DNA and Its Role In Aging

Aging is a process that we all go through. From the wrinkles appearing on our faces, to the onset of diseases like dementia, everyone goes through some level of aging, severe or not. However, have you ever stopped and wondered: What is aging? Why do we go through this? Is it that bad?

Aging is caused by the accumulation of senescent (zombie) cells that damage your organs and internal systems [1]. This induces changes in your cells, such as oxidation, which is basically a reaction that makes an apple turn brown. Molecules called free radicals, which contain an unpaired valence electron on their overarching shell, react with stable molecules in a propagation mechanism, which results in the formation of new and potentially even more unstable free radicals [2]. This is like a game of tag!

Another common change associated with aging is in your DNA. Your DNA, otherwise known as the tongue-twister deoxyribonucleic acid, is what makes up you [3]. It is all of the information in the code that decides your hair color, your type of skin, and even your gender. Your DNA can actually contribute to aging, depending on your lifestyle through concepts such as telomeres, your epigenetic alterations, and DNA degradation. Today, this article will go over different forms of DNAging, why aging is so important, and current research being done.

Telomeres

When your cells divide, they copy your DNA from chromosome (unit of DNA) to chromosome, to be placed into the daughter cell. Unfortunately, during this process, a potentially fatal error occurs. A little bit of the DNA is cut off from the ends of each chromosome. This is primarily  an error, but it occurs very often - every time, in fact.

This is because of the nature of DNA replication. When your double-stranded DNA replicates itself, one strand, dubbed ‘the leading strand’, uses continuous replication. This is because DNA synthesis itself goes from 5’ to 3’, but DNA is read 3’ to 5’. This numbering refers to the polar ends of DNA, which is controlled by the position of carbon atoms in the deoxyribose sugar molecule. DNA must grow and elongate from 5’ to 3’ but is read from 3’ to 5’. This means that it uses one primer - a short single-stranded nucleic acid sequence that provides a starting point for DNA synthesis - to replicate the whole strand. However, the other ‘lagging strand’ uses discontinuous replication, where, due to opposing polarity to the leading strand, it needs to replicate the strands in parts dubbed ‘Okazaki fragments’ [4]. These are short sequences of DNA nucleotides that are later linked up together using the enzyme DNA ligase. To replicate in this way the lagging strand uses multiple RNA primers, while the leading strand only requires one. These need to be eliminated after replication to avoid RNA-DNA duplexes, which are the links between the RNA and DNA (Fig. 1). These aren’t necessary or good for DNA strands.

Figure 1: DNA Replication via the lagging strand. The enzymes and molecules responsible for this have been labelled and shown, and the directions of replication have been shown. Image reproduced from Ref [5].

The problem is, when the RNA primers are eliminated, the enzymes - called DNA polymerase - that fill the gaps don't have an initiator to add more nucleotides, so the leading strand gets slightly longer every time, and the lagging strand gets shorter. So, this shorter end would cut off a bit of DNA. We don’t want to lose this DNA information, so we have pieces of redundant DNA information at the ends of our chromosomes called telomeres. They are almost like “caps on our chromosomes”, and a little piece comes off every single time our cells divide. When telomeres get shorter on the lagging strand, the enzyme telomerase is able to elongate them! After around 50-70 cell divisions, they disappear, and the cells go into a state called senescence [6].

Telomerase has a lot of potential in cancer therapy, as cancer cells express high levels of the enzyme, which infinitely lengthens its telomeres. On these grounds, it can be a target for cancer therapy. 

Interestingly, this enzyme is also a target for aging, as telomeres need to disappear for the cells to turn senescent, meaning they go rogue and release harmful molecules into your body [7]. They are theorised to contribute to many aging-related diseases, such as dementia, Parkinson’s and different cardiovascular diseases [8]. However, they do come with some advantages : they can help speed up the healing of a wound and prevent cells from becoming cancerous [9, 10]. If you express more of the telomerase enzyme, you can prevent cells from becoming senescent by lengthening their telomeres. Overall, cellular senescence is like a zombie apocalypse happening inside your body. 

