Life extension: Resveratrol, spermidine and autophagy (3)
Autophagy mediates the increase in life expectancy caused by spermidine(the end, the beginning of the article is here)
The fact that the cells of practically healthy aging people are characterized by a decrease in the content of polyamines [93], prompted the authors to study the potential ability of polyamine spermidine to slow down the aging process. At the beginning of the study, they selected as an object a yeast line that does not have the enzyme ornithine decarboxylase SPE1, which catalyzes the first stage of polyamine biosynthesis. In experiments to study chronological aging, delta-spe1 (Δspe1) yeast cells demonstrated increased mortality (and, accordingly, shorter life expectancy), which was restored to normal values when small doses (0.1 mM) of spermidine or its precursor putrescine were added to the medium [94]. Unexpectedly, the authors found that high concentrations of spermidine increased the lifespan of wild-type yeast cells with different genomes. Thus, both chronological aging (which is a model of postmitotic aging) and replicative aging (which is a model of stem cell aging) of yeast cells significantly slows down when spermidine is added to the culture medium. An increase in the lifespan of yeast cells treated with spermidine may be due to a decrease in the level of acetylation of a number of lysine residues located at the N-terminal end of the histone H3 molecule (namely Lys9, Lys14 and Lys18) [94]. Neutralization of sir2 (yeast homologue of sirtuin 1) or any other protein of the sirtuin family did not affect the ability of spermidine to increase the chronological lifespan of yeast. On the contrary, the results of epistatic analyses showed that the aging-slowing effect of spermidine was reproduced when histone acetylases were blocked, which indicates their participation in the regulation of the same life-prolonging mechanism influenced by spermidine [94]. Moreover, in an in vitro experiment, spermidine effectively suppressed the total histone acetylase activity in extracts of purified yeast and human cell nuclei [94]. These data indicate the fact that the mechanism of action of spermidine differs from the mechanism of action of resveratrol. Thus, while the former inhibits histone acetylase(s), the latter stimulates the deacetylase activity of sirtuin 1. However, formal evidence that (de)acetylation of histones, and not other proteins (both nuclear and cytoplasmic), lies behind the ability of spermidine to slow aging is still lacking.
Analysis of the state of yeast cells treated with spermidine using microchips revealed the transcriptional activity of several genes associated with autophagy, including atg7, atg11 and atg15, while the authors also obtained evidence that spermidine does indeed induce autophagy in yeast cells. Similarly, spermidine proved to be a highly effective stimulator of autophagic mechanisms when it was added to the culture medium or solid feed of C.elegans and D.melanogaster, respectively. Spermidine concentrations having a pro-autophagic effect also significantly increased the lifespan of yeast, nematodes and fruit flies. Genetic inhibition of important ATG genes (i.e. knocking out the atg7 gene in yeast and drosophila flies or blocking the expression of bec-1 by RNA interference in nematodes) canceled the increase in life expectancy induced by spermidine, which indicates that this polyamine can increase life expectancy by induction of autophagy [94].
Open questionsThe above results indicate that resveratrol and spermidine can increase the lifespan of model organisms by inducing autophagy (Fig. 2).
Figure 2. Hypothetical mechanism of action of resveratrol and spermidine as inducers of autophagy.
Resveratrol functions as an activator of sirtuin 1 deacetylase, and spermidine inhibits one or more histone acetylases. Thus, both resveratrol and spermidine should promote the hypoacetylation of proteins. However, the substrates related to autophagy, the deacetylation of which is induced by resveratrol and spermidine, are not fully characterized, and it is not even known whether they are represented by different, partially coincident or the same proteins. More detailed information can be found in the text of the article.
In addition, the results of the work carried out by the authors raise at least three questions, the search for answers to which future research should be devoted.
Question one:
do resveratrol and spermidine increase life expectancy by acting on the same molecular mechanism? While resveratrol can increase life expectancy by stimulating the deacetylase activity of sirtuin 1 (or its equivalents: SIR2 in yeast cells and SIR-2.1 in C.elegans cells), spermidine inhibits the total histone acetylase activity of yeast extract and mouse liver extract. There is unequivocal evidence that histone (de)acetylation is an important epigenetic regulator of life expectancy [95, 96]. However, the sirtuin 1 fraction is present in the cytoplasm, where it can directly deacetylate proteins that play important roles in the autophagy process (including ATG5, ATG7 and ATG8/LC3) [90]. This fact indicates that (at least partially) the pro-autophagic effects of resveratrol are the result of events occurring outside the nucleus and unrelated to transcription. It is very important to find out whether polyamines (such as spermidine) and sirtuin 1 activators (including resveratrol) can have a cumulative or synergistic effect on autophagy and life expectancy, or whether these agents activate the same molecular mechanism. Moreover, the exact mechanisms by which spermidine and resveratrol regulate the autophagy-triggering mechanism need further study. To clarify this issue, it is necessary to conduct thorough mechanistic and epistatic analyses.
Question two:
do all life-extending manipulations induce autophagy? And is autophagy a necessary condition for increasing life expectancy with the help of such interventions? The data available today clearly indicate that autophagy is necessary for the aging-retarding effects of rapamycin, resveratrol and spermidine. Moreover, it has been suggested that autophagy is a prerequisite for increasing the lifespan of C.elegans in a low-calorie diet, but it has not yet been tested for all calorie intake restriction protocols [73]. It is still unclear whether increased autophagy activity is necessary to increase the lifespan of C.elegans caused by the absence of the RHEB-1 GTPase [97], the transcription fraction of hypoxia-induced factor 1 (HIF-1) [98], and its negative regulator VHL-1 [99], ubiquitin ligase WWP-1 [100], as well as the chaperone proteins CCT4 and CCT6 [101]. A positive answer to this question could form the basis of a new system of concepts in the field of studying the mechanisms of longevity.
The third and most important question:
is it possible to extrapolate the data discussed in this article, most of which were obtained when working with model organisms in laboratory conditions (in which, for example, the immunosuppressive side effects of resveratrol are much less important), to a person in real life? Despite the fact that rapamycin and polyamines can increase the lifespan of mice [80, 102], resveratrol has a similar effect only if animals are kept on a high-calorie diet [86]. There is indisputable evidence that rapamycin and resveratrol can induce autophagy in mice in vivo [23, 24, 103]. However, it is currently unknown whether there really is a causal relationship between increased autophagy activity and healthy aging of mammals, especially humans. Proof of the existence of such a relationship would revolutionize the entire field of research on the mechanisms of aging.
The list of references is given in a separate file.
Portal "Eternal youth" http://vechnayamolodost.ru
30.12.2011