The mystery of longevity
Why human life expectancy is increasing rapidly: solving the "mystery of longevity" using the hypothesis of "manifested slow aging"
Mikhail V. Blagosklonny,
Why human lifespan is rapidly increasing: solving “longevity riddle” with “revealed-slow-aging” hypothesis
Aging Vol 2, No 4, pp 177-182.
Translated by Evgenia Ryabtseva
The life expectancy of healthy people is rapidly increasing and it seems that human aging is delayed in time. Recently, the following statement was published in Nature: the data obtained are so stunning that they can be called the "mystery of longevity". In order to clarify the mechanisms of the current increase in life expectancy, we will discuss the likelihood that certain genetic variants, such as the hyperactive mTOR gene (the target of mammalian rapamycin), may increase the likelihood of survival at an early age at the cost of accelerated aging. In other words, good health and rapid aging may be interrelated, whereas in the past slowly aging individuals died prematurely. Thus, until recently, mostly rapidly aging individuals lived to an advanced age. The development of civilization (especially during the last 60 years) has allowed slowly aging individuals to live to an advanced age and now receive the status of healthy people who have survived the centennial anniversary. Topics discussed: why slow aging manifested itself as delayed (healthy) aging and why the rate of deterioration of the body does not depend on aging, hypothetical results of using rapamycin to prolong life in the middle of the XVII and XX centuries, as well as prospects for human longevity.
Unexpected increase in life expectancy
Death from old age is actually death from age-related diseases, which are a manifestation of the late stages of aging [1]. However, historically, most people died at a young age and, of course, not from senile diseases, but from hunger and epidemics (cholera, smallpox, tuberculosis) and other infections that are currently rare or have become much less dangerous, as well as as a result of physical violence. Three centuries ago, the average life expectancy (including infant mortality) did not reach 16 years, and 75% of people born in London in 1662 died before reaching the age of 26 (Graunt mortality table). The development of civilization has eliminated many causes of mortality that in the past claimed the lives of young people. This has led to a sharp increase in life expectancy. In addition, modern medicine has further increased life expectancy through the treatment of age-related diseases. However, there was no increase in the maximum life expectancy. Experts have expressed the opinion that human life expectancy is approaching its upper limit. However, to the surprise of demographers and gerontologists, evidence has been obtained that the average life expectancy continues to increase at an incredible rate [2, 3]. In the countries with the highest average life expectancy, the growth of this indicator in the long term occurs at a rate of 2.5 years in 10 years, or 6 hours a day [4]. A hundred years ago, the chance to live up to 100 years was 100 times less. Moreover, according to experts, the majority of children born after 2000 in countries with high life expectancy will live to the 100th anniversary [5]. And, most surprisingly, people live to a very advanced age, maintaining the best state of health. However, after that, their health condition begins to deteriorate rapidly, which indicates that the rate of aging has not changed – its onset has simply been delayed [3]. "Taken together, these data are so stunning that they can be called the "mystery of longevity": why do the evolutionary forces that have shaped human life expectancy provide opportunities to change the state of health, but not the speed of the aging process itself?" [3]. Thus, the following questions arise: why aging can be postponed, but cannot be slowed down? Or: is it possible to slow down aging? To solve this riddle, we will have to turn gerontology "upside down". Traditionally, it was believed that aging is caused by damage to the body. According to recent statements, aging is not caused by damage at all levels, from subcellular to organ, but, on the contrary, causes their appearance [6-8]. At the same time, the protein mTOR (the target of mammalian rapamycin) participates in starting the aging process.
TOR-triggered quasi-programmed aging and age-related diseases
The mTOR-mediated intracellular signaling mechanism is activated by a variety of molecules, including glucose, amino acids, fatty acids and other nutrients, insulin and some other hormones, growth factors and cytokines [9-11]. At the same time, cellular functions are activated and cell mass grows [12]. When the cell cycle is blocked, mTOR triggers the process of physiological aging of the cell [13]. Cellular aging can be defined as excessive activation of signaling mechanisms (such as mediated mTOR) with secondary resistance to signals [14]. This, in turn, leads to the development of aging diseases (hypertension, atherosclerosis, macular degeneration, insulin resistance, obesity, neurodegeneration, cancer, osteoporosis and organ hypertrophy). For example, TOR-dependent activation of osteoclasts leads to bone resorption (osteoporosis) [15]. However, these aging processes are relatively asymptomatic, with no visible signs of deterioration (subclinically), until aging reaches a culminating point, manifested by organ damage. For example, osteoporosis can lead to hip fractures, and atherosclerosis can lead to a heart attack. After that, the deterioration of the body's condition can occur very quickly, leading to death within a few years or decades, depending on the level of medical care.
