07 December 2015

Epigenomics of longevity

Aging and longevity:
epigenome reveals secrets

Alexey Rzheshevsky, "Biomolecule" 

Epigenetics is a relatively recent field of science. The subject of its study is changes in the activity of genes that persist steadily in a number of cell divisions, not related to changes in the DNA itself. In other words, due to epigenetic modifications, some genes work, while others are silent. Thirty years ago, many in the scientific community, because of entrenched dogmas, did not want to recognize the importance of epigenetic processes in the biological world. Now this area of knowledge attracts the attention of many laboratories and institutes around the world, including those engaged in the study of the nature of aging. In gerontology, a new direction associated with the description of the epigenetic mechanisms of age-related changes has received a powerful development.

Epigenetics begins the searchEpigenetics is a scientific field that studies all factors that affect the activity of the genome, but are not related to DNA mutations.

Since all our cells contain the same DNA, epigenetic control of gene activity is of paramount importance in establishing cell specialization during the development of the organism and in the subsequent functioning of the genome. Epigenetics, through its mechanisms – for example, methylation of cytosine bases of DNA, modification of histones and RNA interference (Fig. 1) - controls the work of the genome by changing the structure of chromatin and "turning on" or "turning off" our genes*.

* – Read more about the processes of epigenetic modification of the genome in the articles: "Development and epigenetics, or the story of the Minotaur" [1], "Epigenetic Clock: how old is your methylome?" [2], "Epigenetics of behavior: how grandma's experience affects your genes" [3].

Methylation is a method of regulating the activity of genes by attaching a methyl group (-CH3) to the cytosine bases of DNA. Methylation suppresses the activity of the gene: synthesis of RNA (and protein, respectively) by such a matrix becomes impossible. This is a kind of "plug" that the body uses, inactivating certain genes whose work it does not need at the moment or may pose a danger.

Another important mechanism of epigenetic regulation is the modification of histones that are part of chromatin. Chromatin is a complex of proteins and nucleotides that ensures reliable storage and normal operation of DNA. In our cells, DNA packaging is like a jewelry warehouse. Otherwise, it is impossible to put a spiral two meters long into one small cell nucleus. The DNA strand is wound in one and a half turns on numerous "beads" of several special proteins, histones. This is how repeating structural units of eukaryotic chromatin, called nucleosomes, are formed. Each nucleosome contains eight histone molecules – two molecules of each of the four types of proteins (H2A, H2B, H3, H4). Histones have "tails" – protein "growths" that can be lengthened or shortened by special enzymes. The length of such a "tail" directly affects the activity of genes located near it.

The histone "tail" can undergo the process of acetylation, that is, the replacement of hydrogen atoms in it with the remainder of acetic acid. As a result, the connection of histones with DNA, based on the attraction of differently charged particles, will weaken, histone will dissociate (move away from DNA), and DNA packaging will become more "loose" (less dense). Then regulatory proteins will be able to attach to DNA more easily, and the activity of the gene will increase. Epigenetic processes are interrelated with each other: for example, an increase in the level of DNA methylation is usually associated with a decrease in the level of histone acetylation, and vice versa. In addition to acetylation, there are many other ways to modify histones: methylation, phosphorylation, sumoylation, and so on. These modifications can both loosen and "tighten" the DNA packaging, which leads to an increase or decrease in gene expression, respectively.

Not so long ago, another level of epigenetic regulation was discovered, which consists in influencing gene expression through non-coding RNAs (ncRNAs). These RNAs can regulate the activity of the gene both at the transcriptional and post–transcriptional levels - that is, they can both "drown out" transcription, preventing the synthesis of mRNA and thereby preventing the reading of information from the gene, and lead to the destruction of already synthesized mRNA. This mechanism was called RNA interference. In 2006, for its discovery, American researchers Andrew Fire and Craig Mello were awarded the Nobel Prize in Physiology and Medicine*.

