Background
In the 1970s, Elizabeth Blackburn, Carol Greider, and Jack Szostak discovered how chromosomes are protected by telomeres. This research, which has great implications for anti-aging research, won them the 2009 Nobel Prize in Medicine.[12]
Chromosomes are the structures containing our DNA. Inside each of our cells, our DNA is divided into 46 of these structures, 23 near-identical pairs from each of our parents. Together, all the chromosomes contain the entire recipe for making us. They encode the information that controls the cells. This information is obviously very valuable and needs to be protected. Cells host billions of chemical reactions and are constantly exposed to many potentially harmful outside forces. The ends of each chromosome are especially vulnerable to damage, just as a shoelace without an aglet will unravel beginning at the tip. Our cells solve this problem by adding sequences of non-important DNA to the ends of each chromosome. This DNA only serves as protection and can be lost without any harm being done. It just sits there so that valuable DNA does not.
Each time our cells divide, they lose a little bit of telomere.[13] Some cells, such as stem cells, can use the enzyme telomerase to replace the lost telomere. However, most normal cells cannot. This means most cells can only divide a certain amount of times (40-60) before they start running out of telomere and reach Hayflick’s Limit.[14]
When the telomeres become too short, the cell “pulls the emergency brake” on itself. The short telomeres can make it enter a state of senescence.[15] We know from the previous chapter that these strongly promote aging. Even in the absence of senescence, short telomeres are suspected of contributing to aging in other ways as well.[16]
Thus, it seems like telomeres are a very obvious target for anti-aging interventions. If we can elongate them or at least halt their attrition, we can fight cellular aging. This has been successfully demonstrated in cell culture experiments in the lab. When scientists give normal cells access to the enzyme telomerase, they become immortal.[17] This finding has even been replicated in animals. Scientists have created mice that have unusually long telomeres. These mice have a healthier metabolism than normal mice, age better, and ultimately live longer.[18]
Naturally, this has prompted many to look for a telomere effect in humans as well. As with any other trait, there are natural differences between us. Some people naturally have cells with longer telomeres, and the rate of attrition also varies between individuals.[19] Does that mean that people with longer telomeres live longer?
A Danish study of 65,000 people found just that. Having shorter telomeres was associated with higher mortality and a higher risk of heart disease, Alzheimer’s, and diabetes.[20] The scientific evidence for the efficacy of telomerase elongation gene therapy in animals is undisputed,[218] even without increasing cancer.[219]
Challenges
If telomerase is such a wonder enzyme, why don’t all our cells use it?[220] All our cells have the gene for telomerase in their DNA. The normal cells just choose to keep it inactive. In principle, normal cells could just turn on telomerase, elongate their telomerase, and become immortal. But they choose not to, and for very good reason. After all, the trait of immortality is also associated with another kind of cell that we want to avoid at all cost – cancer cells. These enemy cells, which are derived from our own cells, appear when the DNA of a cell becomes damaged in critical places. This can accidentally destroy the safety mechanisms and activate the enzyme mechanism for growth and survival. Cancer cells appear by accident and then develop to grow rapidly and become immortal. Telomerase, one of the cornerstones in this strategy, is overexpressed in up to 90 percent of cancer cells.[21] And just as expected, people with longer telomeres have a higher risk of getting many types of cancer.[22][23][24]
In brief, the tradeoff is the following: Stem cells need telomerase to be able to continuously produce new cells during development, and later to sustain us. However, telomerase can be misused by cells turning cancerous and is kept hard to access to minimize this risk.
This discovery is a big problem for telomerase-based anti-aging therapies. Even if they potentially slow down our biological rate of aging, they might increase our risk of cancer at the same time. This means that such a therapy might not increase our lifespan by much or could potentially even shorten it. However, others see the risk of cancer as less critical.[243]
Road to Success
The tradeoff between telomere length and cancer has to be addressed if anti-aging therapies based on telomere elongation are to succeed. Potential solutions could be based on precise control of telomerase. One could imagine turning on the enzyme in specific cells only, or periodically turning it on and off to maintain telomeres but keep them at a minimum length. Alternatively, this kind of therapy will have to wait for improvements in cancer research to diminish the risk of cancer deaths in treated patients.
