for two different mutations in this gene lived 85% longer than wild-type fruit flies [10]. Both types of mutations in this gene were also accompanied by increased activity of the enzyme superoxide dismutase.

Fig. 1. Schemes of insulin signal transmission in nematodes, fruit flies and mammals.Although the parallels between the insulin regulation systems in nematodes and fruit flies are very clear, there are also certain differences.


So, a line of fruit flies with a mutation called mth (“Methuselah” from Methuselach - Methuselah) not only increased their life expectancy by 35%, but also increased their resistance to stress caused by a variety of factors: starvation, heating or the addition of paraquat - a generator of reactive oxygen species to the feed [11].

With the help of genetic engineering methods, lines of mice with an increased lifespan were obtained. Homozygous mice with the growth hormone receptor gene (ghr-/-) turned off live significantly longer than heterozygous (ghr+/-) or wild-type (ghr+/+) mice. In ghr-/-mice, proportional dwarfs, growth is slowed down, bone length and bone mineral content are reduced, there is no growth hormone receptor and protein binding it, the blood content of insulin-like growth factor I and its binding protein-3 is reduced, and the concentration of growth hormone in the blood serum is increased [12].

Ames dwarf mice (mutants carrying single point mutations in the Prophet pit-1 gene) live 50-64% longer than wild-type individuals. This model is one of the first examples of the ability of a single gene to prolong the life of mammals. In Eisma mice, the level of prolactin, thyroid stimulating hormone, growth hormone, insulin-like factor-1 and insulin in the blood is reduced, insulin sensitivity is increased and body temperature is lowered [13]. Both male and female dwarf mice are infertile and immunosuppressive.

Female Igf1r+/- mice with a partially knocked-out IGF-1 receptor gene have a 33% increased average life expectancy compared to wild-type females (p < 0.001), and males - only by 16%. These mice do not have dwarfism, and the basic metabolism, body temperature, feed intake, physical activity and fertility did not differ from the control, but they are more resistant to oxidative stress compared to the control (Igf1r+/+) [14].

In recent years, an intensive search has been conducted for candidates for the role of death and longevity genes in humans. Currently, it is considered that only one apolipoprotein E (ApoE) gene is important for human longevity. In those who have lived 100 years, the ApoE-E2 allele prevails. On the contrary, an increase in the E4 allele leads to hypercholesterolemia, coronary heart disease and Alzheimer's disease (but not to cancer or diabetes). In people over 90 years of age, the risk of Alzheimer's disease associated with the E4 allele reaches a plateau. It is believed that ApoE should be considered more as a “frailty” gene, rather than as a longevity gene.

This field is one of the most promising in modern gerontology, but it requires sophisticated equipment and large funds to study the genetic markers of aging and age-related diseases. However, the data accumulated to date suggest that there is not and probably will not be a single gene that determines the aging and longevity of both an individual and a species.

Free radicals and agingYour theory is both solid and witty.

However, all theories are worth one another.
M.A.Bulgakov. The Master and Margarita


In recent years, the most popular free radical theory of aging. Almost simultaneously put forward by D. Harman (1956) and N.M.Emanuel (1958), it explains not only the mechanism of aging, but also a wide range of pathological processes associated with it (cardiovascular diseases, age-related immunosuppression, brain dysfunction, cataracts, cancer and some others). According to this theory, reactive oxygen species (O2-., H2O2, BUT·, O2) produced mainly in mitochondria damage cellular macromolecules. It is estimated that over 70 years of human life, the body produces about a ton of oxygen radicals, although only 2-5% of the oxygen inhaled with air turns into its toxic radicals.

Up to 104 DNA damages caused by reactive oxygen species can form in a rat cell per day, and up to 10% of protein molecules can have carbonyl modifications. The vast majority of them are neutralized even before they have time to damage certain components of the cell. So, out of every million superoxide radicals, no more than four escape from enzyme protection.

Today it has been shown that the species life expectancy correlates with the activity of the enzyme superoxide dismutase (SOD), the content of b-carotene, a-tocopherol and uric acid in the blood serum. Thus, in long-lived D.melanogaster lines, the activity of antioxidant enzymes (SOD, catalase, glutathione reductase and xanthine dehydrogenase) is significantly higher than in short-lived fly lines [14].

