Growth and aging: a common molecular mechanism. Part 3
Ending. The beginning of the translation of the article “Growth and aging: a common molecular mechanism” can be found here.
The stages of the signaling mechanism located "below" TORHow does TOR stimulate aging in response to nutrient intake?
In other words, which of the numerous processes controlled by TORC1, activated or slowed down by a lack of nutrients (inactivation of TORC1), increases life expectancy? Recently obtained data indicate that TORC1 controls aging through several processes located "below" it, including autophagy, mitochondrial biogenesis and protein synthesis, transcription and mitochondrial activity. And indeed, there is a pronounced correlation between TOR-controlled processes and processes occurring during the aging of the body. It is also important to note that these processes are part of a normal program through which TOR regulates cell growth. Therefore, it can be assumed that TOR's participation in the aging process is a continuation of its participation in the growth process.
TORC1 inhibits autophagy, the process of degradation of proteins and organelles in lysosomes [27]. Autophagy activity decreases with aging and age-related diseases [28]. The restoration of autophagy leads to the selective destruction of mitochondria carrying destructive mutations of mitochondrial DNA and the preservation of normal organelles [29]. Moreover, stimulation of autophagy is a necessary condition for increasing life expectancy, at least in worms [30]. This indicates that the stimulation of aging carried out by TORC1 is partly due to inhibition of autophagy.
TORC1 activates ribosome biogenesis and protein synthesis. The results of recent studies have shown that inhibition of ribosome biogenesis and total protein synthesis increases life expectancy [31-34]. Reducing the levels of ribosomal proteins and translation initiation factors increases the lifespan of yeast and roundworms. This is in good agreement with the assumption that TORC1 can stimulate the aging process by activating ribosome biogenesis and protein synthesis.
In yeast, TORC1 negatively regulates stress-activated transcription factors GIS1 and MSN2/4. Both factors are necessary to increase life expectancy with a decrease in TOR activity [35, 36]. The longevity-associated gene activated by MSN2/4 upon inhibition of TOR is the nicotinamidase enzyme PCN1 gene. Interestingly, nicotinamidase converts nicotinamide to NAD+, which, in turn, activates SIR2, which indicates that TOR and sirtuins belong to the same mechanism for ensuring longevity [35]. Moreover, as described below, in order to shorten the lifespan, TOR negatively regulates the expression of mitochondrial genes [37].
TORC1 regulates the activity of mitochondria, but the way of regulation depends on the organism. In yeast, TORC1 suppresses mitochondrial respiration, whereas in mammals (at least in muscle tissue) it stimulates it [37-42]. Perhaps this discrepancy in the regulation mechanisms is due to the fact that glucose, a nutrient recognized by TORC1, triggers the process of anaerobic fermentation in yeast cells. Such a glucose-dependent respiratory shift is not characteristic of mammalian cells. In accordance with the above, activation of mitochondrial respiration increases the lifespan of yeast, while the degree of increase in the lifespan of mammalian cells correlates with a decrease in cellular respiration activity [37, 39, 43]. However, the role of mitochondria in increasing life expectancy remains unclear, especially given the recently obtained data, according to which TOR in mammalian adipose tissue, as well as in yeast cells, negatively regulates cellular respiration [26].
The accumulation of proteins prone to the formation of aggregates contributes to neurodegeneration. TOR causes neurodegeneration in fruit flies with simulated taupathy [44]. The TOR-mediated signaling mechanism is involved in the development of Alzheimer's disease by stimulating Tau protein synthesis [45]. Moreover, rapamycin stimulates the excretion of pathologically altered proteins, thus reducing their toxicity [46].
As described below, apparently, excessive activation of TOR contributes to the formation of a hypertrophic phenotype of mammalian cell aging, thus linking TOR-mediated cell hypertrophy with aging at the body level. On the contrary, in vivo experiments have not proved the importance of the replicative limit [47]. It is the hypertrophic secretory phenotype of aging cells that can be associated with the aging of the body [48-50].
Hypertrophic phenotype of aging cellsIf growth and aging are mechanistically interrelated, does aging lead to an increase in cell size?