Companies
Geron Corporation[25]
Website http://www.geron.com
Phone 650.473.7700
Industry Biotechnology
Company size 11-50 employees
Headquarters Menlo Park, California
Type Public Company
Founded 1992
Geron is one of the most mature companies in the anti-aging field. It was founded in 1990 by US gerontologist and stem cell pioneer Michael D. West, who is also the founder of AgeX Therapeutics (see the section on stem cell exhaustion).
Geron focuses on the role of telomerase in cancer. The company has developed a telomerase inhibitor called Imtelstat that can penetrate the cell membrane and bind part of telomerase, blocking it. This prevents the enzyme from working and theoretically prevents cancer cells from escaping Hayflick’s Limit and becoming immortal. Imetelstat is currently being tested in two clinical trials. IMbark is a Phase 2 trial to evaluate two doses of imetelstat in Intermediate-2 or High-risk myelofibrosis (MF) patients who are refractory to or have relapsed after treatment with a JAK inhibitor. IMerge is an ongoing two-part Phase 2/3 clinical trial of imetelstat in red blood cell (RBC) transfusion-dependent patients with lower risk myelodysplastic syndromes (MDS) who are refractory or resistant to treatment with an erythropoiesis stimulating agent (ESA). Detailed results were presented at the European Hematology Association Annual Congress in June 2020.[244]
Blocking telomerase is not an anti-aging therapy, apart from its use in cancer treatment. However, despite the present focus on cancer therapies, Geron has its roots in anti-aging. The company’s name means “old man” in Greek, and its founder is heavily involved in the anti-aging field. The company has acquired extensive knowledge about telomerase and is well positioned to profit from that expertise in the future.
Telocyte[26]
Website http://www.telocyte.com
Industry Pharmaceuticals
Company size 2-10 employees
Type Privately Held
Founded 2015
Telocyte was founded by Dr. Michael Fossel. The company focuses on treating Alzheimer Disease (AD) using telomerase. Decades of study have yielded many insights about potential disease mechanisms, but with very limited success. We know that a sticky molecule called amyloid-β accumulates in the brain, but not why it does so, or how to fix it. There is no good treatment available for AD yet. According to Telocyte’s disease model, telomerase shortening is causative of AD[221]. Telocyte plans to use a gene therapy approach called TEL-01 to overexpress the telomerase gene in glial cells and astrocytes in the brain,[27] which will lead to elongation of telomeres. If all goes as planned, the gene therapy will return the cells to a functional state, and cognitive decline will be stopped and reversed. The company is currently working to get funding for a phase 1 trial of their therapy.[28]
Libella[222]
Website https://www.libellagenetherapeutics.com/
Industry Biotechnology
Company Size 14
Type Privately Held
Founded 2017
Libella is conducting a study on the use of gene therapy to express active telomerase (hTERT) in human cells. It has the potential to treat many neurodegenerative diseases related to aging, including Alzheimer’s disease (AD). This study will entail treating subjects with hTERT delivered via transduction using adeno-associated viruses (AAV). The goal is to extend the telomeres to prevent, delay, or even reverse the development of the pathology of AD. It is expected to have a direct consequence on cognitive function and quality of life in patients with neurodegenerative diseases, such as AD.[223]
While the efficacy of this treatment has yet to be demonstrated, it appears that the Libella therapy is already being made available to wealthy private patients for a price of US$1 million at a clinic in Colombia, beyond the jurisdiction of the US FDA.[224][225] Critics have warned of the ethical issues arising from this select dispensing of unproven medicine.
Integrated Health Systems (Bioviva)[226]
Websites https://www.integrated-health-systems.com and https://bioviva-science.com/pages/partnerships
Industry Biotechnology
Company Size 11-50 Employees
Type Privately Held
Integrated Health Systems is an innovative gene and cell technology company that provides patients with regenerative medicine targeting the aging process with the intent to slow or reverse that process. The CEO of Bioviva, Liz Parrish, claims to be the first person on earth to have received telomer elongation gene therapy.[227]
Sierra Sciences[29]
Website https://www.sierrasci.com/
Industry Biotechnology
Company size 11-50 employees
Headquarters Reno, NV
Type Privately Held
Founded 1999
Sierra Sciences was founded by Dr. Bill Andrews in 1999. While working at the Geron Corporation, Andrews helped discover the RNA and protein components of telomerase. At Sierra Sciences, he has been screening thousands of compounds with his team, aiming to discover the best ones for inducing telomerase expression in cells. The company sells the supplement TAM-818[30] which was shown to activate telomerase in cultured cell. However, the effect in humans is not documented.