* – More information about RNA and its associated mechanisms of action on the genome is described in the articles: "About all RNAs in the world, big and small" [4], "How to get rid of RNA in a few minutes" [5], "microRNAs – the further into the forest, the more firewood" [6].

Important scientific discoveries related to epigenetics appear almost every year. And although scientists are at the very beginning of the path, the data obtained show the exceptional value of this scientific direction. Having received worldwide recognition, epigenetics soon moved from a purely scientific field of research to a very applied one, when its close connection with development and aging was revealed. It is no coincidence that one of the recent articles in Nature was published under the title "Epigenomics begins the search" [7]. And this search is already giving its results.


Figure 1. Chromatin structure and epigenetic mechanisms of influence on the genome. Histone modifications: Ac, acetylation; Me, methylation; Ub, ubiquitination; P, phosphorylation.
 Cytosine methylation of DNA – Me ~C. RNA interference: miRNAs, small non-coding RNAs.
Methylation and its relation to aging

In scientific works on gerontology, a description of the ontogenesis (individual development of the organism) of salmon fish is often found.

And, as is already known, the aging of fish of this species, which develops at lightning speed immediately after spawning, is accompanied by massive DNA demethylation [8]. It has been established that with age there is a general decrease in the level of DNA methylation. The DNA taken from embryos and newborns contains the largest number of methylated cytosine bases. It turns out that some genes that were "silenced" and were silent in childhood and at a young age begin to show activity in old age. Another, smaller part of the genes, on the contrary, "falls silent" with age, having undergone methylation. The consequences of such changes in gene activity have not yet been fully studied, but some aspects are already known.

Thus, quite a large part of the methylated human genome (according to some data, up to 90%) is accounted for by mobile DNA elements – retrotransposons*. Some viral agents, such as adenovirus or hepatitis B virus, entering our body, can also be blocked by methylation. Due to the weakening of its methylation, the retrotransposon Alu, characteristic of humans, can begin to move in old age - to create copies of itself and insert them into different points of the genome, thereby disrupting the normal functioning of genes. Such uncontrolled movements of retrotransposons carry considerable danger and can cause serious pathologies: today about a hundred diseases are associated with the activity of mobile DNA elements [9].

* – You can read about the mobile genetic elements of eukaryotes in the articles: "Secrets of "molecular parasites", or How to travel through the genome" [10], "There is not much diversity: what do mobile elements of the genome do in the brain" [11], "The human genome: a useful book, or a glossy magazine?" [12].

Scientists from the Australian National University, Robert Kuharsky and his colleagues have shown in their works how big the influence of epigenetics on life expectancy can be. In 2008, Science published the results of their research on the effect of the enzyme DNA methyltransferase-3 (DNMT-3) on the duration of bee life [13]. For a long time it remained a mystery how two different castes of bees – workers and queens (or queens) - appear from genetically identical larvae.


Figure 2. DNA-methyltransferase complex with DNA. Drawing from the website www.bionet.nsc.ru .

If worker bees live for only a few weeks, then queens live for several years. Such a huge difference in the length of the life path of genetically identical organisms is a consequence of a special diet: those larvae destined to become queens are fed royal jelly for longer. The molecular mechanisms of this phenomenon became clear when R. Kuharski and his team artificially reduced the amount of DNMT-3 enzyme in bee larvae. This enzyme attaches methyl groups to DNA (Fig. 2), suppressing gene expression. Without DNMT-3, the activity of some genes in the larvae turned out to be increased, and as a result, most of them turned into queens even without feeding with royal jelly. Decoding of the bee epigenome confirmed this assumption: significantly fewer methyl groups were found in the DNA of female bees than in worker bees. A few years later, R. Kuharski's group, conducting a study of the level of cytosine methylation in the nervous system of worker bees and female bees, found 561 genes with significant differences in methylation between the two bee groups [14].

Of course, not only the features of the epigenome affect the life span of the queen bee. As it is known today, a combination of factors makes a long-lived queen: this is the right ratio of polyunsaturated and saturated fatty acids, and a reduced content of cytochrome c (which is able to trigger the process of cell death, apoptosis), and increased antioxidant activity [15].