There is a disease called Hutchinson-Gilford progeria, which results in premature aging; it affects less than 1000 people in the US per year. There is evidence that telomeres are stunted by the mutation of a certain protein, progerin, in the cell [20]. The telomeres of affected skin cells are much shorter than many controls, and telomerase seems to increase the diseased cells’ proliferation [20]!

The Epigenome

Imagine you’re going shopping at your favourite mall. A new clothing store just opened up called “Your Genome.” - trendy and cool, right? Naturally, that is the first store you checked out. However, it’s a bit weird: you’re the only one in there, and you are given an unlimited budget, with a few minor strings attached. You need to pick, using tags, which clothes should be stored in the back, and which you want to wear. So, you pick that pink top you like and the yellow bottoms. You tag away everything else.

Now, let’s translate this into genes. Some genes are stored away, wrapped around proteins called histones, and some are out in the open. This decides whether or not a gene is expressed. These are determined by different chemical tags, and are decided by your environment and your cells [11].

That’s pretty cool, right? It affects aging through its alterations. Alterations via the environment can affect your gene expression, which in turn can affect your aging process. Some genes are more beneficial, and some less, which can affect your aging phenotype.

Now, you may wonder: is there anything else? How does everything mentioned above contribute to DNA in aging? Of course, this article will answer these questions!

How Our DNA Degrades

Our DNA goes through a complicated degrading process. It is caused by many damaging factors and, technically, can be avoided. A few of these factors are pH, temperature, and UV radiation.

pH is the measure of the acidity/basicity of a particular liquid [12]. If a pH in a certain environment is high, the environment is basic; if it’s low, it is acidic. Some organisms can only survive in a particular pH, so when it is altered, it deteriorates . DNA is one of those things: it degrades when the pH gets too basic [13].

Temperature is the measure of the thermal energy of an environment, an object, or really any noun. In high temperatures, our body’s elements tend to not do well as it promotes the breaking down and deteriorating of said elements. An example is enzymes, which “denature” at high temperatures [14]. DNA is similar to a lower extent [15].

Last of all, there is UV radiation, caused by UV light. This is emitted in your doctor’s and dentist’s offices, by the sun, and in many, many other places. It is super effective for killing bacteria and disinfecting, but not so much for your overall health. It tends to promote skin cancer, as it causes damage in DNA because of said radiation [16]. DNA degradation is caused by all of the aforementioned factors, and greatly contributes to our aging process!

Why This is So Bad

DNA is what gives us life (other than all of our organs and brain matter). It powers us, and is  the code that defines us. So, when that code gets damaged, your gene expression, and the quality of the aforementioned gene expression gets out of whack.

When mutations occur because of temperature, pH, or radiation in a gene, genes degrade, swap letters, and aren’t objectively good enough to be translated. When they are translated, the expression is off due to epigenetic alterations, and only part of the genes are expressed. This leads to unusual exhibiting of the phenotype associated with the genes at hand, and damages your body, furthering aging.

What Current Research is Being Done?

There is a lot of research being conducted in many different areas surrounding DNA and senescent cells. For instance, inventions regarding telomeres have been made, with one of the most noteworthy contributions being the increased expression of telomerase, a telomere-lengthening enzyme [17]. Companies are using this to create new innovations in aging biology, and it is turning out to be very successful.

One of the most notable areas of research is epigenetic reprogramming, which enables you to reset the epigenome. The Sinclair lab recently published a study on mice where they reprogrammed an eye successfully [18]. This is now nearing clinical trials!

DNA damage is also being studied: there is a company named Artios that is focusing on DNA damage response (DDR), as cells that disobey the aforementioned response use alternative pathways. When they do, there is a polymerase theta enzyme that can inhibit those pathways! They are bringing this to production [19].

Conclusion

Overall, there are many areas of DNA damage, including telomeres, epigenetics, and DNA degradation. There is promising research in this area, and it looks very exciting and especially hopeful for aging. If you learned something, be sure to comment or submit to Youth STEM Matters with your very own article!

References

[1] Anon (May, 2019). “Aging changes in organs, tissues, and cells”. Mediline plus [Online]. Available: https://medlineplus.gov/ency/article/004012.htm. [Accessed: 12-Jul-2020].

