DNA Methylation: The hand in the 'biological clock' of life

17.06.2014
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Biomarkers of ageing are important tools in the quest for interventions that can prolong life and treat age-related diseases. Now, biomathematician Steve Horvath has come up with a strikingly accurate age predicting 'biological clock' that uses DNA methylation as the hand that tells biological time.

Aging… a word that brings anxiety and fear to the minds of all humans, regardless of age, gender or race. A word associated with wisdom, but also physical and mental decline and in many cases diseases like cancer, atherosclerosis, arthritis, Alzheimer’s and others.  But how does ageing occur? And, is there a way to accurately measure the ageing process and thus help scientists in their quest to discover interventions that can reverse this process?

Amongst the oldest hypothesis regarding the cause of ageing is the damage of macromolecules, like DNA.  Damage to macromolecules can be caused by various sources throughout our life, like chemicals and UV radiation, but also by the by-products of mitochondrial respiration called reactive oxygen species (ROS). In fact, the latter have been the subject of the ‘free-radical hypothesis of aging’ formulated in the 1950s by Harman, stating that ROS were the major source causing damage to macromolecules.

Telomeres, stretches of DNA at the ends of our chromosomes that protect our genetic data, have also been linked to the ageing process. These structures, which prevent the end of our chromosomes from fraying and sticking to each other, become shorter with each cell division. When they become too short, the cell can no longer divide and eventually dies. Geneticist Richard Cawthon and colleagues at the University of Utah showed that shorter telomeres are associated with a shorter lifespan. For some time now, researchers have been looking into using telomeres as a potential mechanism for measuring biological age. It has also been proposed that telomere length and telomerase activity (the enzyme that adds bases to the end of telomeres) could be used as markers for diseases such as cancer, since cancer cells appear to make more telomerase to lengthen their shorter telomeres, and thus escape death. However, application of this method is still in the future, as is the usability of these structures to somehow reverse the process of ageing and the diseases that come with it.

Now, Steve Horvath, a human geneticist at the University of California, Los Angeles (UCLA), has come up with a biological clock that has the potential to measure the age of human cells with impressive accuracy, by making use of epigenetics. Epigenetics is the study of changes in DNA that do not alter the DNA sequence, but are still heritable and can have an effect on how genes are expressed. Such an alteration is DNA methylation, a modification in which a methyl group is attached to DNA. In humans, methyl groups most often attach to DNA at sites where the nucleotide cytosine precedes a guanine, known as 'CpG sites'. Steve, who as a youngster had ‘planned to use mathematical modeling and gene networks to understand how to extend life’, has managed to develop his ‘epigenetic clock’ based on DNA methylation. Using an algorithm he discovered that analyzes methylation data collected from cell samples, Horvath claims he can provide a remarkably accurate estimate of the age of the person the cells were extracted from. In fact, by the time his study was published, using this method, Horvath could guess the age of the cell inhabitants to within 3.6 years of their actual age.

What are the scientific and medical implications of the Horvath 'epigenetic clock'?

In the search for the 'elixir of life' biomarkers are very important tools that allow researchers to assess the biological age of cells at any given time, without having to examine the actual lifespan of an organism -  a very time-consuming process. However, until recently, most known biomarkers of ageing only work in one or two tissues of the human body and thus don't allow scientists to predict the age of the whole organism. Using Horvath's 'epigenetic' clock, it is possible to extract DNA from numerous cells and tissues, from white blood cells to brain and predict the age of the individual it came from very accurately, plus minus a few years. This fact, sets Horvath's method apart from all other tests used to predict human age.

Another potential intriguing use for this method could be the detection of age-acceleration in cells. By making use of the 'epigentic clock' to measure the age of cells, we could observe if they are actually older than the real chronological age of the person they originate from, either in the whole body or in a certain body part. Such differences in biological versus chronological age could be a potential risk factor in many degenerative diseases, thus allowing doctors to identify individuals that are at high risk of developing cancer, Alzheimer's and other age-related diseases. In fact, it has been shown that the ages of tissue from breast, lung, kidney and skin cancers were 40% older on average than the patients they were removed from.

Can this ‘biological clock’ be used as a new anti-ageing tool?

Besides the practical applications of this method, Horvath hopes that ‘the science won’t stop there’. Since DNA methylation is usually a reversible process, would it be possible to slow down the ‘epigenetic clock’ and at the same time ageing and its complications? Such an implication would make young Horvath’s promise, to dedicate his career to the search for ways to prolong life, almost attainable. However, this notion is still debatable and remains to be determined, since skeptics point out that DNA methylation transition patterns observed from young to old could be mostly random, and that this epigenetic modification leads to ageing and disease mainly by interfering with the ability of stem cells to differentiate. If the latter is true, there would be nothing really informative about Horvath’s clock.

Reference article:

http://www.nature.com/news/biomarkers-and-ageing-the-clock-watcher-1.15014

Other references:

http://learn.genetics.utah.edu/content/chromosomes/telomeres/

http://warddeanmd.com/mitochondrial-theories-of-aging-part-i/

 

Image copyright: Bruce Rolff, Thinkstock

Article last time updated on 26.11.2014.

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It may have escaped your notice that the DNA molecule you depicted is left-handed.
#2 at 10.07.2014 from Guest
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Fernando Kawaguchi MD PhD Digestive Oncology. Concepcion University Chile
Dear Proff: Our Group from Concepcion University are working almost 20 years with Dr S Gutierrez , related to Gastric Cancer with high prevalence in our area( 48 vs national prevalence: 9 per 100.000). It means Early Gastric Cancer. Advanced showed different patterns . Using mathematical Horvath algorihm to understand how to extend life’, it is possible estimate age and life prognosis of person and cells were extracted from.
#1 at 20.06.2014 from Fernando Kawaguchi MD PhD Digestive Oncology. Concepcion University Chile (Guest)
  0
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