Growth and aging: a common molecular mechanism. Part 2
The beginning of the article is here.
Aging of budding yeastBudding yeast Saccharomyces cerevisiae is a particularly valuable model system for studying aging processes, as it can be used to study both replicative and chronological aging (see the article "Aging and ways to prolong life: taking lessons from yeast").
The degree of replicative aging is defined as the number of daughter cells (divisions) that a mother cell can produce. Chronological aging, also called postmitotic aging, is estimated as the duration of the period during which a non-dividing cell can maintain its vital activity. Inhibition of the TORC1-mediated signaling mechanism in yeast increases both the replicative [5] and chronological [6] lifespan. Thus, apparently, TOR stimulates the aging process regardless of the physiological context (mitotic or postmitotic cell).
In yeast, the relationship between growth and aging, the existence of which became known already in the 1950s, is particularly clear. As yeast cells age, they increase in size [7, 8]. Usually, S.cerevisiae yeast is characterized by asymmetric division with the formation of a large mother cell and a smaller daughter cell. As the mother cells age, they become larger, while the size of the daughter cells formed during their division also increases in comparison with the size of the cells produced by young mother cells. As well as for larger mother cells, larger daughter cells are characterized by a shorter lifespan [8].
The use of unicellular yeast to study aging is also illustrative because in this case the cell is an entire organism. Therefore, it simultaneously represents a model of aging at the cell level and a model of longevity at the body level. As can be seen from the further discussion, TOR is also involved in the aging of multicellular organisms.
TOR and the aging of organisms ranging from yeast to mammalsInhibition of the TOR-mediated signaling mechanism increases the lifespan of roundworms, fruit flies, and possibly mammals.
The body of the nematode Caenorhabditis elegans contains a constant number of postmitotic cells, and the life expectancy of the worm is approximately 20 days. For the first time, the role of TOR in the regulation of life expectancy was identified by Vellai et al. [9], which showed that knockout of the TOR coding gene increases the normal lifespan of C.elegans by more than two times. They were specifically studying the role of TOR in aging, which they were prompted by existing data, according to which both TOR activity and life expectancy are regulated by nutrient and insulin levels. Indeed, the results of a large number of earlier significant studies demonstrating that a low-calorie diet [10, 11] or suppression of the activity of the signaling mechanism mediated by insulin/insulin-like growth factor-1 [12, 13] increase life expectancy are consistent with the observation that suppression of TOR activity also increases life expectancy. An interesting fact is that the inhibition of TOR, initiated during development or on the first day of adulthood, leads to comparable results with respect to an increase in life expectancy. This fact indicates that TOR determines longevity mainly, and possibly exclusively, in adulthood [9]. Later Jia et al. [14] demonstrated that worms that do not have a TORC1-specific raptor subunit are also characterized by an increased lifespan. This proves that TOR stimulates the aging process through at least TORC1, and possibly both TORC complexes.
In drosophila, TOR is necessary for the growth of the organism during larval development, as well as for accelerating cell growth under the influence of a growth factor-mediated signaling mechanism and the availability of nutrients [15]. Genetic inhibition of the TOR-mediated signaling mechanism in fruit flies increases the lifespan of insects, and this happens regardless of which stages of the mechanism (located "above" or "below" TORC) are affected [16, 17]. Moreover, suppression of TOR functioning in fruit flies leads to a decrease in fat reserves and glucose levels, and also prevents the development of metabolic syndrome [17], which indicates the importance of the role of fat deposits in the aging process [19-21, 12]. Suppression of the TOR-mediated signaling mechanism in adipose tissue not only increases the lifespan of fruit flies, but also reduces the size of the organism as a whole [22], which once again confirms the existence of a relationship between growth and aging. Apparently, the main role of the TOR-mediated signaling mechanism of drosophila adipose tissue cells in determining life expectancy can also be extrapolated to the TOR of mammalian adipose tissue cells. A decrease in the activity of the insulin-mediated/insulin-like growth factor-1 signaling mechanism in adipose tissue and, accordingly, a decrease in the activity of the last stages of the TOR-mediated signaling mechanism increases the lifespan of mice [23, 20]. Moreover, the deficiency of growth hormone or insulin-like growth factor-1 that occurred in adulthood also increases the life expectancy of rodents [24]. It should also be noted that mice lacking the mTORC1 complex or its S6K effector do not suffer from obesity associated with old age and diet [25, 26].
And, finally, a low-calorie diet, under which the intake of nutrients is limited to 60-70% of the voluntarily consumed amount of calories, increases the life expectancy of a large number of species, including mammals [10-12]. Despite the fact that the mechanisms by which a low-calorie diet slows down aging are still being discussed, one of them, with a high degree of probability, is the inactivation of the TOR-mediated signaling mechanism. And indeed, given that 1) inhibition of TOR increases life expectancy and 2) the intake of nutrients activates TOR, the mechanism underlying the increase in life expectancy with a limited intake of calories is obvious.
Ending: Part 3.
Portal "Eternal youth" http://vechnayamolodost.ru30.09.2011