The free radical theory of aging is also supported by experiments in which D.melanogaster transgenic lines with additional copies of genes providing excessive activity of SOD and catalase lived 20-37% longer than control flies. Flies with redundant copies of the genes of one of these enzymes did not have this property [8]. Vitamin E, melatonin, chelating agents and some synthetic antioxidants increased the life expectancy of not only fruit flies, but also laboratory mice and rats. Since the products of the interaction of reactive oxygen species with macromolecules are constantly found in the organs and tissues of the body, this means that the antioxidant defense systems are not effective enough and cells are constantly experiencing oxidative stress. Counteraction to it can play a significant role in the mechanism of geroprotective action of endogenous and exogenous antioxidants.

Fewer calories - longer lifeA diet that is plentiful is dangerous, and excessive satiety is also dangerous.

Those who are naturally fat are closer to death than those who are skinny.

Hippocrates. 477-460 BC

Back in the 30s of the twentieth century, it was established that a diet with a significant (40%) calorie restriction increases the maximum and average life expectancy of rats and mice by 30-50%. Food restriction also increased life expectancy in fish, amphibians, daphnia, insects and other invertebrates. Three large studies on primates (mainly rhesus monkeys) have shown that some of the physiological effects of a low-calorie diet observed in rodents are reproduced in monkeys [4]. Their blood glucose and insulin levels decrease, body temperature and energy consumption decrease. It has been established that the geroprotective effect of fasting determines the overall reduction in calorie intake, and not any food ingredient.

It is estimated that in rodents with a low-calorie diet, 80-90% of the various parameters studied (behavior and learning ability, immune response, gene expression, enzyme activity and hormone action, glucose tolerance, DNA repair efficiency, protein synthesis rate) showed signs of delayed aging. Such a diet stimulated apoptosis, which rejects preneoplastic cells in the tissues of the body, slows down the accumulation of mutations and the development of age-related pathology.

Perhaps the main effect of a low-calorie diet is to weaken the intensity of free radical processes. In rodents, with such a content, the rate of generation of superoxide and H2O2 slows down, oxidative damage and a drop in membrane viscosity decrease; starvation reduces the sensitivity of tissues in vitro to acute oxidative stress. The greatest protective effect of low-calorie nutrition in relation to oxidative stress is manifested in postmitotic cells of the brain, heart and skeletal muscles.

A group of specialists from the USA and Italy [15] evaluated the effectiveness of restricted nutrition in people who followed a low-calorie diet for six years, compared with healthy people who followed a regular American diet. 18 subjects (aged 35 to 82 years) did not smoke, had no chronic diseases, did not take hypolipidemic, antihypertensive or other medications and consumed from 1112 to 1958 kCal daily. Their diet included fruits, vegetables, nuts, cereals, proteins and meat (sugary drinks, snacks and dessert were excluded). They got 26% of calories from proteins, 28% from fats and 46% from carbohydrates. The control group (18 people) consumed 1976-3537 kCal per day without restrictions in sweet. The subjects had lower body weight, total cholesterol, low-density lipoproteins, triglycerides, glucose, insulin, C-reactive protein, platelet growth factor AB (PDGF-AB), systolic and diastolic blood pressure, and higher levels of high-density lipoproteins than in the control group. The authors believe that a low-calorie diet significantly reduced the risk of atherosclerosis, which was confirmed by a 40% decrease in the thickness of the intima media arteries. The subjects also had a lower frequency of inflammatory processes compared to the control group.

However, an ordinary person is unlikely to be able to strictly follow such a diet for many years. The most famous case of such an experiment on oneself (while not completely successful) is the experience of the famous American gerontologist and immunologist Roy Walford. In the most recent years, the search for mimetics (imitators) of a limited diet has become a very “hot spot”. The sugar substitute 2-deoxyglucose proposed by American experts increased the life expectancy of rodents, but had such side effects that its use as a geroprotector had to be abandoned.

Fig. 2. The effect of phenformin (color curve) on life expectancy
and the development of spontaneous tumors (right) in female C3H/Sn mice [3].Back in the 80s of the last century, with the help of some pharmacological agents, in particular antidiabetic biguanides (increase the sensitivity of tissues to insulin, improve tolerance to carbohydrates, reduce lipid levels and eliminate the phenomena of metabolic immunosuppression), it is also possible to prolong the life of mice and rats and reduce the frequency of spontaneous and induced by chemical carcinogens or ionizing radiation neoplasms (fig. 2).

In our laboratory, the antidiabetic biguanide metformin increased life expectancy and inhibited the development of breast cancer in transgenic HER-2/neu mice (Fig.3). And in the clinic, the use of metformin reduces the risk of developing malignant neoplasms in patients suffering from type 2 diabetes mellitus.

