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3. Stem Cell Exhaustion

3.1

Background

As the human body ages, it loses its regenerative ability. For instance, the ability to build up muscle tissue vastly decreases. The same is true for the process of hematopoiesis, by which the cells of the adaptive immune system are created.[50] For this reason, we become more susceptible to infections as we age.

One of the most important reasons for the decline in regenerative ability is the exhaustion of stem cells. Stem cells are special cells that can self-renew indefinitely due to their ability to express telomerase (cf. Section II.1). They are also less differentiated than other cells, meaning they are precursor cells that can later become different specialized cells. 

Visualization of different specialized cell developed from stem cells
Source: Supertrends

With age, the pool of stem cells can become exhausted.[51] This means the stem cells will be less active and thus proliferate less. At this stage, the cell replacement in our tissues slows down, and it becomes harder to replace old or damaged cells. This exhaustion may in fact be due to excessive proliferation earlier in life. For instance, in the fly Drosophila, excessive proliferation of intestinal stem cells leads to exhaustion and premature aging.[52]

Due to the ability of stem cells to regenerate tissue, or even create it from scratch, scientists have investigated their use for treating many different diseases. Historically, embryonic stem cells have been used extensively because they retain the possibility of becoming any other cell type. However, due to ethical and moral concerns, this type of research is controversial, which has slowed down funding.  

In 2012 the Japanese stem cell researcher Shinya Yamanaka was awarded the Nobel Prize for his discovery of a solution to this problem.[53] It had previously been believed that fully mature cells could never go back through development and become stem cell-like again. Yamanaka discovered that fully matured adult cells can, in fact, be reprogrammed to behave just like embryonic stem cells. In other words, a skin cell can regain the possibility of becoming any other cell type. All it takes is the addition of four genes[54] that have been dubbed the Yamanaka Factors. The new cells thus created are called induced pluripotent stem cells (iPSCs).

Stem Cell Therapy
Source: Supertrends

Interestingly, the Yamanaka Factors can also be used for rejuvenation in whole organisms. If all cells are allowed to become stem cells again, all our organs would lose their functionality and we would die. However, some scientists have had success with what is called partial reprogramming by inducing expression of the Yamanaka Factors in specially bred mice. When they activated these four factors for a brief period, the mice became healthier and ultimately lived longer.[55]

Embryonic stem cells or induced pluripotent stem cells (iPSCs) are the preferred option for scientists who want to rebuild entire organs. In Type 1 diabetes, for example, autoimmunity causes the patient to lose all their insulin-producing beta cells in the pancreas. Startups such as PanCryos[56] plans to use embryonic stem cells to create new beta cells to replace what is lost. Similar methods are being researched for many other diseases. Aspen Neuroscience aims to use iPSCs to create new dopaminergic neurons for Parkinson’s patients;[57] PolarityTE[58] is creating new skin for burn survivors; Organovo[59] is working on livers. There are too many other examples to mention, as several companies are working on each organ of the human body. This industry is huge, and exceeds the scope of this report. Nevertheless, it is encouraging for anti-aging researchers and industry observers to see that progress is being made in developing replacements for any damaged body part.

When creating whole tissues from scratch, it is preferable to use embryonic stem cells or iPSCs due to their strongly plastic natures. However, in anti-aging research, the goal is often simply to boost the regenerative ability of a tissue, not to replace it entirely. For this purpose, one can use adult stem cells. These are not pluripotent, meaning they cannot develop into any other cell type (like embryonic stem cells or iPSCs). Rather, they are multipotent cells, meaning they can develop into several related cell types. For example, mesenchymal stem cells can become bone cells (osteoblasts), cartilage cells (chondrocytes), muscle cells (myocytes), and fat cells (adipocytes). In quickly aged mice, transplantation of this kind of stem cell from young mice prolongs life.[60]

Microscope image of mesenchymal (stem) cells in embryonic connective tissue
Source: Getty Images

Obviously, the rejuvenation effect of such a treatment might be attributable to increased regenerative ability due to a replenished stem cell supply. However, factors secreted by the stem cells into the blood might also play a role.  

3.2

Challenges

Historically, stem cell research has been controversial. However, time and recent developments (such as the ability to create induced pluripotent stem cells (iPSCs)) have dampened the controversy.  