As it turned out, the influence of the epigenome on life expectancy is extremely high in humans. So, in 2013, a large group of Italian geneticists, led by Giovanni Vitale, published the results of a study that studied age-related changes in DNA methylation [16]. The objects of the study were two groups of women of the same age, residents of Northern Italy. One group included elderly Italian women who had long-lived mothers and fathers who had lived at least 77 years. The other group included Italian women whose parents died after living for about 70 years (fathers – 67 years, mothers - 72 years). Having distributed the subjects in this way, the scientists set themselves the task of comparing which changes at the gene level can underlie longevity. And also to find out whether there is a clear continuity in this matter – are the factors of longevity inherited?

The results of their work exceeded all expectations and showed the following.

The decrease in DNA methylation (hypomethylation), characteristic of the elderly, occurred much faster in Italian women whose parents did not live to 70 years than in their peers who had long-lived parents. The researchers found that methylation (and hence blocking) of the Alu element was significantly higher in the descendants of centenarians. Even in old age, people who inherited good health from their parents did not differ much at the molecular genetic level from young people. And such potentially dangerous elements of the genome as retrotransposons were reliably blocked by them. It is possible to say with a high degree of confidence that good health (as well as bad) is inherited.

Understanding the nature of epigenetics has shown that parents are responsible for the health of their children to a much greater extent than previously thought. More recently, it has been shown that such a familiar thing today as the excess weight of future parents can have the most negative effect on their offspring. The famous American geneticist Randy Girtle and his colleagues from Duke University conducted DNA studies of leukocytes from the umbilical cord blood of infants born in the hospital at their university. According to scientists, the analysis recorded a significant decrease in the level of methylation of the insulin-like growth factor 2 (IGF 2) gene in those children whose parents were overweight: "We found in newborns whose fathers were obese, a significant decrease in IGF2 methylation in DNA extracted from umbilical cord blood leukocytes. Lowering the level of IGF2 methylation is associated with an increased risk of cancer" [17].

Age-related abnormalities and epigenomeIt is already known that age-related changes in the epigenome are closely related to other age-related phenomena, such as an increase in the production of reactive oxygen species, shortening of telomeres, etc. Reactive oxygen species (ROS) and related processes with the light hand of the famous American biologist Dengam Harman (and no less famous Russian biologist V.P. Skulachev) are considered today by some scientists as one of the main factors of aging.

Although ROS themselves are involved in many physiological processes (especially in the immune system), a dangerous increase in their level can occur with age. Having high chemical activity, ROS are potentially capable of damaging cell membranes, mitochondrial and nuclear DNA*. They are involved in many age-related processes and related pathologies: atherosclerosis, Alzheimer's disease, etc. So, for example, in cardiovascular diseases, ROS block the production of sirtuin proteins (in particular, SIRT1), which leads to a chain of abnormalities and the development of pathologies (Fig. 3). In Alzheimer's disease, ROS are involved in the pathological processes of amyloid formation, and also contribute to the activation of pro-inflammatory factors – for example, nuclear transcription factor NF-kB [18].

* – ROS and related processes are discussed in more detail in the articles "Active oxygen: Friend or foe, or about the benefits and harms of antioxidants" [19] and "Antioxidants against pyelonephritis" [20].


Figure 3. Oxidative stress, epigenetics and diseases of the heart, lungs and nervous system. ROS – reactive oxygen species; SIRT1 – sirtuin 1, a protein from the sirtuin family; iNOS – induced nitric oxide synthase; eNOS – endothelial nitric oxide synthase; NO – nitric oxide; 8-oxo – 8-hydroxyguanine, a marker of oxidative DNA damage; HDAC2 – histone deacetylase 2; NF-kB – nuclear transcription factor kappa-B; p21 – protein, inhibitor of cyclin-dependent kinase 1A; p16 – protein, inhibitor of cyclin-dependent kinase 2A. Figure from [18].
Back in 1994, Sigmund Weizmann and his colleagues from Northwestern University (Chicago) discovered that the oxidation of guanine, the obligatory "partner" of cytosine in double-stranded DNA, by free radicals affects methylation.