Fig. 3. The effect of metformin (color curve) on life expectancy
and the development of spontaneous tumors (right) in female transgenic HER-2/neu mice [18].Aging Cells: Good Citizens, but bad Neighbors

Don't be fooled by the ghost of peace:

Sometimes life is deceptive in appearance.
The hour will come, and the morning is fatal
Your dreams, sparkling, will dazzle.

Nikolai Zabolotsky

In 1971, researcher at the Institute of Biochemical Physics of the Russian Academy of Sciences A.M.Olovnikov, using data on the principles of DNA synthesis in cells, proposed the hypothesis of marginotomy, explaining the mechanism of the counter of cell divisions. According to his hypothesis, DNA polymerase does not fully reproduce the linear matrix during matrix synthesis of polynucleotides, and the replica always turns out to be shorter in its initial part. Thus, with each division of a cell, its DNA is shortened, which limits the proliferative potential of cells and, obviously, serves as a “counter” for the number of divisions and, accordingly, the lifespan of the cell in culture. The discovery in 1985 of the telomerase enzyme, which completes the shortened telomere in germ cells and tumor cells, ensuring their immortality, was a brilliant confirmation of Olovnikov's hypothesis.

In recent years, significant progress has been made in studying the role of telomeres in aging. Telomere dysfunction (whether due to shortening, direct damage, or a defective protein associated with the telomere) can lead to three consequences: aging of the cell, its death (factors suppressing the neoplastic process) or instability of the genome, which can contribute to the malignant transformation of the cell.

Cell aging is considered as one of its protective mechanisms in telomere dysfunction, since it stops proliferation, thereby blocking carcinogenesis (“good citizens”) [16]. Somatic mutations accumulate in the body during life, some of them can inactivate genes involved in cellular aging. In addition, loss of heterozygosity and mutations in suppressor genes (p53 and Rb) and oncogenes (e.g. ras) occur even in normal cells. Another defense mechanism of a cell with telomere dysfunction, in which intact p53 is involved, is apoptosis. In cells where mutations accumulate in the p53 gene or in the components of its regulation, genome instability develops, increasing the likelihood of malignant transformation. The loss of distal telomere regions is associated with a decrease in the proliferative life of cells both in vitro and in vivo. Analysis of data on telomere shortening in 15 different human tissues showed that telomeres lose from 20 to 60 base pairs per year.

Currently, the hypothesis of the important role of telomere shortening and, accordingly, telomerase reactivation in aging and carcinogenesis is actively being developed. In human tumors, the appearance of immortal cells (immortalization) is almost always due to the suppression of the telomerase catalytic subunit gene (hTERT). The multiplicity of mechanisms suppressing or regulating the activity of this enzyme may explain the exceptional rarity of spontaneous immortalization of normal human cells. On the other hand, the introduction of the hTERT subunit stimulates the growth of various types of human cells without the subsequent development of tumor growth. Probably, the main function of the p53 suppressor gene is to stop growth in response to the loss of telomeres in old cells. This hypothesis is not contradicted by data on the behavior of most tumors in which this gene is mutated, and explain the characteristics of rare types of tumors in which the function of p53 is preserved.

It has recently been shown that in vitro old human fibroblasts stimulate the proliferation of precancerous and malignant epithelial cells, which are capable of forming tumors when vaccinated in naked mice (“bad neighbors”) [17]. In fibroblasts at earlier passages (presenile), this ability is less pronounced. Despite the rather convincing arguments in favor of the link between cell aging, telomere biology and human cancer, the data on the role of cellular aging in human aging are quite contradictory and require further research.

Increased life expectancy and cancer riskIt doesn't matter which way to go.

You'll probably get somewhere if you walk long enough. Lewis Carroll.

Alice's Adventures in Wonderland

Calculations show that in humans with a life expectancy of 70 years, rats (2.5-3 years) and mice (2-2.5 years), the frequency of neoplasms is the same and is 30% [3, 19]. However, when normalized by the number of cells in the body, it turns out that a mouse is more prone to developing tumors than a person. This phenomenon is usually explained by the fact that telomerase is more active in mouse somatic cells than in human cells, which corresponds to a significantly longer telomere length in mice compared to humans. At the same time, the species life expectancy of mammals correlates with the efficiency of DNA repair and the resistance of their cells to oxidative stress. Thus, in human DNA, the reduction of guanine alkylated with carcinogenic nitro compounds is hundreds of times higher than in mice, which is associated with greater human resistance to these agents. It turned out that the effectiveness of the repair of carcinogen-induced damage in the DNA of various organs is associated with the lifespan of mice. Analysis of data on the incidence of cancer in genetically modified animals with increased life expectancy indicates a decrease in the frequency of malignant neoplasms in them [3].