Now the biggest hurdles are scientific. Stem cell research is rather slow and very expensive, because a lot of time and resources are often required to care for and differentiate the cells. Going from an embryonic stem cell or an iPSC to a fully mature differentiated cell can easily take a month, during which the cells have to be cared for. This is the primary reason why stem cell research has not yet delivered on its promises.  

Another problem associated with embryonic stem cells is that because they are derived from an unborn fetus (not the patient themselves), they are immunogenic, i.e., the immune system might recognize them as foreign and attack. This problem can potentially be mitigated by using iPSCs. However, these might be immunogenic as well, and there are concerns that they could lead to increased cancer risk,[61] especially of the type called teratoma.[62]

These problems should be mostly avoided by using adult stem cells from the patients themselves. This is a much less comprehensive treatment and should be safer, though the risk of cancer formation cannot be ruled out. 

3.3

Road to Success

Stem cell research is a huge field of scientific study. Many potential treatments are currently in clinical trials, and stem cell-based treatments will undoubtedly emerge in the coming decade. Once successful treatments are on the market and can be studied, they will be very valuable for further research and development. However, many obstacles remain, and the science is complicated. For this reason, each treatment has only a low chance of success. 

3.4

Companies

AgeX Therapeutics[63]

Website http://www.agexinc.com/ 

Phone (510)671-8370 

Industry Biotechnology 

Company size 11-50 employees 

Headquarters Alameda, California 

Type Public Company 

Founded 2017 

AgeX Therapeutics was founded in 2017 by Geron founder Michael West. Until 2020, SENS founder Aubrey de Grey served as the company's Vice President of New Technology Discovery, giving it a solid foundation in the anti-aging field. AgeX mainly focuses on stem cell-based anti-aging treatments and is developing several products. First, the company has developed a method to generate populations of multipotent stem cells named PureStem. The first use for this will be the generation of brown fat cells for the treatment of Type 2 diabetes and generation of vascular endothelial progenitors for treating ischemic diseases. Second, AgeX is developing a technology dubbed induced Tissue Regeneration (iTR) for partial reprogramming, which is expected to have a rejuvenating effect. Third, the company is working on a technology called UniverCyte that aims to address the problem of immunogenicity. By modifying the cells, the company wants to make non-immunogenic cells that can be transplanted into any patient. If successful, this approach will drastically ease treatment, as cells can be mass-produced instead of being specifically tailored to each patient. Finally, the company has a patented biomaterial called HyStem. This material mimics the structural tissue surrounding cells in the body and can be used to ease cellular attachment in the body.  

Turn.bio[64]

Website http://www.turn.bio 

Industry Biotechnology 

Company size 2-10 employees 

Headquarters Menlo Park, California 

Type Privately Held 

Founded 2018 

Turn.bio is a Silicon Valley-based company founded by Jay Sarkar and Marco Quarta. The company plans to use partial reprogramming to rejuvenate humans, hoping to achieve similar results to those seen in mice, as described above. Transient expression of nuclear reprogramming factors supports rapid and large-scale amelioration of cellular aging, including by resetting the epigenetic clock, less inflammation in chondrocytes, and restoration of youthful regenerative response to aged stem cells in human muscle tissue.[232] So far, they have managed to achieve this rejuvenation in multiple human cell lines and tissues as measured by several biochemical and histological markers. They have also managed to deliver treatments to mice targeting their hypothalamus, muscles, and eyes. These developments are good early indicators, but partial reprogramming in humans is risky and requires thorough safety studies.

Iduna Therapeutics[65]

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. A number of prominent anti-aging experts are involved in the company, but it is still in its early stages. 

Stem cell research 

Around the world, hundreds of companies are working on stem cell treatments for every conceivable disease. Though these are not strictly anti-aging treatments, all of these approaches have anti-aging potential by curing diseases and providing an unprecedented range of options for regenerative medicine. It is also likely that some of these companies will move into the field of anti-aging therapy in the coming decade.  

Gallant[211]

Website https://www.gallant.com/

Phone 1-855-442-5526

Industry Biotechnology

Company size 11-50 employees

Headquarters San Diego, CA

Type Privately Held

Founded 2018

Gallant collects and stores stem cells from dogs for future treatment. After undergoing a very successful stem cell treatment for his back injury, the company’s founder Aaron Hirschhorn had the idea of making stem cell treatments available for pets. Currently, scientists are developing a diverse array of these treatments for humans, targeted towards all sorts of interventions, from healing injuries to building entire spare organs. When they arrive, many of these could be translated to work in dogs. Presently, five stem cell treatments are already approved for dogs, including against osteoarthritis and dry eyes. Gallant retains the cells because, for many stem cell treatments, it is desirable to use cells from the patient themselves.

