Aging-Related Diseases: Technologies That Are Changing the Game

Imagine forgetting everything you’ve ever known. Your family, your friends, your talents, and even you as a person. Imagine forgetting how to eat, and having your neurons, otherwise known as brain cells, die off cell by cell. That’s frightening, right? Unfortunately, this happens to 50 million people all around the world, in a group of diseases called dementia.

Dementia is the term for a group of neurodegenerative diseases which cause patients to forget, due to the killing of neurons, which store their memories [1]. Patients may forget everything around them, go through behavioural changes, and lose a lot that is dear to them.

So, why does this happen? There are a few causes, one of them being lifestyle choices/habits, such as not getting enough sleep. Another cause is aging. As you age, you go through many processes that lead to aging-related diseases. 

These processes include your cells aging, changes in your genetic landscape, which controls a lot about you, and fluctuations in the bacteria in your body [2]. These are all factors which contribute to aging, and which make you you.

I explored these processes in my previous article for Youth STEM Matters, “DNA and Its Role In Aging”, so check it out if you want to know about them in more depth [3]. This article however will focus on the current landscape of aging research, with overviews of amazing and promising technologies, and my company, Biotein.

Currently, there are many avenues being explored in aging research. I surely won’t be able to cover all of them, but I can definitely cover a few important and cool ones. However, if you’re interested, I’d recommend reading Laura Deming’s Longevity FAQ [4]. They include telomere extension research, epigenetic rejuvenation, and senolytics. Let’s get into this, bit by bit.

Telomere Extension Research

As our cells grow old, they divide many times, until they enter a zombie-like state. This is generally the process of senescence, after which cells release harmful factors into our body, and further aging-related diseases. When our cells divide, they copy their DNA, or genetic code, from chromosome to chromosome.

There is a tiny error in this process, which causes a bit of DNA to be cut off at the ends of the chromosomes. Luckily, our body has a protective measure so as to not lose valuable DNA information.

Telomeres are situated at the ends of our chromosomes, and unlike our real valuable DNA information, they are cut off [5]. They’re typically considered as repetitive bits of DNA information, and are like the chromosome equivalent to aglets at the ends of your shoelaces!

If we are able to extend these telomeres, we can consequently  extend the number of divisions it takes until our cells become senescent and more prone to ageing-related diseases. Right now the limit, known as the Hayflick limit, is around 50-70 divisions; using different mechanisms, we can potentially extend it to 100 or more!

One such mechanism is telomerase. This is an enzyme that naturally extends telomeres, and is actually a driving factor of cancer [6]. When your cells won’t stop dividing due to extended telomeres, this uncontrolled cell division actually leads to cancerous tissue. If we are able to express telomerase more, we will be able to prevent cells from becoming senescent sooner [7].

Epigenetic Rejuvenation

Speaking of expression, the next topic is epigenetics! Imagine you’re going shopping at your favorite 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.

Your pink top and yellow bottoms will be worn by an excited shopper (you)! Relating this back to your genetics, your pink top and yellow bottoms (or maybe your genes for 2 protein products) will be expressed and transcribed by your cells.

Some genes are stored away, and some are out in the open. Using chemical tags, genes arrange themselves to either have the ability to be expressed, or be hidden away [8]. This changes due to age, and environmental factors, which also affect many other aging problems.

If we are able to manipulate this system, and express some more desirable genes more, and some more problematic genes less, that would be amazing, right? Or, even better, if we’re able to reset all the damage and age-related change this epigenome has gone through, that would be fantastic.

The latter has actually been done! The Sinclair lab in Harvard University reversed the aging and injury-related damage in an eye, using delivery of chemicals that could reset the epigenome [9]. That is so cool! That means, in a few years, we might be going for a checkup to reset aging using just 1 or 2 chemicals!

Senolytics

Another very cool field is senolytics. The earlier problem of senescent cells has many solutions. There is telomere extension, which is a really important and amazing field of research. However, there are also senescent drugs, and pharmaceuticals that target senescent cells.

The main type of drug being researched is senolytics. These are small molecules which, when administered, eradicate senescent cells from the body. Many drugs are currently being researched for this purpose, for example, Fisetin (a molecule from strawberries), and the duo Quercetin + Dasatinib [10, 11]. So watch out everyone, strawberries might actually be healthier than you thought!

These are showing promising and rejuvenating results, however, these are actually not completely validated. Right now, they are validated with clinical analysis, meaning that they are validated using questions like “Do you feel better?” or “Are you feeling less tired?”, which aren’t super quantitative or exact. Better tests are being developed right now, one of which is being conceived at Biotein! 

