By Nermina Lamadema,
Postdoctoral Research Associate at King's College London
Epigenetics is a study of the way the cells read the genes and which of the genes become expressed and therefore translated into the proteins which is what ultimately controls body functioning. The changes are heritable and do not involve genetic sequence so we normally talk of a change in phenotype rather than genotype of the individual.
Epigenetics is an area influenced by several key factors including age, the environment/lifestyle, and disease state. The epigenetic modifications studied most extensively are DNA methylation, histone ‘code’ and non-coding RNA gene silencing. These modifications by affecting and establishing specific gene expression patterns have an effect on the way cells differentiate and proliferate. Whilst the genetic code determines the way the genes are translated into the proteins the epigenetics determine how these genes are expressed. This is achieved through the addition of small chemical marks methyl and acetyl groups which are continually being attached and removed on DNA and histones which are spools around which DNA is wound up in the cell nucleus for storage. The marks affect the way the DNA is packed in the nucleus thereby turning particular genes on and off depending on the cellular requirements.
DNA methylation which is associated with gene silencing occurs with the addition of methyl chemical marks on C5 carbon of cytosine bases. Typically human genome does not contain many of these marks globally except for highly repetitive satellite sequences and viral genes which need to be kept silent in the genome. Other regions are typically methylation free particularly so called ‘CpG islands’ which are cytosine and guanine rich stretches of DNA important for the gene regulation.
We have previously mentioned that in cancer we observe a complete reversal of DNA methylation status with repetitive retroviral sequences loosing methyl marks and gene regulatory promoter regions also known as CpG islands gaining the marks. It is also important to note here that DNA methylation can persist and become permanent mode by which a gene is silenced permanently. Furthermore this mark can become heritable as the cell divides and copies its DNA its methylation patterns can also be copied. By this mode the epigenetic inheritance across generations is established without any change to the primary DNA sequence.
We have previously discussed the modes of epigenetics mediated transmitting of the behavioural and disease patterns within the individuals and across generation and would now like to focus on current findings on the way the epigenetics and aging interact. On cellular level aging is regulated by the process of telomere shortening and cellular senescence.
Telomeres are short protective caps consisting of DNA and proteins at the end of the chromosomes which we inherit from our parents and which serve as aging clocks because they shorten as we age. As the cells divide the telomeres become shorter and shorter until the cell division eventually stops and the cells enter senescence. The field of telomere research is very active particularly because they are also implicated in cancer (the telomeres in cancer cells escape shortening and never die because of inactivated telomerase enzymes) and there is a potential that the shortening of telomeres may one day be used as biomarker of aging.
Epigenetics of aging
Research studies in the field demonstrate a very close association of specific methylation patterns with the age of the body. It appears that the ‘methylome’ changes significantly as we age and that has an effect on the gene expression which not only starts acquiring randomness not normally observed in youth but also there are clear observed changes to the genes becoming silenced in the old age whilst they were active in youth and vice versa. Indeed when analysing the methylation patterns of any individual researchers nowadays must take a person’s age into consideration as one of the normalising patterns of the study. We have indeed arrived at the age where by looking at the methylation pattern of the person cells we are able determine the age of the individual. If the reader would like to get more information on this exciting area of research relating to what some call the ‘Epigenetic clock’ a starting point of information should be a paper by Steve Horvath titled ‘DNA methylation age of human tissues and cell types’ published in the Genome Biology in 2013.
That the epigenetics and aging are closely co-related is firmly established but whether the DNA methylation is a cause or effect of aging is still very much an unknown. According to one body of research it is proposed that the explanation for the difference in the change to the expression patterns as we age is that the changes are a way of body protection mechanisms in response to the damage it was exposed during the lifetime. This proposal is in agreement with the theory of evolution where the body would want to maintain itself alive and healthy as long as possible and by switching the gene expression pattern to minimize the damage this would be one way of ensuring this happens.
Other researches into the aging clock such as Mitteldorf, J.J. propose and alternative view which although in opposition to the traditional evolutionary theory in is nevertheless equally valid as it’s based on the data available of the genes that become up or down regulated in the old age. This view is that the DNA methylation in the old age is the blueprint for the self-destruction of an organism. As the evidence for this the researchers point towards the accumulated data for the genes that become expressed in the old age none of which belong to the protective mechanisms such as genes responsible for the apoptosis or cell death and inflammation in cancer. On the other hand genes that play protective roles such as DNA repair, proliferation or free radical protection are silenced or down regulated.
In a never ending quest to prolong life or at least improve the quality of aging determining which hypothesis of the two above may provide answers required for improving the quality of life in the old age.
Članak „Epigenetika i starenje“ na bosanskom jeziku možete pročitati u petnaestom broju magazina AŠK, decembar 2016.