DNA methylation, personalized medicine and longevity

We as people are very different from each other.  And a medicine that may work well on one person may not work well on another or even poison him.  The dream of personalized  medicine is that your genetic and epigenetic signature is identified in sufficient detail to indicate your disease susceptibilities and your likely responsiveness to treatment options.  Even further, the signature at any point in time may tell you about diseases you already possess that you do not know about, like silent cancers.  This is where DNA methylation comes in,  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 ancesteral 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.  See the Feb 28 post in this blog on Epigenetics, Epigenomics and Aging.  Also, this subject is discussed in yesterday’s post Rebooting cells and longevity.

The DNA methylation profiles of individuals are unique, change with aging, and include valuable clues to disease and treatment progress.  For example, DNA methylation of tumor suppressor genes predicts the relapse risk in acute myeloid leukemia for patients in clinical remission(ref).   So, research groups throughout the world are building databases of DNA methylation epigenomic information, in part to establish methylation markers that are “normal” and other markers that indicate diseases, susceptibility to particular disease conditions and associated information . Epigenomics is a company that is focusing on cancer diagnostics based on looking at DNA methylation.  Its goal is to develop and commercialize easy-to-use diagnostic tests for cancer, tests that can be applied at early stages before symptoms occur.  The tests Epigenomics has under development use readily-available body fluids such as blood or urine and are based on detecting differences in DNA methylation patterns between healthy and sick individuals or between subgroups of patients within disease classifications.  One intent is to identify cancer-specific DNA methylation patterns while a patient’s cancer is in a very early stage and more likely to be curable(ref).  For example, researchers in Epigenomics have identified a region in the Septin9 gene that is methylated in 90% of colorectal cancer tissues.  This methylation is found little or not at all in normal colorectal tissues.  DNA methylation testing is not yet part of regular clinical practice but probably will be starting very soon.  Epigenomics has three products in the development pipeline, one for colorectal cancer screening, one for prostate cancer screening and one for lung cancer screening.

DNA methylation is impacted by aging and impacts on aging(ref).  Methylation in the promoter region of genes is thought generally to be associated with gene silencing.  Longevity-related and health-promoting genes may be turned off in the process of aging due to progressive methylation.  The P66Shc gene for example, associated with longevity in mammals, appears to be silenced through some combination of histone deactylation (resulting in protein folding) and cytosine methylation(ref).  Little is known yet about how to go about DNA demethylation, but demethylation appears to be necessary for epigenetic cell reprogramming(ref).  Also, relatively little is known yet about how DNA methylation plays out in aging, yet alone how to work with DNA methylation in order to stop or reverse aging.  Again, it appears that the more we discover, the more there is that we know we don’t know.