• Mackenzie Cullip

Epigenetics 101


WHAT IS EPIGENETICS?

Written By: Mackenzie Cullip


Your genes and the proteins they instruct make you, you. Genetic expression is strongly impacted by your parents, yet there are also other non-genetic factors that can influence which genes are turned on or off throughout our lifetime. Epigenetics is the study of how and why we inherit and exhibit certain traits other than through genetic (DNA related) mechanisms [1]. AgeRate uses epigenetics to determine why your genes are on or off and what that means for your health and biological age.


What is DNA?

Our bodies have different systems made from trillions of small components called cells. Almost all types of cells have a special molecule called DNA, which acts as the blueprint for gene expression. DNA has the information to tell the cell what to do. It does not change and is passed down from parents, creating an individual’s characteristics. All of the cells in our body have the same set of genetic instructions yet how does a liver cell become a liver cell and not a blood cell or a skin cell? In order to create this incredible cellular diversity, genes in the DNA are expressed differently between cells. When a gene is expressed it creates a protein, the functional or structural component of the cell.


Epigenetic Modifications vs. Genes

Genes are inherited from your parents and provide our cells the instructions for what proteins can be created. Not far past conception, genes are permanently established and cannot be altered unless a mutation occurs, which would only happen in certain cells [2]. However, genes must be read (expressed) in order to create a given protein. Epigenetic modifications determine which genes are being read by our cells. Genes are turned on or off by epigenetic modifications, which are constantly influenced by environmental and behavioural determinants, such as alcohol intake, stress levels, sleep quality, exercise routines, and diet. These epigenetic modifications act as dimmer switches that alter genetic expression, increasing or decreasing your biological age.


Genetic Testing vs Epigenetic Testing

Genetic testing is commonly used to determine the genetic sequence of an individual. Understanding the genetic sequence of an individual allows both researchers and consumers to unlock a variety of insights such as someone's predisposition towards disease and their ancestry. Epigenetic testing is an emerging approach to identify how lifestyle and environmental conditions are affecting the expression of genes. The results of an epigenetic test will change as opposed to genetic testing where the results will never change. This information can then be used to advise changes in diet, physical activity, and behaviour to delay ageing. AgeRate is one of the first companies to offer direct-to-consumer epigenetic testing, which will enable users to make more informed choices about their health and measure what lifestyle choices and health conditions are affecting their lifespan.


Epigenetics Timeline

1940’s - Conrad Waddington coins the term “epigenetics” as the mechanisms that affect development and are influenced by the environment

1953 - Wilkins, Franklin, Watson and Crick determine the structure of DNA

1975 - Riggs, Holliday and Pugh suggest DNA methylation as an epigenetic mark

1990 - Human Genome Project begins and begins the movement towards open access data, allowing for the analysis of publicly available methylation data sets

1994 - Robin Holliday redefines epigenetics as changes in gene function that do not involve changing the DNA sequence

2013 - Steve Horvath develops the first epigenetic ageing clock using DNA methylation

2018 - Cole Kirschner and Nathan Cawte develop the first cost-effective and powerful biological age prediction method, leading to the creation of AgeRate


What is DNA Methylation?

DNA methylation is the addition of a methyl group onto a specific site in DNA and represents one type of epigenetic modification. Methylation is a controller of gene expression, which can turn genes on or off, producing cell-specific proteins. The exciting part about DNA methylation is that it can change with the environment. Acting like a journal, DNA methylation keeps track of actions that individuals take. For example, if an individual is a smoker, different DNA methylation markers will be presented compared to non-smokers. DNA Methylation changes can account for ageing, alcohol intake, stress levels, sleep quality, exercise routines, and diets. With all the cumulative change in the methylome due to lifestyle factors and innate ageing processes, it is possible to use the phenomenon as a tool for health measurements.


Where does DNA methylation occur?

DNA is made up of four molecular letters called nucleotides, including adenine, glycine, cytosine, and guanine, that instruct cell mechanisms depending on their sequence. The non-genetic factors used in epigenetics are specific sequences within a piece of DNA, namely CpG dinucleotides [3]. These occur when guanine follows a cytosine in the chain of nucleotides. There are 28 million CpG dinucleotides within all of our genetic material, and millions of them can be methylated to help us determine biological age [3].


What is biological age?

We have heard it all before, age is just a number, but is it really? We all have two types of age, chronological age, which is the difference between the day at which a person is born to the current date. The second type of age is biological age, which is the age that someone’s body physically and physiologically represents. Biological age is a predictor of the functional capability of someone and their body. How well someone’s body is ageing can be determined by several biomarkers and AgeRate uses the best, DNA methylation [4].


Why use DNA methylation to determine biological age?

Biological age can be calculated with several methods. If the biomarker satisfies the following criteria presented from the American Federation for Aging Research: (#1) the marker must predict the ageing rate, (#2) the marker observes the nature of the ageing process, (#3) the marker is not from disease(s) caused by aging (#4) the test is harmless and repeatable, (#5) the test can work in humans and animals [5].

Six types of biomarkers can currently satisfy these conditions: DNA methylation, telomere length, transcriptomic-based, proteomic-based, and metabolomic-based estimators as well as composite biomarkers. A recent study concluded that the DNA methylation clock is the most promising estimator of biological age, given its astonishing accuracy and capability [4].