Phase of the disease
The transition of diseases into the clinical phase may be accompanied by an acceleration of deterioration of the body. For example, high blood pressure, thrombosis and atherosclerosis can culminate in a stroke. This will trigger a sequence of disastrous consequences for the body independent of TOR (immobility, pneumonia, etc.). The duration of this phase of the disease (deterioration) depends almost exclusively on the level of medical care. Moreover, age-related blindness and Alzheimer's disease are no longer lethal. Medicine can significantly increase the duration of the disease phase, postponing death. Thus, the rate of deterioration of the body's condition practically does not depend on the aging process and cannot serve as an indicator of aging or the rate of aging. In fact, the rate of aging is determined by the age at which age-related diseases begin to manifest themselves. Slowing down the aging process (with the help of a low-calorie diet, rapamycin or genetic manipulation) delays the appearance of diseases.
Thought experiment: Comparison of the alleged effect of rapamycin on longevity in 1667 and 1967
Rapamycin is an aging-slowing drug currently used to prevent rejection of transplanted organs [16]. Rapamycin delays the appearance of malignant tumors in animals and humans [17]. It also postpones the manifestations of other age-related diseases in animal models of accelerated development of such diseases. For example, rapamycin and its analogues delay the development of atherosclerosis [18-23]. mTOR is involved in the development of age-related diseases for the same reason that it is involved in the aging process. Rapamycin actually increases the lifespan of mice and fruit flies [24-27]. It is logical to assume that rapamycin (if the correct dosages and administration schemes are observed) can increase the duration of a healthy life, as well as the maximum life expectancy of a person [16]. Try to imagine that rapamycin is taken throughout life, starting from childhood. In this case, its effects will depend on the level of development of civilization and will be opposite in the 17th and 20th centuries.
Scenario 1. Suppose that in 1667, three out of four randomly selected newborns were assigned to take rapamycin for life. Rapamycin would slow down their development (a disadvantage in terms of survival ability, especially for orphans). Rapamycin deactivates the nutrient recognition mechanism, which would reduce resistance to malnutrition and stress. Reducing muscle mass and body fat would increase the likelihood of violent or starvation death. In infants with a weak immune system, rapamycin would further reduce the ability to resist infectious diseases, which in the XVII century were numerous, incurable and had no preventive measures. Thus, if 3 out of 4 people were destined to die before reaching the age of 26 (1667, London), they would all be part of the group receiving rapamycin. The control group would have survived, and the individuals included in it would have developed senile diseases at a normal age for that time (by today's standards – early).
Scenario 1. London of the XX century. Sanitation, vaccination and other measures have significantly reduced the incidence of epidemics. The discovery of antibiotics has further reduced the likelihood of death from infectious diseases. Hunger and violent death are no longer the norm. Under such conditions, individuals who received rapamycin throughout their lives would live to adulthood, after which they would slowly begin to age. Representatives of this group would have delayed the development of age-related diseases. Moreover, even the ability of rapamycin to induce immunological tolerance ("rejuvenate" immunity) would be useful for elderly people due to the suppression of excessive and autologous immune reactions. (Note: rapamycin improves immunity in old animals [28]). Therefore, in the described case, individuals receiving rapamycin would have crossed the centennial milestone "in good health". However, given that the deterioration of the body's condition occurs independently of mTOR, in representatives of this group, the deterioration process would occur at the same rate (but at later stages of life) as in individuals of the control group, assuming that both groups would receive the same medical care (in reality, young patients are treated more intense).
The hypothesis of "manifested slow aging"
Thus, if in 1667 slow aging would have been a disadvantage, in 1967 it turned into an advantage.
In the past, most rapidly aging individuals could live to a chronologically advanced age (Fig. 2A). Currently, slowly aging individuals can live up to chronologically advanced age (Fig. 2B). Thus, demographers observe an increase in the number of individuals who maintain good health until chronologically advanced age with a delayed onset of age-related diseases, whose body condition subsequently begins to deteriorate at the same rate as the health status of younger patients (Figure 1A compared to Figure 1B).
Fig. 1. Fast and slow aging
With slow aging, the onset of deterioration of the body (deterioration) is delayed,
but the speed of the process remains unchanged
It is important that the increase in healthy life expectancy (living to a more advanced age with the late appearance of symptoms of age-related diseases) is not the result of natural selection. It occurs within one generation. Slow aging was not "selected", it simply manifested itself with a change in living conditions. Until recently, most slowly aging individuals died prematurely. They (we) did not always die at a young age, but in any case their death did not occur as a result of aging. For example, at the same chronological age when rapidly aging individuals died from myocardial infarction, healthy slowly aging individuals died from malnutrition, infectious diseases or other causes. The elimination of premature mortality significantly enriched the chronologically elderly population with slowly aging (biologically young) individuals (Fig. 2).
Fig. 2. Selective survival of rapidly aging individuals compared to slowly aging
(A) In the past, slowly aging individuals (empty mugs) died prematurely,
whereas rapidly aging individuals (painted circles) lived to an advanced age.
