Homicide by DNA methylation

A recent publication suggests that DNA methylation may be the cause of aging and death in higher organisms.  The May 2009 publication by Alexander L. Mazin from Lomonosov Moscow State University is entitled Suicidal function of DNA methylation in age-related genome disintegration and presents a very dark view of DNA methylation as possibly being at the heart of the aging process.

The 13^th theory of aging covered in my treatise is called Programmed Epigenomic Changes and envisages aging as a systematically articulated set of epigenomic changes, involving changes in DNA methylation in cells accumulated with aging.  The new Mazin review publication proposes a mechanism for such programmed aging, seeing DNA methylation as a wrecking-ball process that progressively introduces mutations in key genes, eventually wrecking the genome causing aging and death.

I introduced the topic of DNA methylation in this blog in the post Epigenetics, epigenomics and aging and have mentioned it in a number of subsequent posts.  Its role in aging is outlined in the post DNA methylation, personalized medicine and longevity. As I said there, DNA methylation is a process by means of which sites adjacent to genes on chromosomes (promoter regions) are chemically methylated after a cycle of DNA replication(ref).   The methylation is passed on in the course of cell divisions and through generations of people. The methylation pattern captures the ancestral history of the cell that is not in the genes themselves and is unique to every cell. DNA methylation is thought to be one of the main ways epigenetic information is captured and passed on.

The Mazin paper states “This review will put forward the hypothesis that the host-defense role of DNA methylation in silencing and mutational destroying of retroviruses and other intragenomic parasites was extended during evolution to most host genes that have to be inactivated in differentiated somatic cells, where it acquired a new function in age-related self-destruction of the genome.” He is saying that cell differentiation and specialization requires silencing of certain genes, which ones depending on the destination cell type, and that task – necessary for the development of complex organisms – is accomplished by DNA methylation. Further, he is saying that DNA methylation does something else too, and that is eventually wrecking the genome by creating mutations in certain genes. The paper goes on to say “The proposed model considers DNA methylation as the generator of 5mC > T transitions that induce 40–70% of all spontaneous somatic mutations of the multiple classes at CpG and CpNpG sites and flanking nucleotides in the p53, FIX, hprt, gpt human genes and some transgenes.” “The accumulation of 5mC-dependent mutations explains: global changes in the structure of the vertebrate genome throughout evolution; the loss of most 5mC from the DNA of various species over their lifespan and the Hayflick limit of normal cells; the polymorphism of methylation sites, including asymmetric mCpNpN sites; cyclical changes of methylation and demethylation in genes. The suicidal function of methylation may be a special genetic mechanism for increasing DNA damage and the programmed genome disintegration responsible for cell apoptosis and organism aging and death.”

The theory is plausible. DNA methylation is known to be capable of exercising mutagenic and epigenetic effects. Multiple publications discuss mutations in relationship to methylation in CpG sites within genes(ref)(ref)(ref). In a previous paper DNA Cytosine Methylation Produces CpG and CpNpG Hotspots for Various Types of Mutations in Human Genes Mazin stated “The evidence is presented that both CpG and CpNpG sites of DNA methylation and their 5`-, 3`-neighboring nucleotides are hotspots not only for 5mC>T transitions, but also for most types of mutations. 40-70% of all spontaneous mutations are found at these sites, and mutation frequencies at the hotspots are 10-40 times higher than the average for the genes studied. 52-77% of CpG sites could be lost because of relict germ-line 5mC>T substitutions, and 10-20% of somatic mutations result in the emergence of new sites of methylation in these genes. Various mutagenes induce significant changes in mutation spectra at sites of methylation. Thus, one of the basic functions of DNA methylation is mutation destruction of most host genes that responsible for human genetic diseases, aging, and cancer.”

The most recent post in this blog, The NRG1 Gene – an important new tumor suppressor gene, points to a specific mechanism of how DNA methylation can lead to cancers – through silencing the NRG1 tumor suppressor gene. According to the Mazin hypothesis more than silencing of genes is involved through methylation – they are mutated, irreparably damaged. Numerous other “housekeeping” genes are likewise affected by the methylation. Such gene damage, according to my reading of the hypothesis, leads to multiple disease susceptibilities and degenerative processes associated with aging.

If the Mazin hypothesis is correct, the mutational damage due to DNA methylation is in the genes themselves and therefore cannot be corrected through demethylation or any form of epigenomic reversal. It says you start out in life with mostly good genes and end up with enough bad ones to kill you. Further old cells with such damage reverted to iPSC pluripotent status would continue to contain age-related mutational damage and, in that way, would be genetically different than embryonic stem cells were for the same individual. Because the reverted cells would continue to contain the genetic seeds for age-related self-destruction, they could not be used to close the loop in the stem cycle supply chain as suggested in the blog post The stem cell supply chain – closing the loop for very long lives. This is a rather gloomy outlook on life extension for it says that without constant gene-correction therapy to reverse the results of constant mutations due to DNA methylation, aging is indeed irreversible.

I would strongly prefer a scenario where our genes are more or less constant through life and aging mainly goes on in the epigenome where it might, in principle at least, be reversible. We will have to see what happens if and when other researchers pay attention to Mazin’s hypothesis. Meanwhile there is more that can be said about DNA methylation and you can probably expect another post on that topic soon.