The oxidized guanine product, 8-hydroxyguanine (8-OHdG), a well-known marker of oxidative DNA damage, not only increased the mutation rate, but also prevented normal cytosine methylation [21]. It turned out that the epigenome is closely related to the regulation of ROS levels: the overall age-related decrease in DNA methylation develops in parallel with an increase in ROS levels and oxidative stress. And these processes are interconnected. Thus, age-related oxidative stress caused by increased production of ROS significantly reduces the number of already mentioned sirtuins, to which gerontologists are paying close attention today. Sirtuins are a family of conservative (that is, found in all living organisms) proteins that perform one of the epigenetic functions – deacetylation of histones. Numerous experiments have shown the beneficial role of sirtuins in maintaining health and increasing life expectancy. ROS also reduce the level of these proteins, thereby shortening the life span.Folate cycle, p66Shc, epigenome and aging

If we take at random any pathology from a long list of age-related diseases (such as atherosclerosis, Parkinson's disease, diabetes or rheumatoid arthritis), then the direct involvement of the epigenome in their development will definitely be revealed. This issue has been well studied today and no one has any doubts. For example, patients with atherosclerosis have an increased level of homocysteine toxic to the arteries. And the reason for this is a malfunction of a complex biochemical process called the folate cycle, which is closely related to DNA methylation and the epigenome.

The folate cycle is a cascade of biochemical reactions involving a large number of enzymes (Fig. 4). Vitamins B9 (folic acid), B6 and B12 are necessary for the normal course of the folate cycle. In this cycle, there is a transfer of methyl groups that attach to homocysteine, and excess homocysteine is converted into methionine. Methionine passes into its active form, S-adenosylmethionine (SAM), which in the cell serves as the main donor of methyl groups necessary for the synthesis and methylation of DNA, RNA, proteins and phospholipids [22].


Figure 4. Folate cycle diagram. In the reaction catalyzed by the MTHFR enzyme, 5.10-methylenetetrahydrofolate is formed from tetrahydrofolate and serine, which is then reduced to 5-methyltetrahydrofolate. In the next step, the methyl group from 5-methyltetrahydrofolate is transferred to homocysteine in a reaction catalyzed by B12-dependent methyltransferase. As a result of remethylation of homocysteine, methionine is formed. This reaction is catalyzed by the cytoplasmic enzyme methionine synthase (MTR). The enzyme requires methylcobalamin, a derivative of vitamin B12. Methionine synthase provides the conversion of homocysteine to methionine through a reaction in which methylcobalamin acts as an intermediate carrier of the methyl group. In this case, cobalamin is oxidized, and the MTR enzyme goes into an inactive state. Figure from [22].The folate cycle may fail for two reasons: genetic (due to mutations in the genes of the enzymes of the folate cycle) or alimentary (due to a deficiency of methionine, folic acid and other B vitamins).


Deficiency occurs if the diet lacks foods rich in these substances, or if these substances are poorly absorbed – as a rule, against the background of bad habits, medication, infections, etc.

Violation of the folate cycle threatens the body with three consequences at once. First, a low level of one of the derivatives of this cycle, 5.10-methylenetetrahydrofolate, leads to breaks in DNA and disruption of repair processes [23]. Secondly, there is a deficiency of the main donor of methyl groups, S-adenosyl methionine (SAM), without which it is impossible to produce DNA methylation. And the third consequence: the metabolism of homocysteine is disrupted, and its level in the blood begins to rise. And then homocysteine, toxic to cells, triggers a chain reaction with many pathological branches.