[2] V. Lobo, A. Patil, A. Phatak, N. Chandra, “Free radicals, antioxidants and functional foods: Impact on human health,”. Pharmacognosy Reviews, vol. 4, no. 8, pp. 118, 2010.

[3] Anon (July, 2020) What is DNA? - Genetics Home Reference - NIH,” U.S. National Library of Medicine. [Online]. Available: https://ghr.nlm.nih.gov/primer/basics/dna. [Accessed: 12-Jul-2020].

[4] R. Bailey (October, 2019) “Steps of DNA Replication,” ThoughtCo. [Online]. Available: https://www.thoughtco.com/dna-replication-3981005. [Accessed: 12-Jul-2020]

[5] Vedran, “DNA Replication,” DNA Replication | Free SVG. [Online]. Available: https://freesvg.org/dna-replication. [Accessed: 19-Jul-2020].

[6] Anon. “What is a Telomere?: Human Cellular Aging: TA-65 TA Sciences,” T.A. Sciences®. [Online]. Available: https://www.tasciences.com/what-is-a-telomere.html. [Accessed: 12-Jul-2020].

[7] J.-P. Coppé, P.-Y. Desprez, A. Krtolica, and J. Campisi, “The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression,” Annual Review of Pathology: Mechanisms of Disease, vol. 5, no. 1, pp. 99–118, 2010.

[8] D. Mchugh and J. Gil, “Senescence and aging: Causes, consequences, and therapeutic avenues,” Journal of Cell Biology, vol. 217, no.1, pp. 65–77, 2017.

[9] M. Demaria, N. Ohtani, S. A. Youssef, F. Rodier, W. Toussaint, J. R. Mitchell, et al., “An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA,” Developmental Cell, vol. 31, no. 6, pp. 722–733, 2014.

[10] S. Lee and C. A. Schmitt, “The dynamic nature of senescence in cancer,” Nature Cell Biology, vol. 21, no. 1, pp. 94–101, 2019.

[11] D. Simmons (2018), “Epigenetic Influences and Disease,” Nature News. [Online]. Available: https://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895/. [Accessed: 12-Jul-2020].

[12] Anon. “pH and Water”. USGS [Online]. Available: https://www.usgs.gov/special-topic/water-science-school/science/ph-and-water?qt-science_center_objects=0. [Accessed: 12-Jul-2020].

[13] Anon (2017). “Does the pH influence the stability of double stranded DNA,” Biosynthesis [Online]. Available: https://www.biosyn.com/faq/Does-the-pH-influence-the-stability-of-double-stranded-DNA.aspx. [Accessed: 12-Jul-2020].

[14] R. M. Daniel, M. Dines, and H. H. Petach, “The denaturation and degradation of stable enzymes at high temperatures,” Biochemical Journal, vol. 317, no. 1, pp. 1–11, 1996.

[15] M. Karni, D. Zidon, P. Polak, Z. Zalevsky, and O. Shefi, “Thermal Degradation of DNA,” DNA and Cell Biology, vol. 32, no. 6, pp. 298–301, 2013.

[16] H. Jacobe, A. Chien (2019). “UV Radiation,” The Skin Cancer Foundation. [Online]. Available: https://www.skincancer.org/risk-factors/uv-radiation/. [Accessed: 12-Jul-2020].

[17] S.R.W.L. Chan and E.H. Blackburn, “Telomeres and telomerase,” Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, vol. 359, no. 1441, pp. 109–122, 2004.

[18] Y. Lu, A. Krishnan, B. Brommer, X. Tian, M. Meer, D. L. Vera, et al., “Reversal of ageing and injury-induced vision loss by Tet-dependent epigenetic reprogramming,” bioRxiv, 2019.

[19] Anon. “Artios Pharma,” Crunchbase. [Online]. Available: https://www.crunchbase.com/organization/artios-pharma. [Accessed: 12-Jul-2020].

[20] O. Dreesen and C. L. Stewart, “Accelerated aging syndromes, are they relevant to normal human aging?,” Aging, vol. 3, no. 9, pp. 889–895, 2011.