Frequency Therapeutics[233]

Website https://www.frequencytx.com/

Industry Biotechnology

Company size 51-200 employees

Type Public Company

Founded 2015

Frequency Therapeutics is engaged in research to treat or reverse sensorineural hearing loss (SNHL) stemming from damage to hair cells in the inner ear or to the nerves connecting the inner ear to the brain. Its compound FX-322, currently undergoing a Phase 2a trial that began in the last quarter of 2019, is designed to treat the underlying cause of SNHL by regenerating hair cells through activation of progenitor cells already present in the cochlea. In a Phase 1/2 study, FX-322 was shown to improve key measures of hearing loss, including clarity of sound and word understanding.  

Athersys[234]

Website https://www.athersys.com

Industry Biotechnology

Company size 51-200 employees

Type Public Company

Founded 1995

Athersys is developing MultiStem®, a patented, off-the-shelf stem cell therapy platform for treatment of neurological, inflammatory and immune, and cardiovascular diseases, as well as other critical care indications. It is based on Multipotent Adult Progenitor Cells obtained from healthy adult bone marrow and expanded outside the human body using proprietary manufacturing processes. These cells, which can be administered without tissue matching or immune suppression, promote healing and tissue repair. As such, it can offer a path for treatment of certain age-related indications. 

Longeveron[235]

Website https://longeveron.com

Industry Biotechnology

Company size 11-50 employees

Type Privately Held

Founded 2014

This life science company researches regenerative treatments based on mesenchymal stem cells for various conditions related to aging frailty, Alzheimer’s disease, and metabolic syndrome. It is currently conducting four clinical trials using human mesenchymal stem cells. In June 2020, the company announced that Japan’s Pharmaceutical and Medical Devices Agency (PMDA) had approved a Phase 2 clinical study on the treatment of aging frailty using Longeveron’s stem cells. 

Lineage Cell Therapeutics[236]

Website https://lineagecell.com

Industry Biotechnology

Company size 51-200 employees

Headquarters Carlsbad CA

Type Public Company

Founded 1990

Lineage Cell develops and manufactures specialized, terminally-differentiated human cells from pluripotent and progenitor cells, developed to replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury, or to support an effective immune response to cancer. One of its ongoing programs, OpRegen®, aims at delivering a cell replacement therapy that comprises retinal pigment epithelium cells. It is currently being tested in a Phase 1/2a multicenter clinical trial for the treatment of advanced dry age-related macular degeneration (dry AMD) with geographic atrophy. 

3.5

References

[50] Globerson, A. 1999. Hematopoietic stem cells and aging. Experimental Gerontology 34(2):137-46.

[51] López-Otín et al. 2013.

[52] Rera, M. et al. 2011. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metabolism 14(5):623-34.

[53] https://www.nobelprize.org/prizes/medicine/2012/press-release/

[54] Takahashi, K. et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861-72.

[55] Ocampo, A. et al. 2016. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167(7):1719-33

[56] http://pancryos.com/

[57] Silva, C. 2019. “Aspen Neuroscience Receives $6.5M to Advance New Patient-specific Cell Therapy for Parkinson’s.” Parkinson’s News Today, 16 December 2019. https://parkinsonsnewstoday.com/2019/12/16/aspen-neuroscience-funding-patient-specific-stem-cell-therapy-parkinsons/ (last accessed 11 August 2020).

[58] https://www.polarityte.com/

[59] https://organovo.com/

[60] Lavasani, M. et al. 2012. Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nature Communications 3:608.

[61] The Yamanaka factors make the iPSCs practically immortal (while they are undifferentiated), and they grow quickly. They share both of these characteristics with cancer cells.

[62] Cao, J. et al. 2014. Cells derived from iPSC can be immunogenic — Yes or no? Protein Cell 5(1):1-3.

[63] https://www.agexinc.com/

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

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

[211] https://www.gallant.com/

[232] Sarkar TJ, Quarta M, Mukherjee S, et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun. 2020;11(1):1545. Published 2020 Mar 24. doi:10.1038/s41467-020-15174-3

[233] https://www.frequencytx.com/

[234] https://www.athersys.com/home/default.aspx

[235] https://longeveron.com/about/about-us/

[236] https://lineagecell.com/company/