What kind of appearance can it have? As the work of American and Korean biologists, S. Kim and co–authors, has shown, an increased concentration of homocysteine in the blood has a direct connection with endothelial dysfunction (a thin layer of cells lining the surface of blood vessels) and atherosclerosis [24]. Moreover, an active participant in the damaging effect of homocysteine on endothelial cells is a protein with a "bad reputation", p66Shc, which has oxidative and pro-apoptotic (inciting the cell to suicide) activity. Experimental mice with the p66shc gene knocked out ("turned off") showed a significant increase in life expectancy [25]. At the same time, such mice were surprisingly resistant to the effects of oxidative stress and the development of the main pathologies traditionally associated with aging: hypercholesterolemia (increased cholesterol levels), hyperglycemia (increased glucose levels) and ischemia. And even shock doses of alcohol did not kill such mice!

As it turned out, homocysteine in elevated concentrations is able to increase the expression of endothelial p66shc by hypomethylation of specific CpG dinucleotides in the promoter (regulatory region of the gene) of p66shc. And this mechanism plays an important role in homocysteine-induced endothelial pathology. The fact is that p66Shc increases the production of ROS, which are recognized as one of the main causes of age-related endothelial dysfunction [24]. It is noteworthy that low-density lipoproteins (LDL, or, in layman's terms, "bad" cholesterol) have exactly the same effect on p66Shc as homocysteine, which are considered as one of the factors in the development of metabolic syndrome, to which a huge number of people in the world are subject. It turned out that LDL is able to cause hypomethylation of two CpG dinucleotides and acetylation of histone 3 in the p66shc promoter, which leads to an increase in its activity [26].

The Italian researcher Giovambattista Pani linked the age–related activity of p66Shc and ROS with another protein of increased interest to gerontologists - mTOR (the target of rapamycin in mammals), which regulates the processes associated with development and cell growth in the cell (Fig. 5) [27]. According to one of the most authoritative mTOR researchers, Mikhail Blagosklonny (Roswell Park Cancer Institute, USA), this protein occupies one of the central places in the aging processes of living organisms, stimulating the development of age-related pathologies that shorten life [28].


Figure 5. Two models showing how p66Shc can combine ROS and mTOR/S6K cascade in the aging process. a–ROS activate the protein p66Shc (or simply p66), which in turn activates ribosomal S6 kinase (S6K). ROS can be produced in mitochondria in response to the intake of nutrients (nutrients), thus creating an alternative route for the detection of nutrients by S6K. b – Activated p66 kinase S6K increases the formation of ROS in mitochondria. In this case, p66 can be stimulated by cellular stress, p53 protein or exogenous oxidants. In both examples, the effect of p66 on aging is inhibited by calorie restriction, which reduces the supply of nutrients. Activation of p66 occurs as a result of increased expression (shown by an enlarged icon) and phosphorylation of serine (letter "P"). Both changes occur in response to various stresses in mammalian cells. Figure from [27].But not only endothelial dysfunction and cardiovascular diseases are associated with homocysteine and increased p66Shc activity.

It is already known that p66Shc is directly related to the deviation, which today is most often considered as the starting point of accelerated aging – with insulin resistance, when cells stop interacting with this hormone [29]. Together with insulin resistance, lipotoxicity and glucose toxicity develop - the destructive effect of excess fatty acids (primarily palmitic) and glucose on cellular structures. And then the volume of consequences grows like a snowball: increased production of pro-inflammatory cytokines, accumulation of dangerous metabolites (diacylglycerol, sorbitol, ceramide), oxidative stress, impaired ATP synthesis and mitochondrial dysfunction, endothelial damage and atherosclerosis, glycosylation of proteins, amyloid accumulation, cell damage, accelerated aging. The vast majority of centenarians do not acquire insulin resistance until very old age. And vice versa – most of the people who died prematurely from cardiovascular pathologies had resistance to this hormone.