Fig. 4. The effect of three types of geroprotectors (color curves) on the life expectancy of animals
and the frequency of spontaneous tumors (in the inset).I - the life expectancy of all individuals increases, the rate of aging does not change, neoplasms develop later than in the control group, but with the same frequency;

II - the rate of aging decreases, the frequency of neoplasms decreases;

III - life expectancy does not change, but the rate of aging and the number of neoplasms is growing.
t max is the maximum life span, t 50 is the half-life time.

It has been shown that different geroprotectors have different effects on the development of neoplasms, which is mainly determined by the type of slowing down of aging in the population (Fig.4). Our observations indicate that the more “rectangular” nature of the survival curves is associated with an increased rate of development of fatal tumors in rats.

From the end of the XVIII century and up to the middle of the twentieth century, the incidence of cancer gradually increased in economically developed countries. The incidence of all malignant neoplasms in the United States and many other countries, including Russia, increased markedly from 1960 to 1990 in both men and women, which coincided with an increase in life expectancy. Since the 90s of the twentieth century, in the most economically developed countries, such as the USA, Sweden and Denmark, the incidence of cancer began to decrease somewhat (Fig.5). And it was in the second half of the twentieth century that the nature of mortality trajectories changed in the most developed countries, which was accompanied by a decrease in mortality at the oldest ages (Fig.6). At the same time, in other countries, for example in Russia, the frequency of malignant neoplasms continues to grow. It is obvious that an increase in life expectancy and the nature of the trajectory of mortality by the type of parallel shift or even an increase in its slope will contribute to a decrease in the frequency of malignant neoplasms.

Fig. 5. Dynamics of morbidity (color curve) and cancer mortality in the USA in the XX century [19].Fig. 6. Dynamics of changes in the survival rate of women (left) and men in Sweden from 1861 to 1999 [20].

* * *

Our great compatriot I.I. Mechnikov - the founder of modern gerontology and the author of the term “gerontology” - in the spring of 1907, in his preface to the first edition of “Studies of Optimism" wrote: “Science in Russia is going through a long and severe crisis. Not only is there no demand for science, but it is in a complete pen.” Unfortunately, the situation in Russia today is not much different from what it was 100 years ago. The budget of the entire Russian science does not exceed the budget of the US National Institute of Aging - one of the “smallest” in the system of the National Institute of Health, and significantly less than the funds allocated by the state for the maintenance of officials. However, they are also getting old.

Our great compatriot I.I. Mechnikov – the founder of modern gerontology and the author of the term “gerontology” – in the spring of 1907, in his preface to the first edition of “Studies of Optimism" wrote: “Science in Russia is going through a long and severe crisis. Not only is there no demand for science, but it is in a complete pen.” Unfortunately, the situation in Russia today is not much different from what it was 100 years ago. The budget of the entire Russian science does not exceed the budget of the US National Institute of Aging – one of the “smallest” in the system of the National Institute of Health, and significantly less than the funds allocated by the state for the maintenance of officials. However, they are also getting old.

And to them, as well as to our deputies, we address an open letter published recently on the Internet, signed by 54 leading gerontologists of the world. The following is a translation of this letter into Russian:

“To all whom it concerns.
On models of many very different types of laboratory animals (nematodes, fruit flies, mice, etc.), it is possible to achieve slowing down aging and prolonging active life. Therefore, based on the generality of the fundamental mechanisms of aging, there is reason to believe that it is possible to slow down aging in humans.

Expanding our knowledge about aging will make it possible to better resist such debilitating pathologies associated with aging, such as cancer, cardiovascular diseases, type II diabetes and Alzheimer's disease. Therapy based on knowledge of the fundamental mechanisms of aging will contribute to a better counteraction to these age-related pathologies.

That is why our letter is a call for increased funding in this area, which is extremely necessary for the intensification of both research on the fundamental mechanisms of aging and the search for ways to slow it down. All this can lead to much greater dividends than if the same funds and efforts were invested in direct opposition to age-related pathologies. As the mechanisms of aging become more and more understood, effective means of intervention in this process can be developed. This will allow a significant number of people to prolong a healthy and productive life.”

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