Senolytics are the first therapies that directly target an aging process in order to delay or prevent age-related diseases, and they are now in human trials. Today, we think that it is the ideal time to have a look at how they work and what companies are involved.
Senescent cells and aging
As we get older, more and more of our the cells in our bodies become dysfunctional and enter into a state known as senescence. These senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are known as the senescence-associated secretory phenotype (SASP).
Dr. Judith Campisi from the Buck Institute for Research on Aging, along with her research team, identified that senescent cells secreted the various harmful chemicals that characterize the SASP in 2008, which was when interest in senescent cells really began . In 2010, building on this initial research, Dr. Campisi went on to show the link between the SASP and cancer . We are delighted to have Dr. Campisi on our Scientific Advisory Board, given her contribution to the field.
The SASP is a real problem: it increases inflammation, harms tissue repair and function, causes the immune system to malfunction, and raises the risk of developing age-related diseases such as cancer.
Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis before being cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and the senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.
Okay, so senescent cells lead to age-related diseases; what is the solution?
A few years ago, researchers set out to see what would happen if you removed these harmful cells from the body. Jan van Deursen and his team at the Mayo Clinic demonstrated the potential of clearing senescent cells in 2011; this experiment kickstarted interest in clearance therapies . They created a special kind of mouse that destroyed senescent cells in the presence of a certain chemical.
The results were striking. Both of these old mice are littermates and the same age. The one on the right was given senolytics, and the one on the left was left to age normally. The removal of senescent cells appeared to delay some aspects of the aging process in mice.
This simple photograph from the experiment ignited a spark of interest in the removal of senescent cells as a therapeutic approach to age-related disease. That initial spark was soon to become a fire after the results of a follow-up experiment were published in 2016 .
The previous experiment had used a specially engineered mouse, whose senescent cells were not strictly the same as those accumulated naturally during aging. This follow-up used a drug in normally aging mice to demonstrate that the removal of senescent cells is beneficial. As before, the researchers found that treatment improved mouse health and appeared to delay the aging of various organs and tissues.
Essentially, this was the proof the researchers needed, as it showed that the approach is viable in normal animals, not just specially created ones.
A new class of drugs that target this aging process
With these experiments, the biotechnology industry had initial proof that targeting one of the aging processes directly could improve health by delaying aging in mice; this began the search to develop therapies that target and destroy these harmful cells. This was the birth of a new class of drugs and therapies that would become known as senolytics.
So far, there have been a number of drugs and naturally occurring compounds with senolytic potential and multiple mouse experiments demonstrating that the clearance of these cells can delay the onset of diseases such as cancer, heart disease, osteoporosis, arthritis, and Alzheimer’s.
Some more recent studies suggest that lifespan is improved along with healthspan, the period of life spent disease free. We recently talked about how fisetin, a compound found naturally in strawberries, improved healthspan, and lifespan in mice , and another recent study showed senolytics increased both healthspan and lifespan in mice .
This has led some people to speculate if senolytics might increase both healthspan and lifespan in people. Of course, until clinical trials are completed, we cannot really say; however, the data so far appears to favor healthspan rather than lifespan. However, if it does both, then more people will be able to enjoy longer lives in good health.
A booming industry
Interest in senolytics has seen a meteoric rise in the last couple of years, with investment money pouring in as confidence in the approach has reached new heights. There are also a number of companies developing therapies to destroy senescent cells, and it is likely that more will join them in the coming years.
Leading the charge is UNITY Biotechnology, which was founded in 2011 and has raised over $385 million in funding since then. This company has enjoyed backing from many investors, including big names such as Jeff Bezos and Peter Thiel. UNITY went public in May this year and is currently valued at over $700 million. Van Deursen, the pioneer of senescent cell clearance, is a scientific co-founder at UNITY.
The company’s first candidate drug, UBX0101, entered human trials back in June of this year with a focus on treating osteoarthritis, an age-related disease. As you can see in its development pipeline, the company has other diseases, such as idiopathic pulmonary fibrosis, COPD, kidney disease, and glaucoma, all earmarked for future trials.