Today, much attention of gerontologists is focused on the mechanisms of beneficial effects on the body of calorie restriction. Studies have shown that a calorie-reduced diet can prolong life. The most striking and often cited example of such an influence is the inhabitants of the Japanese island of Okinawa, who, with a daily diet of less than 2000 kcal, confidently hold the first place in the world in terms of the number of centenarians. The essence of this phenomenon consists of many factors, including epigenetic ones. It was found that calorie restriction changes the DNA methylation profile in a positive way: the methylation of tumor suppressor genes decreases, which leads to their activation, and the methylation of oncogenes increases. In addition, limiting the amount of glucose consumed, which gives a considerable part of calories, in the experiment led to the phenomenon of expanding the Hayflick limit – the limit of cell division underlying the limited life span of the cell (Fig. 6). And again this happened together with epigenome changes – changes in DNA methylation and histone modifications affecting activity the key genes are p16 and hTERT [30].



Figure 6. The effect of limiting glucose intake on life expectancy. Restriction of glucose intake can affect epigenetic regulation in both normal and cancer cells. In normal cells, this leads to the repression of the p16 gene and activation of hTERT, which makes it possible to expand the Hayflick limit. The p16 protein slows down the process of cell reproduction, the hTERT gene encodes the enzyme telomerase, which is able to build up the end sections of DNA that contract during cell division – telomeres. In precancerous cells, the opposite effects on p16 and hTERT lead to apoptosis and death of dangerous cells. Figure from [30].Epigenome and telomeres

Another age–related process, the shortening of telomeres (repetitive DNA sequences that stabilize the end sections of chromosomes, but decrease in length with each cell division), also turned out to be closely related to the epigenome.


American biologists from the Salk Institute and Harvard University, Roderick O'Sullivan and his colleagues, conducted research to find out the effect of cell division on the structure of chromatin. As can be seen from the work of O'Sullivan and co-authors, in aging cells with strongly shortened telomeres, the nature of DNA packing in chromosomes changes significantly [31]. It also turned out that with age, with each cell division, along with the shortening of telomeres, there is a decrease in the synthesis of special proteins-histones*. On nucleosomal histones, like a sewing thread on a spool, a DNA molecule is wound, thus being packed in the nuclei of cells. By acetylation-deacetylation of histones, DNA packing density is regulated. If the genes need to be "silenced", the packaging is compacted, and the information-reading proteins cannot join the regulatory nucleotides. If, on the contrary, the work of some gene is necessary, chromatin is "loosened", DNA packaging becomes less dense and accessible to regulatory proteins.

* – The properties of these proteins are described in the article "Histone rolls, rolls to DNA" [32].

It is obvious that chromatin histones play a very important role in the normal functioning of the genome. And the age-related decrease in their synthesis found by American researchers, associated with cell division and telomere shortening, can lead to the destabilization of the genome. According to the assumption of O'Sullivan and his colleagues, a chronic stress signal is generated by the reduction of telomeres and leads to a decrease in the synthesis of histones of two types, H3 and H4. In turn, this does not allow to accurately restore the chromatin landscape at the next division, and DNA damage gradually limits the life of the cell. Even minor changes in the equilibrium of the DNA–histone system, according to scientists, can disrupt DNA synthesis, chromatin architecture and cell viability.

But, as it turned out, this is not the only possible relationship between telomeres, aging and the epigenome. Not so long ago, another potential connection was traced. V.A. Galitsky and his colleagues from the Palladin Institute of Biochemistry (Kiev) described the possibility of telomere shortening against the background of age-related genomic instability. And here's what it might look like.

According to Ukrainian biochemists, microRNAs in stem cells support the initial profile of epigenetic markers, which underlies the unique qualities of stem cells (first of all, their ability to live a long life). But differentiation – the transformation of stem cells into specialized ones* – requires the repression of some microRNA genes so that they do not interfere with the activity of a number of necessary genes. As a result, age-related loss of epigenetic markers occurs, and the level of DNA methylation decreases. And this can lead to the derepression of retrotransposons and other mobile elements "dormant" in DNA and, as a result, to their movements and DNA damage. In response, DNA repair systems can be launched in the cell, provoking unauthorized recombination in telomere regions (the so-called telomeric caps). And for this reason, telomeres will lose their length [33]. And telomere shortening, as we know, is one of the recognized markers of aging of the body.

