Background
After dividing 40 to 60 times, cells will enter a state of senescence.[31] This boundary, known as Hayflick’s Limit, is due to shortening of the telomeres. However, short telomeres are not the only thing that can make cells become senescent. Serious DNA damage will have the same effect.[32]
In a senescent cell, the cell cycle is arrested, and there are some stereotypical changes in shape and function. These cells enter an “undead” state, hovering between life and death. They no longer grow and divide, but emit large numbers of molecules displaying the senescence-associated secretory phenotype (SASP).[33] SASP includes highly inflammatory and immune-modulating cytokines that cause inflammation and immune cell activation in the surrounding tissue. Furthermore, the SASP can make healthy cells become senescent as well.[34]
Aging is accompanied by an increase in inflammation, and we know the number of senescent cells increases with age in most tissues.[35] This correlation seems to be causal. If senescent cells are transplanted into young mice, they quickly become weak and frail.[36] Scientists have also tested this hypothesis by creating special mice in which the senescent cells can easily be targeted. When the senescent cells are continuously removed from these mice, they are healthier and live longer.[37]
Challenges
Drugs used to selectively target and kills senescent cells are called senolytics. While this whole research area is very new, senolytics have quickly become a promising area of anti-aging research for the near future. The animal studies are solid, and the mechanism is promising. For this reason, there has been a lot of activity in this area during the last decade, both in terms of research and of companies being founded.
There is a high likelihood that senolytics will work in humans. The main challenge is to find senolytic drugs or therapies that kill senescent cells without hurting normal cells. Since the senescent cells are broadly dispersed among normal cells, and because there are many more normal cells than senescent cells, even in very old patients, a highly accurate weapon is required. If it mistakes normal cells for senescent cells in just a few percentages of the cases, the intervention might do more harm than good.
Senescent cells appear continuously. Thus, a potential treatment would have to be repeated occasionally, and with time, the benefits might decrease as the effects of other causes of aging gradually increase in strength.
Road to Success
Research in senolytics is ongoing, but several major players have already moved to clinical trials. Two treatments showed promising results in Phase 1 trials (which are made to assess the safety, not the effectiveness, of a treatment[38][39] and were allowed to move on to Phase 2. One of these, a trial of Unity Biotechnology’s senolytic compound UBX0101, failed to show results, and work on UBX0101 was suspended on 17 August 2020 (see below). Other approaches for treating cellular senescence are expected to follow in the coming years.
Companies
Unity Biotechnology[40]
Website http://unitybiotechnology.com/
Industry Biotechnology
Company size 51-200 employees
Headquarters South San Francisco, California
Type Public Company
Founded 2009
Unity Biotechnology was founded by a team including Jan van Deursen (who did the first mouse study of senescent cell clearing) and senescence expert Judith Campisi. The company has developed a number of senolytic compounds designed to promote apoptosis (cellular suicide) of the senescent cells. Despite promising Phase 1 results, the company announced on 17 August 2020 that its Phase 2 trial of compound UBX0101 had failed in tests with patients suffering from osteoarthritis of the knee. It continues to conduct clinical trials with other compounds including UBX1325 for retinal diseases, which inhibits Bcl-xL, a distinct senolytic target.[41] In the future, the company plans to start clinical trials in diseases such as age-related macular degeneration, idiopathic pulmonary fibrosis, and neurodegenerative diseases.[42] If the compounds prove to be effective in treating diseases known to be influenced by senescent cells, studies on their use in healthy people will likely commence.
Oisin Biotechnologies[43]
Website http://www.oisinbio.com
Industry Biotechnology
Company size 2-10 employees
Headquarters Seattle, WASHINGTON (WA)
Type Privately Held
Founded 2014
Oisin Biotechnologies aims to use gene therapy to kill senescent cells. The treatment consists of a proapoptotic gene (suicide gene) that is delivered to the cells using a liposomal vector. The suicide gene will only be expressed in cells where the senescent cell protein p16 is already expressed. Otherwise, nothing will happen. In this way, Oisin hopes to be able to selectively make senescent cells kill themselves without affecting regular cells. Because the gene is delivered by a liposomal vector, not a virus (as is usually the case), Oisin hopes there will be no immune response. This will allow the treatment to be administered multiple times without being targeted by the immune system. The treatment is currently being developed and has not yet reached clinical trials.
Everon Biosciences[44]
Website http://www.everonbio.com
Industry Pharmaceuticals
Company size 11-50 employees
Type Privately Held
Everon Biosciences was founded in 2010 by Andre Gudkov. The company wants to empower the innate immune system to remove senescent cells. Its approach is based on the premise that the human body is able to clear out senescent cells perfectly well while we are young, but that this ability is gradually lost as we age. Currently, Everon is testing a compound named EBS3899 for its ability to sensitize a type of immune cell called macrophages to senescent cells. If it works, the macrophages (“large eaters”) will gobble up the senescent cells and destroy them.
Siwa Therapeutics[45]
Website http://www.siwatherapeutics.com
Industry Biotechnology
Company size 2-10 employees
Headquarters Chicago, Illinois
Type Privately Held
Siwa Therapeutics is a pre-clinical stage company founded by Lewis S. Gruber. Its researchers have developed a humanized monoclonal antibody (“SIWA318H”) to target both senescent and cancer cells. Antibodies are proteins made by immune cells called B-cells. They recognize specific molecules and bind to them. Other immune cells can recognize the antibodies and will destroy whatever they are bound to. In other words, antibodies tag something for destruction by the immune system. Thus, if the antibody SIWA318 can recognize a protein on the surface of senescent cells, immune cells such as macrophages will gobble up the cells and destroy them. This approach entails the risk of triggering an autoimmune response (where the body is attacked by its own immune system). If the antibodies also bind to healthy cells, these will be destroyed too.
