Autophagy and aging
Review of research articles published in 2009 that have made or will make a significant contribution to the study of aging – Part 9.
In 2009, the dogma was questioned, according to which autophagy is always associated with physiological aging or causes it. Despite the fact that autophagy remains an important mechanism for slowing down aging, it seems that the relationship between these phenomena is very complex. Thus, it has been demonstrated that autophagy is activated in the phase of physiological aging, while activation correlates with negative feedback in the signaling mechanism mediated by PI3K-mTOR. With physiological aging, an increase in the activity of a subgroup of autophagy–related genes is observed: overexpression of one gene – ULK3 - induced autophagy and the onset of physiological aging. Moreover, inhibition of autophagy delayed the formation of the phenotype of physiological aging, including secretory activity associated with physiological aging. These data indicate that autophagy and the protein processing triggered by it can contribute to the acquisition of the phenotype of physiological aging [84]. Inhibition of autophagy in adult fruit flies [85] and C.elegans worms [86] had no effect on life expectancy, whereas autophagy was a necessary condition for increasing the life expectancy of yeast, fruit flies and C.elegans worms caused by a number of pharmacological and genetic manipulations [87-90]. This indicates that autophagy may be a factor limiting life expectancy only in certain (but not in any) conditions. It is also interesting that resveratrol-mediated inhibition of human kinase-S6 suppressed autophagy [91]. Several reports published in 2009 also demonstrated that the TOR-mediated signaling mechanism controls autophagy by acting on the Atg1/Atg13 protein kinase complex [92-94]. Moreover, TOR-mediated autophagy regulates cell death in neurodegenerative diseases in fruit flies [95].
The natural polyanion spermidine can increase the lifespan of yeast in both chronological and replicative aging models, as well as increase the average and maximum lifespan of fruit flies and nematodes (C.elegans). It turned out that spermidine is a powerful inducer of autophagy in the cells of all tested species, including yeast, drosophila and C.elegans [96]. The addition of a dietary supplement containing polyanions (including spermidine) to the feed of mice also increases life expectancy and the period of preservation of health [97], however, the dependence of this phenomenon on autophagy has not yet been studied. In yeast cells, spermidine induces autophagy and increases life expectancy due to its ability to inhibit histone acetylases [96].
Sirtuin-1 and its orthologue in C.elegans induce autophagy of human cells and nematodes. Sirtuin-1 is also necessary for the induction of autophagy carried out by its allosteric activator resveratrol (both in human cells and in the body of nematodes), when cultured in a nutrient-free environment (human cells) or in a low-calorie diet (nematodes). Experiments on C.elegans have shown that activation of sirtuin-1 increases life expectancy in a manner independent of autophagy. Thus, inactivation of the Beclin1/ATG6 gene, which is necessary to trigger autophagy, eliminated the increase in life expectancy caused by activation of sirtuin-1 [87]. These results emphasize the role of autophagy in the regulation of life expectancy with the help of pharmacological agents [98].
Continuation: Post-transcriptional regulation of gene expression and aging.
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