* – This process is perfectly illustrated (literally) in the comic book "Who to be? How the hematopoietic stem cell chooses a profession" [34]. – Ed.

Conclusion. "Epigenetic drift"How much the epigenome changes with age, depending on external factors, was clearly shown by studies of the DNA of twins performed by Spanish scientists, Mario Fraga and his colleagues.

Studying monozygotic (identical) twins, they determined that twins at the age of three years are identical not only genetically, but also epigenetically [35]. But 50-year-olds – who are still the same genetically - have significant epigenetic differences (Fig. 7). Moreover, the greater the geographical distance between their places of residence and, consequently, the difference in living conditions. This may indicate that such differences do not arise by chance, but depend on the conditions in which people live.



Figure 7. The difference in DNA methylation of twins aged three and 50 years. In order to determine the epigenetic differences between twins, researchers have developed an original technique for coloring identical sites (loci) of homologous chromosomes. In the case of the same expression, these loci were colored yellow, if they were hypomethylated – red, and if hypermethylated – green. So, if the chromosomes of 3-year-old twins were colored almost completely yellow, then green and red clearly dominated in 50-year-olds. Figure from [35].The results of all these studies allowed the German geneticist Axel Schumacher to develop the concept of "epigenetic drift" – a gradual change in the DNA methylation profile with age* [36].

According to the concept, age-dependent "epigenetic drift" is a natural process observed in everyone, even completely healthy people. But for those who are strongly influenced by the environment, bad habits, stress, and malnutrition, drift can "tilt" towards unfavorable profiles, negatively changing the work of the genome.

* – The article "Why cells age" figuratively tells about the nature of various, not only epigenetic, age-related changes in cells and possible ways to overcome them [37]. – Ed.

After all the studies conducted, scientists can confidently say that the basis of longevity and good health, along with other factors, is largely determined by the state of the epigenome. And it consists of two components: from what we inherited from our parents, and from the habits that we have developed in our lives. As one of the founders of epigenetics, Professor of Moscow State University B.F. Vanyushin, said, "there is no doubt that DNA methylation and histone modifications, as well as selective silencing of genes by small RNAs play a very important role in the life of the cell and the organism, therefore further exhaustive research in this exciting field of knowledge is a very important and fruitful task of our centuries" [38]. And it's hard to argue with that. It remains to wait for new discoveries that will give us a field of knowledge that has rapidly burst into our lives – the science of EPIGENETICS.