In yeast, old cells are larger in size, while cell size is an indicator of replicative lifespan [51, 52]. It seems that this pattern also applies to mammalian cells entering the phase of physiological aging. An increase in cell size is a criterion for identifying physiologically aging fibroblasts [53]. The volume of such cells is several times higher than the volume of proliferating cells. As we approach the phase of physiological aging, the cell size in culture progressively increases [54-56]. Moreover, 20 years ago it was suggested that the cell size is a marker of its physiological aging [54, 57]. Paradoxically, the existence of TOR was not yet known at that time, and the importance of this phenomenological observation is unclear. Now the assumption that TOR is simultaneously involved in the processes of growth and development provides a mechanistic explanation of the old observation.
Cell growth consists in increasing its volume or mass as a result of metabolic activity, including the synthesis of macromolecules (RNA, proteins, lipids) and organelles. If a cell grows without dividing, it becomes hypertrophied. In other words, blocking the cell cycle in the presence of growth-stimulating signals leads to an increase in cell size [56, 58, 59].
Thus, the growth of the cell is balanced by its division, which ensures that the size of mammalian cells is maintained at a certain level. The easiest way to simultaneously cause cell hypertrophy and its physiological aging is to prevent cell division without inhibiting its growth. Inhibition of TOR by rapamycin smoothes the manifestations of hypertrophic phenotype caused by induction of cyclin-dependent kinase inhibitor p21 [58-60].
All these observations indicate that the mTOR-mediated signaling mechanism plays a role in the aging of individual cells. What does this have to do with the aging of multicellular organisms? According to discussions in other papers [1, 61], changes caused by TOR may be associated with the aging of multicellular organisms and, in particular, with the development of aging diseases such as cancer, metabolic syndrome, atherosclerosis, hypertension and cardiac hypertrophy.
The use of rapamycin by humansDaily intake of rapamycin for several years is prescribed to patients who have undergone kidney transplantation to prevent rejection of the donor organ.
We view this fact as an unintended clinical trial of a potentially aging-slowing drug. Firstly, when examining such patients, it unexpectedly turned out that rapamycin prevents the development of cancer [62-64] and, in some cases, even cures pre-existing tumors of certain types [65, 66]. Secondly, two years after transplantation, the body mass index of patients taking rapamycin was significantly lower than the body mass index of patients taking cyclosporine, which indicates the ability of rapamycin to prevent the development of obesity [67].
Rapamycin is safe enough to be taken by healthy volunteers in order to study its pharmacokinetics [68-70]. When taken by healthy individuals, a single dose did not cause the development of adverse reactions. In 11 healthy men (29 years old, BMI=23), taking 6 g of rapamycin reduced S6K phosphorylation, preventing the development of nutrient-induced insulin resistance. Thus, the active state of the mTOR-mediated signaling mechanism can influence the sensitivity of human tissues to insulin, and mTOR inhibitors prevent the development of nutrient-induced insulin resistance [70].
Why TOR?Cell growth and division are the two most fundamental characteristics of the living.
Using simple compounds and energy, living organisms, according to their own instructions, synthesize biomolecules, transforming foreign material into their own components. It is not surprising that the TOR-mediated signaling mechanism controlling the growth process has been preserved in the course of evolution and has reached humans. In unicellular organisms, it maximizes growth during the entire period of nutrient availability. However, it turns out that the life-stimulating TOR-mediated signaling mechanism to some extent brings death to the body. Aging and its manifestations, such as age-related diseases, arise as a result of excessive activity of growth-stimulating signals in conditions of impossibility of further growth. Aging is not part of the program, but a meaningless continuation of the process underlying growth during the development of the organism. Given that aging does not limit life expectancy in nature, the mechanism for terminating this "growth program" could not have been formed during evolution. The growth process should be stable and should not slow down in order to avoid aging of the body. Moreover, the growth-aging program cannot be disabled by a random mutation, since such a mutation would be lethal or, at least, would reduce physical endurance during the development of the organism. However, the activity of TOR can be inhibited by pharmacological methods.
The list of references is given in a separate file.
Portal "Eternal youth" http://vechnayamolodost.ru30.09.2011