My Work With Biotein

At Biotein, we are a pretty multifaceted company working on some cool stuff. Curing aging-related and neurodegenerative diseases is a passion of both of us co-founders, so we are working hard on that. Our projects include one which has a focus on cellular senescence, and another which has a focus on developing a pipeline to cure brain aging. This article will focus on the former, as the latter is still on the down low :).

Right now, senescent cells do not have a universal biomarker that is deemed suitable by scientists. In relation to senescence, a biomarker would be a small molecule which can reliably be used to assess the abundance of senescent cells in a particular sample of human tissue. There is no reliable senescence biomarker currently, as all proposed ones have been debunked in some way or another [13]. 

Part of the reason for this is because there are many different types of senescent cells. Senescence is a cell state that can happen to almost any cell within the body, and they all display it in different ways. There is no way to target all of them at the moment, but that’s what Biotein wants to create.

We are analysing images of senescent versus non-senescent cellular mitochondria. The mitochondria, as you might know from all the memes out there, is the powerhouse and the feeder of the cell. If its numbers decline, the cell won’t produce enough energy to survive. As you may expect, it severely declines during senescence. We studied that.

We used many image analysis softwares and algorithms, including artificial neural networks, image software analysis, and Principal Component Analysis. Overall, all of these components combine to create many features that we have identified and are excited to present soon. If you want to hear more about what we’re doing, sign up for our newsletter, via our website: https://bioteinresearch.ca/.

References

[1] M. MacGill (Dec 2017). “Dementia: Symptoms, Treatments, And Causes”, MedicalNewsToday, [Online]. Available: https://www.medicalnewstoday.com/articles/142214. [Accessed 11 August 2020].

[2] S. Liochev, “Which Is the Most Significant Cause of Aging?,” Antioxidants, vol. 4, no. 4, pp/ 793-810, 2015. 

[3] N. Khera, (2020). “DNA And Its Role In Aging,” Youth Stem Matters, [Online]. Available: https://www.youthstem2030.org/youth-stem-matters/read/dna-and-its-role-in-aging. [Accessed 11 August 2020].

[4] L. Deming, “Longevity FAQ: A beginner’s guide to longevity research,” Laura Deming, [Online]. Available: https://www.ldeming.com/longevityfaq. [Accessed 11 August 2020].

[5] A. Bernadotte, V. M. Mikhelson, and I. M. Spivak, “Markers of cellular senescence. Telomere shortening as a marker of cellular senescence,” Aging, vol. 8, no. 1, pp. 3–11, 2016, doi: 10.18632/aging.100871.

[6] M. A. Jafri, S. A. Ansari, M. H. Alqahtani, and J. W. Shay, “Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies,” Genome Med, vol. 8, no. 1, p. 69, 2016, doi: 10.1186/s13073-016-0324-x.

[7] M. Shawi and C. Autexier, “Telomerase, senescence and ageing,” Mechanisms of Ageing and Development, vol. 129, no. 1–2, pp. 3–10, 2008, doi: 10.1016/j.mad.2007.11.007.

[8] W. Zhang, J. Qu, G.-H. Liu, and J. C. I. Belmonte, “The ageing epigenome and its rejuvenation,” Nat Rev Mol Cell Biol, vol. 21, no. 3, pp. 137–150, 2020, doi: 10.1038/s41580-019-0204-5.

[9] 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,” Cold Spring Harbor Laboratory, Jul. 31, 2019, doi: 10.1101/710210.

[10] M. J. Yousefzadeh, Y. Zhu, S. J. McGowan, L. Agnelini, M. Xu, Y. Y. Ling, et al., “Fisetin is a senotherapeutic that extends health and lifespan,” EBioMedicine, vol. 36, pp. 18–28, Oct. 2018, doi: 10.1016/j.ebiom.2018.09.015.

[11] L. J. Hickson, L. G. Prata, S. A. Bobart, T. K. Evans, N. Giorgazde, S. K. Hashmi, et al., “Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease,” EBioMedicine, vol. 47, pp. 446–456, Sep. 2019, doi: 10.1016/j.ebiom.2019.08.069.

[12] A. Hernandez-Segura, T. V. de Jong, S. Melov, V. Guryev, J. Campisi, and M. Demaria, “Unmasking Transcriptional Heterogeneity in Senescent Cells,” Current Biology, vol. 27, no. 17, pp. 2652-2660, 2017, doi: 10.1016/j.cub.2017.07.033.