LiteratureBiomolecule: "Development and epigenetics, or the story of the Minotaur";
  1. Biomolecule: "Epigenetic clock:
  2. how old is your methylome?";Biomolecule: "Epigenetics of behavior:
  3. how does grandma's experience affect your genes";biomolecule: "About all RNAs in the world, large and small";
  4. biomolecule: "How to get rid of RNA in a few minutes";
  5. biomolecule: "microRNA – the further into the forest, the more firewood";
  6. Callaway E. (2014).
  7. Epigenomics starts to make its mark. Nature. 508, 22;Vaiserman A.M., Voitenko V.P., Mekhova L.V. (2011).
  8. Epigenetic epidemiology of age-related diseases. Ontogenesis. 42, 1–21;Hancks D.C. and Kazazian H.H. (2012).
  9. Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 22, 191–203;Biomolecule: "Secrets of "molecular parasites", or How to travel through the genome";
  10. biomolecule: "There is never much diversity: what do mobile genome elements in the brain do";
  11. biomolecule: "Human genome: a useful book, or a glossy magazine?";
  12. Kucharski R., Maleszka J., Foret S., Maleszka R. (2008).
  13. Nutritional control of reproductive status in honeybees via DNA methylation. Science. 319, 1827–1830;Lyko F., Foret S., Kucharski R., Wolf S., Falckenhayn C., Maleszka R. (2010).
  14. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol. 8, e1000506;Corona M., Velarde R.A., Remolina S., Moran-Lauter A., Wang Y., Hughes K.A., Robinson G.E. (2007).
  15. Vitellogenin, juvenile hormone, insulin signaling, and queen honey bee longevity. Proc. Natl. Acad. Sci. USA. 104, 7128–7133;Gentilini D., Mari D., Castaldi D., Remondini D., Ogliari G., Ostan R. et al. (2013).
  16. Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring. Age (Dordr). 35, 1961–1973;Soubry A., Schildkraut J.M., Murtha A., Wang F., Huang Z., Bernal A. et al. (2013).
  17. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med. 11, 29;Cencioni C., Spallotta F., Martelli F., Valente S., Mai A., Zeiher A.M., Gaetano C. (2013).
  18. Oxidative stress and epigenetic regulation in ageing and age-related diseases. Int. J. Mol. Sci. 14, 17643–17663;Biomolecule: "Active oxygen: friend or foe, or about the benefits and harms of antioxidants";
  19. biomolecule: "Antioxidants against pyelonephritis";
  20. Weitzman S.A., Turk P.W., Milkowski D.H., Kozlowski K. (1994).
  21. Free radical adducts induce alterations in DNA cytosine methylation. Proc. Natl. Acad. Sci. USA. 91, 1261–1264;Grechanina E.Ya., Lesovoy V.N., Myasoedov V.V., Grechanina Yu.B., Gusar V.A. (2010).
  22. There is a natural connection between the development of certain epigenetic diseases and a violation of DNA methylation due to a deficiency of folate cycle enzymes. Ultrasound perinatal diagnostics. 29, 27–59;Zijno A., Andreoli C., Leopardi P., Marcon F., Rossi S., Caiola S. et al.
  23. (2003). Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects. Carcinogenesis. 24, 1097–1103;Kim C.S., Kim Y.R., Naqvi A., Kumar S., Hoffman T.A., Jung S.B. et al. (2011).
  24. Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc. Cardiovasc. Res. 92, 466–475;Galimov E.R. (2010).
  25. The role of p66shc in oxidative stress and apoptosis. Acta Naturae. 4, 49–56;Kim Y.R., Kim C.S., Naqvi A., Kumar A., Kumar S., Hoffman T.A., Irani K. (2012).
  26. Epigenetic upregulation of p66shc mediates low-density lipoprotein cholesterol-induced endothelial cell dysfunction. Am. J. Physiol. Heart Circ. Physiol. 303, 189–196;Pani G. (2010).
  27. P66SHC and ageing: ROS and TOR? Aging (Albany NY). 2, 514–518;Blagosklonny M.V. (2013).
  28. MTOR-driven quasi-programmed aging as a disposable soma theory: blind watchmaker vs. intelligent designer. Cell Cycle. 12, 1842–1847;Ranieri S.C., Fusco S., Panieri E., Labate V., Mele M., Tesor V., Ferrara A.M. et al. (2010).
  29. Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance. Proc. Natl. Acad. Sci. USA. 107, 13420–13428;Tollefsbol T. (2014).
  30. Dietary epigenetics in cancer and aging. Cancer Treat. Res. 159, 10;O’Sullivan R.J., Kubicek S., Schreiber S.L., Karlseder J. (2010).
  31. Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat. Struct. Mol. Biol. 17, 1218–1225;biomolecule: "Rolling, rolling to DNA histone";
  32. Galitsky V.A. (2009).
  33. The epigenetic nature of aging. Cytology. 5, 388–397;Biomolecule: "Who to be?
  34. How a hematopoietic stem cell chooses a profession";Fraga M.F., Ballestar E., Paz M.F., Ropero S., Setien F., Ballestar M.L. et al.
  35. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA. 102, 10604–10609;Wang S.C., Oelze B., Schumacher A. (2008).
  36. Age-specific epigenetic drift in late-onset Alzheimer’s disease. PLoS ONE. 3, e2698;biomolecule: "Why cells age";
  37. Vanyushin B.F. (2013).
  38. Epigenetics today and tomorrow. Vavilov Journal of Genetics and Breeding. 17, 805–832.Portal "Eternal youth" http://vechnayamolodost.ru
07.12.2015
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