Epigenetic changes

Authors

This area of investigations is developing by a number of scientists, among them are A. D. de Grey, J. Vijg, R. Holliday et al.

History:

The history of epigenetic researches is linked with studies of evolution and development. For a long time, many scientists did not acknowledged epigenetics at all or even intentionally passed it over in silence. 

That occurred mainly due to the fact that knowledge about the nature of epigenetic signals and ways of their realization in the organism was very indistinct. Actually, epigenetics in modern interpretation was developing and promoting by scientists of our country — I. v. Michurin, F. D. Lysenko and their followers, and by some foreign researches, e.g. D. L. Nanney an investigator of the ciliated protozoa. It should be noted that understanding of the molecular mechanisms providing epigenetic regulation of gene expressing has come only at the beginning of 2000s.

Example:

Enzygotic twins are known to be clones, i.e. exact genetic copies of each other. In the early childhood, their chromosomes have nearly the same patterns of DNA methylation in the same tissues. Nevertheless, when such twins grow old, they have sharply different patterns of DNA methylation in spite of the genetic identity and the same age.

Description:

Though chromosomes are regularly damaging and the effectiveness of the repair mechanisms declines with age, mutations occur quite rare and slowly accumulate with age.

 But the frequency of cancer and other age-related diseases indicates that gene activity changes much faster. It was found that the other type of chromosome changes appears substantially more often and makes more valuable contribution in aging. That is epimutations, i.e. changes in gene activity which are not accompanied with changes in DNA sequence. Epimutations influence gene activation and deactivation via changs in the pattern of methyl labels set in various areas of genome. If the methyl label present at nucleotides of definite gene, that gene becomes silent. On the contrary, taking methyl labels away activates the gene. The organism needs those manipulations with DNA methylation to be able to create cells and tissues with different sets of active genes and proteins synthesized on the basis of the same genotype. Proteins and functions necessary for brain neurons are vain for liver cells, and vice versa. 

When we age, global demethylation of genome takes place, and that activates genes that must normally be «silent». Demethylation is provoked by chromosome damages, age-related decline in the activity of enzymes putting methyl label through genome, redundancy of homocysteine amino acid, insufficient level of sex hormones. On the contrary, some important genes, e.g. genes of receptors of sex hormones, genes of telomerase and DNA repair ungergo selective hypermethylation in some tissues. That sort of epimutations switch the function of the gene off. All in all, as we age, epimutations accumulate in different tissues in a random way and change activity of a number of genes (1 to 10%). Now we know that epimutations can cause cancer, atherosclerosis, coronary heart disease, diabetes and Alzheimer’s disease.

Additions and Criticism:

Life style (including the type of diet) and environment influence substantially the probability of demethylation. For example, deficiency in uptake of vitamins (folic acid, B12) and microelements (zinc, selenium) in old age is one of the reasons of demethylation.

It is not clear as yet why age-related hypermethylation occurs. But there is no doubt that if we are able to control the process of methylation, we will possess one of the approaches allowing to control aging.

Publications:

• de Grey, Aubrey DNJ. «Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging." Mechanisms of ageing and development 128.7 (2007): 456–459.
• Vijg, Jan. «The role of DNA damage and repair in aging: new approaches to an old problem." Mechanisms of ageing and development 129.7 (2008): 498–502.
• Gravina, Silvia, and Jan Vijg. «Epigenetic factors in aging and longevity." Pflügers Archiv-European Journal of Physiology 459.2 (2010): 247–258.
• Holliday, Robin. «Perspectives in aging and epigenetics." Epigenetics of Aging. Springer New York, 2010. 447–455.