The reason for this is simple: senescent cells are found in all tissues and organs and are thought to be instrumental in many age-related diseases, so it makes sense that if a senolytic drug works in one trial, it may have potential to treat other diseases and tissues.
UNITY is not alone in its search for ways to remove senescent cells; multiple other companies are hot on its heels developing ways to seek and destroy these harmful cells.
Oisin Biotechnologies, based in Seattle, is one such company. Founded in 2016, it has raised around $4 million to date and is developing a unique lipid nanoparticle-based system to deliver senolytic and cancer therapies. Oisin is poised to begin human trials for cancer and then senolytics in 2019.
Stephen Hilbert, head of corporate development for Oisin Biotechnologies, gave a talk at our recent industry conference, Ending Age-Related Diseases 2018, at the Cooper Union, New York City about the company’s therapies.
Cleara Biotech, based in the Netherlands, is another company busy developing senolytic therapies, and it includes Dr. Peter de Keizer, who we interviewed earlier this year and is one of the pioneers of senolytics for his work on the FOXO4-DRI peptide. Cleara is currently trying to optimize the FOXO4-DRI peptide to increase its potency and safety profile prior to entering human trials; the current version is good enough for proof-of-concept testing, but the team wants to optimize the therapy to translate it to humans.
Spain-based Senolytic Therapeutics is another company developing senolytics and includes Dr. David Sinclair, who is famous for his work with NAD+ and its precursors and is an accomplished biochemist. David is involved in a number of projects, and we are proud to help crowdfund his lab’s NAD+ mouse project at Lifespan.io. Senolytic Therapeutics has so far been silent running, and little is known about the company, although one rumor is that they have enough funding lined up to get to the clinic.
Finally, the company CellAge, which hosted a project at Lifespan.io at the end of 2016, is taking a different approach from the traditional drugs of UNITY and the lipid nanoparticles of Oisin. CellAge is developing a synthetic biology approach to senolytics that can identify senescent cells and eliminate them through the creation of “genetic circuits”.
The current methods that researchers use to identify and clear senescent cells have some serious limitations, including being too large to place inside current gene therapies, not being selective enough when targeting cells, and not removing enough senescent cells. CellAge is creating synthetic promoters, which are special DNA sequences that can regulate the activity and expression of genes to overcome these limitations.
CellAge is currently working with Circularis to screen for new senescent cell promoters using a unique technological platform that has never been used before with human senescent cells. If this is successful, the company will then move onto screening from a library of over 100,000 novel synthetic promoters. After identifying suitable promoters, CellAge intends to develop highly accurate methods of senescent cell detection that surpass the current state of the art.
The field of senolytics looks set to be a competitive one, and that can only be a good thing from our perspective, as that fierce competition will hopefully serve to drive prices down and accessibility up.
The good news is that the first wave of senolytic drugs and therapies would likely not even need to be particularly efficient to make an impact. Previous mouse studies show that even removing as few as 30% of senescent cells is enough to significantly benefit health. This also suggests that treatment could be infrequent, which would potentially make such therapies less expensive overall.
We have now reached the point at which the first true rejuvenation therapy that directly targets an aging process is now in human trials. Should the results observed in mouse studies translate, and there is plenty of reason to be optimistic, it will become increasingly evident that something can be done about other aging processes in humans once real, clinical results are achieved regarding this particular process.
Hopefully, this will lead to a wider public appreciation that aging is not a one-way street and that we can potentially end age-related diseases in our lifetimes. That, dear readers, will be a good thing indeed.
 Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., … & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology, 6(12), e301.
 Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathological Mechanical Disease, 5, 99-118.
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 Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … & Khazaie, K. (2016). Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184
 Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., … & McGuckian, C. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine.
 Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., … & Onken, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. Nature medicine, 24(8), 1246.[/column]