(C) Currently, slowly aging individuals (empty mugs) live to an advanced age
in good health (at a biologically young age)
and they survive rapidly aging individuals (painted circles)
The hypothesis under consideration can be true only if a large proportion of the population at birth is represented by slowly aging individuals (Fig. 2). Otherwise, there will be too few slowly aging individuals to ensure the appearance of differences in the future (Fig. 2A compared with 2B). Why has slow aging failed natural selection? Slow aging should be an advantage for women, as it increases their reproductive period. In fact, female fertility begins to decline at an early age (even before the age of 30, long before the onset of menopause). This reproductive aging is one of the earliest manifestations of aging in women. Therefore, slow aging is an advantage for them. In addition (I'll come back to this later), women do not have to be as physically strong as men, so they can afford to age more slowly (see the upcoming article "Why men age faster, but reproduce longer: from the point of view of mTOR and evolution"). In turn, men also inherit longevity genes, which explains a large proportion of slowly aging individuals at the stage of birth.
According to the hypothesis of "manifested slow aging", certain particularly unfavorable conditions can shorten the duration of healthy life in the population after several decades. For example, it can be assumed that in conditions of war, camps and orphanages, physically strong young men survived mainly. If this assumption is correct, then the death of weak, slowly aging young men in the period of the 40-50s of the last century can serve as an explanation for the sharp decrease in healthy life expectancy of Russian men 50 years later. The hypothesis also explains the data on early mortality and mortality of subsequent generations in the same populations. Thus, Finch and Crimmins demonstrated that an increase in life expectancy and a decrease in mortality of elderly people occurs in the same age cohorts in which a decrease in mortality at an early age was observed [29, 30]. According to the hypothesis of "manifested slow aging", a high incidence of infectious diseases at an early age leads to the removal from the population of young individuals with "weak" mTOR (slowly aging individuals who, under other conditions, would live longer than the rest of the population).
The prospect of longevity
Currently, slowly aging individuals with less active variants of the mTOR protein do not die at an early age due to hunger and infections and have every chance of living to chronological old age. It is due to the fact that they are slowly aging (biologically young), they are able to reach a very advanced age in good health. This may explain the increase in life expectancy observed in the modern world. However, it is likely that this trend is already close to its maximum limit and in countries with the highest life expectancy will reach it by 2025 (100 years after the invention of antibiotics). The reason for this lies in the fact that the victory over death from hunger and infections did not change the speed of the aging process.
However, the rate of aging can be slowed down with the help of rapamycin, a drug currently approved for the prevention of rejection of transplanted organs. (Note: apparently, as a drug that slows down aging, rapamycin should be taken after the completion of the growth process of the body). Based on the data obtained in experiments on mice devoted to the study of the effects of rapamycin and a low-calorie diet, life expectancy can be increased by 30%. In this case, the average life expectancy will exceed 100 years, while among us there will be individuals aged 140-150 years.
Solutions to the health crisis and further prospects for longevity
Today, by treating each disease separately and paying special attention to diseases in the late stages of development, traditional medicine increases the duration of the disease phase (Fig.3).
Fig. 3. The use of traditional medicine methods increases survival
(increases the duration of the phase of deterioration of health),
without affecting the age of the onset of the disease phase
Thus, traditional medicine increases the number of elderly people with poor health. However, an increase in life expectancy solely due to the prolongation of the disease phase will eventually raise the cost of medical care to unacceptable values for society. Anti-aging medicine can provide a way out of this crisis by delaying the onset of the disease phase (deterioration of health) (Fig.4).
Fig. 4. Aging-slowing drugs will delay the onset of the phase of deterioration of health,
without changing the rate of development of this phase
There is an incorrect idea that taking drugs that slow down aging will lead to an increase in the number of people suffering from age-related diseases. On the contrary, such elderly people will have good health, since they will be chronologically elderly, but biologically young. They will maintain a good state of health for longer (until they reach the biological age of the phase of deterioration of health). Biological age itself is determined by the sum of all age-related diseases [1]. In other words, age-related diseases are manifestations of biological aging. Age-related diseases and biological aging are integral parts of one whole. In fact, healthy aging is healthy non-aging (or slow aging).
Slowing down aging, known as "healthy aging", increases the quantitative ratio between healthy and sick people (Fig.4). Moreover, biological age determines an individual's ability to work. Slow aging can delay a person's retirement until an older age (which Vaupel also suggested [3]) and, in turn, can provide society with funds for the development of traditional medicine, the effectiveness of which (as well as the corresponding costs) is constantly increasing. In this case, the duration of life can be increased both by medical interventions aimed at slowing down aging (postponing the phase of the disease) and by specialized medical interventions (prolonging the phase of the disease).
Conclusion
60-100 years ago, the progress of medicine in the prevention and treatment of diseases not related to aging increased the life expectancy of slowly aging individuals so much that they had the opportunity to die from senile diseases developing at a late age (in other words, to die from delayed aging). Civilization has increased the proportion of slowly aging people in the age population, without slowing down the aging process. The use of rapamycin will slow down the aging process itself, which will lead to a further increase in the duration of a healthy life. The degree of increase in life expectancy will depend on the discoveries of the future, the nature of which is obviously unpredictable [31].
See the list of references here.
Portal "Eternal youth" http://vechnayamolodost.ru
08.07.2011