Genetics of aging
Review of research articles published in 2009 that have made or will make a significant contribution to the study of aging – Part 8.
Numerous papers published in 2009 have significantly expanded the scope of our knowledge about the role of sirtuins [35], the TOR-mediated signaling mechanism [59, 60] and the stress response factors HSF-1 and DAF-16 [61] in the aging process. It is especially important that the removal of the gene encoding ribosomal S6 kinase-1 (S6K1) and the elimination of protein kinase A increases the lifespan of mice [62, 63], whereas the gene encoding the protein binding eukaryotic translation initiation factor 4E (4E-BP) was necessary to increase the lifespan of flies-drosophila in a low-calorie diet [29]. Moreover, it has been shown that the 4E-BP protein is a component of the "lower" part of the TOR-mediated signaling mechanism that modulates the aging of the heart tissue of fruit flies [64]. Finally, it has been demonstrated that SIRT6 plays a critical role in the repair of double-stranded DNA breaks [65].
In 2009, Kenyon and his colleagues advanced further in understanding the mechanisms underlying their earlier observations (Hsin and Kenyon, Nature, 1999, 399:362-6), according to which the aging of the soma (body, with the exception of germ cells) of C.elegans worms and drosophila flies occurs under the influence of gametocytes (cells, giving rise to germ cells): the removal of gametocytes slows down the aging process and increases life expectancy. In 2009, data were published according to which the key role in this process belongs to the translation elongation factor TCER-1, the existence of which was predicted earlier [66]. When gametocytes are removed, the level of TCER-1 in somatic tissues increases. This increase is sufficient to trigger the main events of the "lower" part of the signaling cascade, since overexpression of the tcer-1 protein increases the life expectancy of normal animals with an unchanged reproductive system. Interestingly, TCER-1 specifically links the activity of the widespread transcription factor DAF-16/FOXO with longevity signals generated by reproductive tissues [66]. In mice, Foxo1 provides integration of the insulin-mediated signaling mechanism and mitochondrial functioning, while inhibition of Foxo1 can improve liver metabolism in insulin resistance and metabolic syndrome [67].
In an earlier work, Willcox et al. (PNAS 2008, 105:13987) established that the genetic variability of the FOXO3A gene is characterized by a pronounced relationship with human longevity. Long-lived men also demonstrated several additional phenotypes associated with healthy aging, including a low probability of developing cancer and diseases of the cardiovascular system, as well as high levels of physical and cognitive activity. These men also had higher insulin sensitivity associated with homozygosity of the FOXO3A GG genotype. In support of Willcox's observation, a whole series of papers was published in 2009, the results of which demonstrated the existence of a relationship between single nucleotide polymorphisms (snips) of the FOXO3a gene and the exceptional life expectancy of certain populations living in Japan, Germany, America, Italy and China [68-71].
Several interesting papers have also been published on the complex role of the p53 protein in the mechanisms of longevity. In drosophila flies, p53 had stage-specific and sex-specific effects on adult life expectancy, which indicates sexual antagonistic pleiotropy [72, 73]. Moreover, the existence of an association between the snips of genes involved in the implementation of the p53-mediated signaling mechanism and human fertility indicates that p53 regulates the effectiveness of human reproductive function. These results provide a plausible explanation that selection pressure contributes to the preservation of certain p53 alleles, and also indicate that these alleles are a clear example of antagonistic pleiotropy [74].
Interestingly, the snips of the p21 gene correlate with life expectancy in the Italian population [75]. Several studies have demonstrated the important role of p53 in maintaining the physical condition of tissues, through its contribution to preventing the mobilization of stem cells carrying irreversible DNA damage (for example, having abnormally functioning telomeres) [76, 77]. However, phenotypically, the result depends on the type of tissue and the situation. Removal of the p53 gene in epidermal cells ensured the possibility of organ functioning and physical health of newborn mice with abnormally functioning telomeres [76]. Conversely, the removal of p53 in the intestinal epithelial cells of aging mice with abnormally functioning telomeres accelerated tissue destruction and reduced life expectancy [77]. The latter phenotype was associated with abnormal survival of stem cell clones with unstable chromosomes, leading to differentiation disorders and p53-independent apoptosis. Apparently, limiting the survival of stem cells with unstable chromosomes is a key component of the well-known function of p53, which consists in suppressing tumor growth. It was also shown that the TAp63 protein belonging to the p53 family is necessary to maintain the functioning of the precursor cells of the epidermis and dermis, as well as the fact that in its absence these precursor cells enter the phase of physiological aging, which leads to premature aging of the skin [78].
Model systems continue to help researchers deepen their understanding of longevity genetics. The WRN gene, whose defect causes the Werner syndrome, which characterizes premature aging, encodes a protein that simultaneously has helicase and exonuclease activity [79]. To clarify its genetic functions, the ability of human WRN to eliminate symptoms characteristic of sgs1-associated phenotypes was tested. It has been shown that WRN interacts with topoisomerase-3 at the genetic level and eliminates the symptoms of the slow-growing sgs1 top3 phenotype. Helicase, but not exonuclease activity of WRN at the genetic level is necessary to restore the growth phenotype associated with top3, which indicates the separation of functions of different types of catalytic activity of WRN. In the presence of top3 mutations, unwinding of the DNA chain by the WRN helicase can have a detrimental effect on cell growth and genome homeostasis [80].
In 2009, the results of several studies on the genetics of aging of insulin-producing beta cells of the pancreas of humans and mice were published [81-83]. The aging-associated loss of the ability of beta cells to divide contributes to an age-related increase in the likelihood of developing type 2 diabetes. The results of earlier work showed that the tumor growth suppressor p16 INK4a causes an age-related decrease in the level of beta cell replication. In 2009, data were published according to which aging mice and humans have a loss of the p16 INK4a inhibition mechanism carried out by polycomb group proteins (PcG), mediated by histone methyltransferase EZH2 [82]. The removal of EZH2 in the somatic cells of mice led to the loss of the ability of beta cells to divide and develop diabetes, and these effects could be eliminated by simultaneous removal of p16 INK4a and Arf.
This work revealed the relationship between aging-related disorders of chromatin architecture and the expression of molecules with an antiproliferative effect. Bhushan (Bhushan) et al. A similar mechanism of regulation of p16 INK4a expression during aging has also been identified, mediated by the Bmi-1 protein belonging to the polycomb family, whose function is to suppress p16 INK4a expression together with EZH2 [81]. Finally, it was shown that p38MAPK activates p16 INK4a in aging beta cells, which indicates the possibility of a pharmacological approach to regulating the aging process of this tissue [83].
Continuation: Autophagy and aging.
Portal "Eternal youth" http://vechnayamolodost.ru28.09.2011