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4. Epigenetic Alterations

4.1

Background

All the cells in the human body (apart from red blood cells) contain the entire genome of the individual in question. In other words, each cell holds the entirety of the DNA or blueprint for creating the whole body and all of its constituent parts. However, not every cell needs to use all of that information. A skin cell does not need digestive enzymes, and a muscle cell has no use for making bone. Each cell type only needs access to some of its genes. Even then, it might only need a certain gene at a certain time or in certain amounts.  

This is why our cells have a sort of genetic control system. This system is called epigenetics, meaning “on top of” genetics. It consists of various chemical changes to the DNA or the surrounding proteins that can be used to turn genes on or off with various amounts of strength.  

One such control function is a process known as DNA methylation, a simple (and reversible) chemical modification. It converts cytosine,[66] one of the four bases that make up our DNA, into 5-methylcytosine. This modification is used to prevent the expression of genes (to turn them off).[67] The more cytosine methylation occurs in an area of the gene called the promoter, the lower the likelihood that the gene will be used.[68]

Methylation of cytosine as an example for epigenetic modification of DNA
Epigenetic modifications represent a level of molecular information on top (“epi”) of the information encoded in the genetic code itself. A very frequent epigenetic modification at the level of the DNA is the enzymatically driven methylation of cytosine leading to 5-Methyl-cytosine. Methylation mostly leads to the inactivation of genes, gene silencing. Methylation can be changed by environmental and life-style influences and can also be restored. Epigenetic modifications at the level of chromatin modulate the accessibility for transcription factors and can thereby define which genes in a cell are transcribed.

This phenomenon has been shown to play an unexpectedly large role in the aging process. In 2013, Steve Horvath of the University of California published a paper on what he dubbed the “epigenetic clock”.[69] To understand what it is and how it works, we need to look at how DNA methylation changes during our development. That it does so is not surprising. Our early cells have to differentiate into the many specialized cell types of the body, and as we grow, the tasks of those cells continuously change. Thus, the cells must occasionally turn some genes on or off.

However, Horvath found that DNA methylation patterns keep changing even after we finish growing. At one time, this was thought to be a random process that occurred as our cells lost control,[70] just as many other abilities are weakened with age. But in his research on the epigenetic clock, Horvath found a very clear pattern in the changes[71] that progresses predictably during development and continues until death. Using advanced statistics, Horvath essentially created a biological clock using the DNA methylation changes in 513 areas. While the matter is a complex one, his discovery, in a nutshell, was that as the DNA methylation patterns (where and how much) change predictably throughout our lives, a couple of cells and some statistics can determine how old we are at the biological level. Thus, if we compare two twins, the one who is ‘older’ in epigenetic terms will most likely die first.[72] The two may be equally old in terms of calendar years, but in biological terms, they are not.

The epigenetic clock presents enormous opportunities for the field of anti-aging treatments. Scientists can use it to study the aging process itself. For instance, women live longer than men and also have lower epigenetic ages than men with the same birth date (on average).[73] And semi-supercentenarians (105-109 years) are younger biologically than expected,[74] which may help to explain their longevity.

Visualization of the biological and chronological age
Source: Supertrends

The clock can also be used to evaluate life extension therapies. If we imagine a scenario where a new drug is developed to slow down aging, which has proven efficient in lab environments and in testing on short-lived animals, the next step would be a clinical trial on humans. The challenge here is that if the drug is tested on humans, it might take decades before one could compare its effects on longevity against the control group. If the trial was designed to involve only very old people, it might not have enough time to take effect, or the effect might be too small to measure.  

To circumvent this problem, scientists often use other markers than death. In our example, they could study biological changes known to correlate with aging, such as changes in telomere length. However, this approach has problems of its own, since most biological changes that occur with age – such as greying of hair – are not sufficiently correlated to the aging process to be useful. With the epigenetic clock, though, the correlation is strong enough to use.[75] Changes in epigenetic age can be used to evaluate life extension therapies by measuring the epigenetic age of the treatment group against that of a control group before, during, and after the drug is administered. If the drug works, epigenetic aging is expected to proceed at a slower rate.

Whether DNA methylation patterns merely track aging or actually play a causal role is not yet known. Other types of epigenetic changes, such as histone deacetylation, are known to be causal in lab organisms,[76][77] and it is very suggestive that the age-associated changes affect inflammation, mitochondrial function, and lysosomal degradation, among other pathways.[78]

4.2

Challenges

The epigenetic clock might appear to be a great biomarker for aging, but it is uncertain whether it will work in every situation. Even if DNA methylation patterns closely track the aging process, there might be life extension therapies that work, but do not affect epigenetics. The effects of such therapies would not be detectible in terms of the epigenetic clock, and we should be careful about discarding them. If DNA methylation patterns play a causal role in aging, it raises many interesting questions: Why does the cell change its gene expression, if it seems to be detrimental? Can we do anything about it? More research is needed to answer these questions. 

4.3

Road to Success

The epigenetic clock has already been validated in many different cohorts and conditions. This should continue. It has been shown to be useful for monitoring aging across groups, but the question is whether it will be useful for indicating a clear and actionable age status for an individual person as well. 

Furthermore, scientists will have to make sure to include other biomarkers of aging in their studies to make sure we do not miss anything. Changing epigenetic changes one by one will not be feasible. We will have to find a central intervention to “turn back the clock”. 

4.4

Companies

Iduna Therapeutics[80]

Website http://www.lifebiosciences.com 

Industry Biotechnology 

Company size 51-200 employees 

Headquarters Boston, Massachusetts 

Type Privately Held 

Founded 2017 

Iduna Therapeutics is a life science company developing partial reprogramming therapies. This procedure partially resets the epigenetic clock. A number of prominent anti-aging experts are involved in the company, but it is still in its early stages. 

Epimorphy[81]

Website https://www.mydnage.com/ 

Phone (833)693-6243 

Industry Health, Wellness & Fitness 

Company size 2-10 employees 

Headquarters Costa Mesa, CA 

Type Privately Held 

Founded 2016 
Epimorphy offers direct-to-consumer DNA methylation testing. Just like at-home genetic tests have become popular in the 2010s, Epimorphy hopes to popularize epigenetic clock testing among consumers. The test can serve as an early warning sign or be used to track lifestyle changes. However, they have not yet been approved by the FDA.

4.5

References

[66] The others are adenine, guanine, and thymine.

[67] There are several exceptions to this rather simplified account.

[68] Zemach, A. et al. 2010. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 328(5980):916-9.

[69] Horvath, S. 2013. DNA methylation age of human tissues and cell types. Genome Biology 14(3156).

[70] Bahar. R. 2006. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441(7096):1011-4.

[71] Horvath 2013.

[72] Christiansen, L. et al. 2016. DNA methylation age is associated with mortality in a longitudinal Danish twin study. Aging Cell 15(1):149-54.

[73] Horvath, S. et al. 2016. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biology 17, article number: 171.

[74] Horvath, S. et al. 2015. Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging 7(12): 1159-70.

[75] Horvath, S. and K. Raj 2018. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics 19:371-84.

[76] Peleg, S. et al. 2020. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328(5986):1634.

[77] Krishnan, V. et al. 2011. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proceedings of the National Academy of Sciences of the USA 108(30):12325-30.

[78] De Magalhães, J.P. et al. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25(7):875-81.

[79] https://www.turn.bio/

[80] https://www.lifebiosciences.com/our-science

[81] https://www.mydnage.com/