Life Length[228]
Website https://lifelength.com/
Industry Biotechnology
Company Size 11-50 Employees
Type Privately Held
Founded 2010
Spanish biotech company Life Length provides advanced and accurate services in telomere length analysis and diagnostics. As a spin-off of the Spain’s National Cancer Research Centre, the company has received €3.1mn in funding from the EU’s Horizon 2020 research and innovation program under grant agreement 738707. It provides screening for prostate cancer, various COVID-19 tests, and contractual services. Its research studies the significance of telomeres as a biomarker for biological age and life expectancy.
References
[12] https://www.nobelprize.org/prizes/medicine/2009/summary/
[13] Blasco, M. 2007. Telomere length, stem cells and aging. Nature Chemical Biology 3(10):640-9.
[14] Hayflick and Moorhead 1961.
[15] Shay, J.W. and W.E. Wright 2005. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26(5):867-74.
[16] López-Otín et al. 2013.
[17] Bodnar, A.G. et al. 1998. Extension of life-span by introduction of telomerase into normal human cells. Science 279(5349):349-52.
[18] Muñoz-Lorente, M.A. et al. 2019. Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Nature Communications 10, article no. 4723.
[19] Okuda, K. et al. 2002. Telomere length in the newborn. Pediatric Research 52:377-81.
[20] Rode, L. et al. 2015. Peripheral blood leukocyte telomere length and mortality among 64 637 individuals from the general population. Journal of the National Cancer Institute 107(6).
[21] Yuan, X. et al. 2019. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene 38:6172-83.
[22] Nan, H. et al. 2011. Shorter telomeres associate with a reduced risk of melanoma development. Cancer Research 71(21).
[23] Pellatt, A.J. et al. 2013. Telomere length, telomere‐related genes, and breast cancer risk: The breast cancer health disparities study. Genes, Chromosomes & Cancer 52(7): 595-609.
[24] Rode, L. et al. 2016. Long telomeres and cancer risk among 95 568 individuals from the general population. International Journal of Epidemiology 45(5):1634-43.
[25] https://www.geron.com/
[26] https://telocyte.com/
[27] https://www.telocyte.com/alzheimers-therapy/alzheimers-therapy
[28] https://www.longevity.technology/global-investment-consortium-slated-to-back-telocyte-into-phase-1/
[29] https://www.sierrasci.com/
[30] https://www.tam818.com/
[218] Jaskelioff et al. Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice. Nature. 2011; 469:102–106. https://doi.org/10.1038/nature09603/
[219] de Jesus et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 2012; 4:691-704. https://doi.org/10.1002/emmm.201200245
[220] Jäger K, Walter M. 2016. Therapeutic Targeting of Telomerase. Genes (Basel). Jul 21;7(7):39. doi: 10.3390/genes7070039 (https://pubmed.ncbi.nlm.nih.gov/27455328/)
[221] (Fossel M. A unified model of dementias and age-related neurodegeneration. Alzheimers Dement. 2020;16(2):365-383. doi:10.1002/alz.12012)
[222] https://www.libellagenetherapeutics.com/
[223] https://clinicaltrials.gov/ct2/show/NCT04133649?term=libella+gene+therapeutics&draw=1
[224] https://www.technologyreview.com/2019/12/06/131657/buyer-beware-of-this-1-million-gene-therapy-for-aging/
[225] https://onezero.medium.com/scientists-dodge-fda-to-offer-a-1-million-anti-aging-treatment-in-colombia-38756dfb3ad1
[226] https://www.integrated-health-systems.com/
[227] https://bioviva-science.com/pages/partnerships
[228] https://lifelength.com/
[243] See, for example, the following statement by telomere expert and President of Telocyte Ltd., Michael Fossel: “In short, telomere extension might increase mortality in patients with a pre-existing cancer, but if patients don’t already have cancer, then telomere extension would prevent cancer from occurring in the first place. Neither telomerase nor long telomeres cause cancer, but either telomerase or long telomeres could permit cancer to grow once it gets a foothold.” M. Fossel, “Telomeres and Cancer”. 12 November 2013. http://www.michaelfossel.com/blog/?p=47 (last visited 21 September 2020).
[244] https://www.geron.com/file.cfm/53/docs/EHA2020_S183_IMerge%20Phase%202_06.12.2020%20FINAL.pdf (last accessed 21 September 2020).