DNA methylation vs. telomere length

Telomeres are caps at the ends of DNA that protect our genetic material. As we age and cells divide, telomeres can become shorter or even lead to cell death [5]. However, telomere length can be unreliable and inaccurate when predicting biological age because the length is difficult to quantify in the lab, as shown in figure 2. Compared to extremely variant telomere length, DNA methylation is a stable marker that is relatively binary, meaning the CpG leans towards being methylated or not. From this tighter range, we can leverage slight changes to more accurately predict biological age [6]. The relationship between telomere length and age is much weaker than the one defined with DNA methylation technology, as used by AgeRate.


DNA methylation vs. histone modification

Histones are proteins in our cells that help package DNA before it can initiate the formation of other proteins. It is not well understood how histones might drive ageing, but histone levels and the rate of histone synthesis is much lower in older people [5]. Certain histones have been identified, however, current approaches only work with single tissue types and yield partial information about biological age [7]. Additionally, only 16 histone modifications that affect lifespan have been identified, compared to the millions of CpG sites analyzed during DNA methylation [8]. The DNA methylation clock is a more reliable option and it consistently works with any tissue, cell, or organ at any stage in life [3].


How does DNA methylation tell us about biological age?

Multiple studies show DNA methylation (DNAm) is a tried and true indicator of ageing [3], [9], [10], [11]. Certain combinations of DNA methylation markers can represent different age populations. These methylation profiles are accumulated from environmental impact and innate age-related changes. This is how AgeRate calculates the biological age. The investigation that DNA methylation differs across a group of individuals of the same chronological age can help determine the impact of stress factors on actual biological ageing. Most importantly, these DNA methylation markers are reversible, so biological age predictors have the potential to spark true anti-ageing interventions [12].


How can you alter your biological age?

Multiple lifestyle factors that can be changed are associated with biological age. From self-reported data, individuals that exercise regularly have a lower biological age compared to participants that are inactive. Higher BMI and blood pressure are associated with age acceleration. Choosing to have a healthier diet, consisting of whole grains, fish and omega 3, and fruits and vegetables also on average results in lower biological ages [13]. Having higher blood-based biomarkers like insulin and glucose, c-reactive protein, and triglycerides are related to accelerated ageing [13]. These biomarkers can all be reduced with regular exercise, a healthy diet and beneficial lifestyle habits (non-smoking) [14], [15], [16].

Accelerated biological age is also associated with the information in table 1. Making healthier decisions can make you biologically younger. Together, AgeRate and our enthusiastic clients can discover new anti-ageing therapies and achieve optimal ageing.


Sources

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S. Song and F. Johnson, “Epigenetic Mechanisms Impacting Aging: A Focus on Histone Levels and Telomeres,” Genes, vol. 9, no. 4, pp. 203–204, Apr. 2018.

[2]

“What is a gene mutation and how do mutations occur? - Genetics Home Reference - NIH,” U.S. National Library of Medicine, 16-Jul-2019. [Online]. Available: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutation. [Accessed: 23-Jul-2019].

[3]

Steve Horvath, Kenneth Raj , "DNA methylation-based biomarkers and the epigenetic clock theory of ageing," Nature Reviews Genetics, pp. 371-384, 2018.

[4]

Juulia Jylhävä, Nancy L. Pedersen, and Sara Hägg, "Biological Age Predictors," EBioMedicine, no. 10.1016/j.ebiom.2017.03.046, pp. 29-36, 2017.

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Xia X, Chen W, McDermott J, Han JJ, "Molecular and phenotypic biomarkers of aging.," F1000Res. , no. doi:10.12688/f1000research.10692.1, 2017;6:860.

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D. Molina-Serrano, D. Kyriakou, and A. Kirmizis, “Histone Modifications as an Intersection Between Diet and Longevity,” Frontiers in Genetics, vol. 10, Mar. 2019.

[9]

Hernandez DG, Nalls MA, Gibbs JR, et al. , "Distinct DNA methylation changes highly correlated with chronological age in the human brain.," Hum Mol Genet., p. 1164–1172. , 2011;20(6).

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Christensen BC, Houseman EA, Marsit CJ, et al. , "Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context.," PLoS Genet. , vol. doi:10.1371/journal.pgen.1000602, p. 5(8):e1000602. , 2009.

[12]

Steve Horvath, "DNA methylation age of human tissues and cell types," Genome Biol, no. doi:10.1186/gb-2013-14-10-r115, p. 14(10):R115. , 2013;.

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Quach A, Levine ME, Tanaka T, et al., "Epigenetic clock analysis of diet, exercise, education, and lifestyle factors.," Aging (Albany NY). , no. doi:10.18632/aging.101168, p. 9(2):419–446, 2016.

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R. Link, "13 Simple Ways to Lower Your Triglycerides," Mayo Clinic, 9 March 2017. [Online]. Available: https://www.healthline.com/nutrition/13-ways-to-lower-triglycerides.

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M. R. Arlene Semeco, "15 Easy Ways to Lower Blood Sugar Levels Naturally," Health line, 3 May 2016. [Online]. Available: https://www.healthline.com/nutrition/15-ways-to-lower-blood-sugar.

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P. M. Ridker, "C-Reactive Protein, Inflammation, and Cardiovascular Disease," Texas Heart Institute Journal, vol. 32, no. 2, pp. 384-386, 2005.

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