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Living by the Clock: How DNA Methylation Affects Lifespan

cassandra 1Have you ever wondered why skin cells and liver cells that contain the exact same DNA are so different? The answer is in gene expression. Although skin and liver cells do have the same DNA, different parts of the DNA are expressed in each type of cell. This cell type-specific expression results from different genes being “read” or transcribed by transcription factors in different kinds of cells. Sometimes, transcription factors of certain cell types do not process certain areas of DNA because chemical tags make these areas unreadable [1]. These chemical tags make up the “epigenome” and could provide insight into aging.

Analysis of the effects of these chemical tags is known as epigenetics. Recently, there has been a surge of focus specifically on methyl tags. These tags naturally accumulate throughout a person’s life but can fluctuate with the physical, social, and cultural environments outside of the body [2]. To illustrate epigenetics at work, let us look at a real-world example. The Dutch Famine occurred during a seven-month period at the end of World War II. Germany banned the transportation of food to some cities in the Netherlands, so residents of these cities were rationed six hundred calories per day [3]. This diet was a significant drop from the two thousand calories that these residents were used to, but with no say in the matter, the Dutch carried on with normal life.

Normal life includes pregnancy. Infants that were in utero during the famine had increased methylation, the addition of methyl tags to DNA, in many areas of their genomes. These areas included specific stretches of DNA involved in metabolism that helped the body better cope with famine, such as the gene IGF2, which codes for insulin growth factor. Inhibiting IGF2 expression made the children less responsive to the chemical signal of insulin, which regulates body sugar [4]. Insulin resistance causes the body to retain high levels of glucose: a good thing in a famine, but not in times of plenty.

Methylation increased because of the famine, but this methylation did not go away once the famine ended. Infants who were in gestation at the time of the famine were much more likely to develop metabolic conditions like diabetes, heart disease, and obesity as adults. The development of these conditions was due to higher levels of methylation in these infants than compared with their siblings who were not in utero during the famine. Methylation was not confined to one generation, either, but was passed on to their children, as the DNA of the ova present in infants who were in utero during the famine was also affected [3].

Methylation mechanism can potentially be manipulated medically. In 2013, Dr. Steve Horvath, a professor at the University of California, Los Angeles, developed an “epigenetic clock”. This clock was based on measurements of methylation levels at many sites across the genome that have been shown to change predictably with increasing age. Horvath determined the typical rate of methylation change that occurs with each chronological year and matched a person’s chronological age with a “methylation age”. Horvath’s research found that the rate of the epigenetic clock slows when people reach about twenty years old, and this rate can be affected by outside factors, such as observed in Dutch Famine research [5]. These findings opened the door to further exploration into the effects of methylation on lifespan.

cassandra 2Most recently, in September 2016, scientists at UCLA announced the results of an experiment that compiled epigenetic data from blood samples taken by sixty-five researchers from seven countries and ultimately yielded a dataset of DNA from thirteen thousand people. Employing Dr. Horvath’s epigenetic clock, UCLA researchers predicted subjects’ lifespans from their “methylation age”. Researchers discovered that different peoples’ epigenetic clocks tick at slightly different rates. In fact, this study indicated that people with a higher methylation age than average for their chronological age have an increased rate of aging; so, often a person who has been exposed to factors that increase the rate of the epigenetic clock has a higher internal biological age than chronological age [6]. This means that this person is likely to have a shorter lifespan than typically expected. Individuals truly do appear to “live by the clock”.

The findings of the UCLA research, though significant, are still in the preliminary stage of analysis and do not currently surpass other risk factors in predicting mortality [7]. These results prompt questions such as, “can the rate of methylation be decelerated to slow down aging” to be asked. After studying historical evidence, such as the Dutch Famine, the next step to getting answers is studying the biological clocks of animals. Scientists hope that with more research and an increased understanding of the process of methylation, humans will be able to actively control the ticking of their own clocks.

References:

  1. “Gene Expression and Regulation,” University of Leicester. http://www2.le.ac.uk/departments/genetics/vgec/schoolscolleges/topics/geneexpression-regulation.
  2. Newman, Tim. “Epigenetics: The keeper of the code”. Medical News Today (August 2016).
  3. Roseboom, Tessa, et al. “Hungry in the womb: What are the consequences? Lessons from the Dutch famine” in Maturitas 70, issue 2: 141-145.
  4. “IGF2 gene,” U.S. National Library of Medicine. https://ghr.nlm.nih.gov/gene/IGF2 .
  5. Schmidt, Elaine. “UCLA scientist uncovers biological clock able to measure age of most human tissues”. UCLA Newsroom (October 2013).
  6. Chen, Brian, et al. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging 8, issue 9: 1844-1865.
  7. Newman, Tim. “Epigenetic clock can calculate biological age, predict lifespan”. Medical News Today (September 2016).

Image References:

  1. Benayoun, Berenice, et al. “Epigenetic regulation of ageing: linking environmental inputs to genomic stability”. Nature Reviews: Molecular Cell Biology 16 (October 2015).
  2. Brock, Christopher. “DNA Methylation”. Max Planck Institute for Informatics (February 2006).

Cassandra White is a first-year member of the Triple Helix at the George Washington University. She is a freshman who will be graduating in 2020 with a BS in Biological Sciences and a minor in Public Health.

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