Senolytx[46]
Website http://www.senolytx.com
Industry Pharmaceuticals
Company size 2-10 employees
Headquarters Barcelona, Barcelona
Type Privately Held
Senolytx is a bioscience company co-founded by Manuel Serrano and Marc Castelltort. The company works to identify novel senolytic drugs. Currently, it is working on the following programs:
- STX084: a series of small molecules that targets a new senescent cell marker
- STX020: a program aiming to discover new vulnerabilities in senescent cells
- STX019: a collaborative research project with academic institutions aiming to exploit targets identified in a large screen for senolytic compounds.
Mayo Clinic
Website http://www.mayoclinic.org
Industry Hospital & Health Care
Company size 10,001+ employees
Headquarters Rochester, Minnesota
Type Nonprofit
Mayo Clinic is a nonprofit medical center and academic organization. As such, it does not really belong on this list of companies. However, scientists based at Mayo Clinic have done a lot of the fundamental senescence research and are responsible for many of the breakthroughs. Currently, Mayo Clinic is performing clinical trials in humans for the use of the senolytic drugs dasatinib and quercetin. Dasatinib is a drug used in the treatment of certain leukemias (a group of blood cancers), and quercetin is a pigment found in many plants. The two have potent senolytic activity together,[47] but as existent drugs, they cannot be patented (this could be the reason why pharmaceutical companies are not testing them for anti-aging uses). Fisetin is a plant flavonol whose senolytic properties have been demonstrated in mice to increase lifespan, reduce senescence markers in tissues, and reduce age-related pathologies.
In a Phase 1 trial, Mayo Clinic found the combination to be safe and saw early signs of effectiveness in patients with diabetic kidney disease.[48] In another trial, Mayo Clinic is collaborating with the University of Texas to test the combination against Alzheimer’s.[49] The data from this study is expected to be available in August 2023.[229]
Ichor[230]
Website https://www.ichortherapeutics.com/
Industry Biotechnology
Company size 11-50 Employees
Type Privately Held
Founded 2013
Ichor is a biopharmaceutical company founded by Kelsey Moody in 2013. With a US$540,000 seed grant awarded by the Life Extension Foundation, Ichor began working on research with immunocompromised mice. In 2014, the company solved several technical problems that had prevented further development of SENS Foundation’s macular degeneration enzyme therapy program (which would later become Lysoclear, intended for treatment of age-related macular degeneration and Stargardt’s Disease) and acquired all rights to the program. With over US$1 million in new funding led by Ichor’s first major investor and partner Roger Bagg, multiple research programs in progress, and a growing client base for contract research, Ichor established its first commercial research facilities. The company now focuses exclusively on the diseases of aging and research on undisclosed senolytic therapies.
Cleara[231]
Website https://www.clearabiotech.com
Industry Pharmaceuticals
Company size 2-10 Employees
Type Privately Held
Founded 2018
This company studies how senescent cells avoid natural elimination, and has developed therapeutics for diseases causes by the failure to clear these cells. Cleara is also developing new biomarkers for senescence that support diagnostics and drug targeting. The search for compounds that can selectively target and eliminate senescent cells, as well as cancer cells that exhibit similar characteristics, is still at the preclinical stage. The ultimate aim is to discover treatments for age-related symptoms and for therapy-resistant cancer.
References
[31] Hayflick and Moorhead 1961.
[32] Rodier, F. et al. 2009. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature Cell Biology 11:973-9.
[33] Coppé, J.-P. et al. 2010. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annual Review of Pathology: Mechanisms of Disease 5:99-118.
[34] Tchkonia, T. et al. 2010. Fat tissue, aging, and cellular senescence. Aging Cell 9(5): 667-84.
[35] Jeyapalan, J.C. and J.M Sedivy 2008. Cellular senescence and organismal aging. Mechanisms of Ageing and Development 129(7-8):467-74.
[36] Xu, M. et al. 2018. Senolytics improve physical function and increase lifespan in old age. Nature Medicine 24(8): 1246-56.
[37] Baker, D.J. et al. 2016. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530:184-9.
[38] Hickson, L.J. et al. 2019. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47:446-56.
[39] https://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-reports-promising-topline-data-phase-1-first
[40] https://unitybiotechnology.com/
[41] Unity Biotechnology 2020. UNITY Biotechnology announces 12-week data from UBX0101 Phase 2 clinical study in patients with painful osteoarthritis of the knee. 17 August 2020. https://www.globenewswire.com/news-release/2020/08/17/2079116/0/en/UNITY-Biotechnology-Announces-12-week-data-from-UBX0101-Phase-2-Clinical-Study-in-Patients-with-Painful-Osteoarthritis-of-the-Knee.html (last accessed 8 September 2020).
[42] https://unitybiotechnology.com/pipeline/
[43] https://www.oisinbio.com/
[44] http://everonbio.com/
[45] https://siwatherapeutics.com/
[46] http://senolytx.com/
[47] Kirkland, J.L. et al. 2017. The clinical potential of senolytic drugs. Journal of the American Geriatrics Society 65(10):2297-301.
[48] Hickson et al. 2019.
[49] Senolytic Therapy to Modulate Progression of Alzheimer's Disease (SToMP-AD). https://clinicaltrials.gov/ct2/show/NCT04063124
[229] https://clinicaltrials.gov/ct2/show/NCT04063124?term=senolytic&draw=2&rank=1
[230] https://ichortherapeutics.com/pipeline/
[231] https://www.clearabiotech.com