Growth and aging: a common molecular mechanism. Part 1
Article by Mikhail V. Blagosklonny and Michael N. Hall Growth and aging: a common molecular mechanism
published in Aging magazine, March 2009, volume 1, No. 4.
Translated by Evgenia Ryabtseva
ResumeAccording to the generally accepted opinion, growth and aging of the body are somehow interconnected, but the nature of this relationship is not completely clear.
In this article, we consider the aging process as a continuation of the TOR protein-mediated growth process. TOR is necessary for the growth of a developing organism, however, upon completion of the development process, it causes aging and the appearance of age-related diseases. Thus, the signaling mechanism that recognizes nutrients and drives the growth process, mediated by TOR, may well be a molecular "bridge" between the processes of growth and aging, universal for a huge number of organisms, ranging from yeast to humans.
IntroductionAt first glance, growth and aging are opposites.
Growth is an energy–dependent synthesis of macromolecules from simple nutrients, manifested by an increase in the degree of ordering and a decrease in entropy. Aging is destruction, manifested by a decrease in the degree of order and an increase in entropy. It would seem that these concepts are mutually exclusive. Infinitely proliferating cells, like the legendary hydra, do not show signs of aging. And, on the contrary, the loss of the body's ability to grow is followed by aging. However, the effects that suppress growth simultaneously slow down aging, thus increasing life expectancy. For example, a low-calorie diet (eating a limited amount of nutrients) suppresses growth and increases the life expectancy of representatives of various species, ranging from yeast to mice. Rapamycin, which suppresses yeast growth, also successfully slows down their aging. Inactivation of the growth-stimulating signaling mechanism mediated by insulin/insulin-like growth factor-1 also increases the lifespan of various species, ranging from yeast to mice. Why do growth-suppressing conditions slow down the aging process? Are these processes mechanistically similar? In this article we discuss the theory that growth and aging are rather not opposites, but two parts of the same whole, driven by the same molecular mechanism. The essence of the relationship between aging and growth may be that growth leads to aging. In other words, overgrowth is the driving force behind aging. Apparently, the molecular mechanism underlying both growth and aging is a signaling mechanism preserved during evolution, mediated by the TOR protein (target of rapamycin, target of rapamycin).
TOR-mediated signaling mechanismTOR, as evidenced by the name of this protein, was first identified in yeast as a target of the antifungal drug rapamycin.
Rapamycin is a secondary natural metabolite produced by soil bacteria to suppress the growth of fungi competing for food resources. Thus, it is a mirror image of penicillin produced by fungi to inhibit bacterial growth. It is noteworthy that the structure and functions of TOR have been preserved during evolution in a wide range of organisms, ranging from yeast to humans (including roundworms, fruit flies, plants and mice); this protein is the main component of the cell growth control system [1]. Mammalian TOR (mTOR) controls cell growth and metabolism depending on the intake of nutrients (e.g. amino acids), growth factors (e.g. insulin, insulin-like growth factor-1, platelet growth factor) and the energy status of the cell (ATP level). Nutrients are the dominant stimulant of TOR, since high levels of amino acids are able to compensate for the absence of other mTOR stimulants, but this relationship does not work in the opposite direction [2]. At the same time, only nutrients can activate TOR in unicellular organisms. The growth factor-mediated signaling mechanism, which developed as a complement to the older TOR-mediated nutrient recognition mechanism, evolved simultaneously with multicellularity. TOR activates cell growth by positively regulating several anabolic processes and negatively regulating catabolic processes, which, in general, determines the accumulation of mass. Anabolic processes include transcription, protein synthesis, ribosome biogenesis, nutrient transport, and mitochondrial metabolism. At the same time, TOR negatively regulates catabolic processes such as mRNA degradation, ubiquitin-dependent proteolysis and autophagy. TOR is an atypical serine/threonine kinase identified as part of two functionally and structurally distinct multi-protein complexes TORC1 and TORC2 (mTORC1 and mTORC2 in mammals), each of which triggers signaling mechanisms using different effectors. TORC1 is sensitive to rapamycin, whereas TORC2 is insensitive to this compound. The most well-described substrates of mTOR phosphorylation are S6K and 4E-BP1, through which mTORC1 controls translation, and Akt/PKB, through which mTORC2 controls cell survival mechanisms and other processes [3]. Like TOR itself, the two complexes containing it and the system of the signal network mediated by it as a whole look preserved in the course of evolution in a large number of organisms, ranging from yeast to humans [1, 4]. As described below, there is evidence that TOR and many of its regulated mechanisms are involved in the aging process (in addition to the growth process) of a wide range of organisms.
Continued: Part 2.
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