What Are Senolytics? Senotherapeutics for Senescent Cells

In this article, we take a look at senolytics, how they have the potential to reverse some aspects of aging, and companies developing these sorts of therapeutics.

Senescent cells and aging

As your body ages, increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby cells to enter the same senescent state. The signals they secrete are pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP.

Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer. Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and build up.

By the time people reach old age, significant numbers of these senescent cells have accumulated in the body, causing inflammation and damage to surrounding cells and tissue. The accumulation of senescent cells is one of the reasons we age [1,2].

What are senolytics?

It has long been proposed that the therapeutic removal of senescent cells could be a solution to the problem of their accumulation.

A new class of drugs known as senolytics focuses on the destruction of these stubborn “death-resistant” cells in order to reduce inflammation and improve tissue function. These drugs are being developed to be selective, meaning they can trigger apoptosis in senescent particular cells while leaving healthy cells alone.

How do senolytics work?

Senolytics work by targeting one of several pro-survival pathways that senescent cells use to evade apoptosis and cling onto life. One of the challenges in dealing with senescent cells is that there are a number of different populations of these cells in our tissues and organs, each using different pro-survival pathways. It could be that multiple senolytic drugs need to be used to remove senescent cells using different pathways to survive.

Also, some senescent cells play a role in wound healing too so a better understanding of what these different populations of senescent cells are doing is critical before deciding which ones to target.

How senolytics were discovered

The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells (and reducing the SASP) using a transgenic suicide gene [3], and additional experiments showed that the same could be achieved using small molecules. The SASP is thought to significantly contribute to aging [4] and cancer [5]; thus, senolytics and the removal of the SASP are a potential strategy for promoting health and longevity.

It was discovered through transcript analysis that senescent cells have increased expression of pro-survival genes consistent with their resistance to apoptosis [6]. Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were dasatinib and quercetin, which were both able to remove senescent cells but were better in different tissue types.

However, it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types [7].

In other studies, removing only 30% of senescent cells was sufficient to slow down age-related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics in alleviating the diseases of aging and promoting healthy longevity [8,9,10].

Senolytics and age-related diseases

Further confirming the potential of senolytics to treat age-related disease, a recent study demonstrated the benefits of senolytics for certain aspects of vascular aging [11]. This was the first study to show that clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, thus making senolytics a possible viable method of reducing morbidity and mortality from cardiovascular diseases.

Even more recently, progress has been made in treating atherosclerosis using senolytics to address the “foam cells” that contribute to this disease [12]. There has also been progress in ways to treat type 2 diabetes using senescent cell removal [13]. Senolytics also have the potential for slowing skin aging [14] and treating osteoarthritis [15].

Senescent cells, however, are not all bad, and evidence shows that they play a role in cellular reprogramming [16] and wound healing. Like all things in biology, it is therefore clearly a question of balance: too much clearance of senescent cells would be bad for wound healing and cellular reprogramming, but too many senescent cells lead to damage [17,18].

Therefore, the key to developing effective senolytic therapies that combat the diseases of aging is the creation of even more accurate biomarkers to measure senescent cell numbers in tissue [19] combined with effective delivery methods for the selective removal of senescent cells.

The companies developing senolytics

In the last few years, interest in senolytics has massively increased. There has been an influx of investment money flowing into this area of the field and today there are multiple companies developing senolytic drugs. This is by no means an exhaustive list and we will keep adding to it over the coming months.

Unity Biotechnology

Based in South San Francisco, Unity Biotechnology was founded in 2011 by Drs. Nathaniel David, Jan Van Deursen, Judy Campisi, and Daohong Zhou. The company saw significant investment from the Longevity Fund, Jeff Bezos Expeditions, Founders Fund, and ARCH Venture Partners. Unity gained $200 million in venture funding and raised $85 million at IPO.

Unity was created based on the discoveries of the van Deursen lab at the Mayo Clinic and the Campisi lab at the Buck Institute, which suggested that clearing senescent cells was beneficial in mice and could increase healthspan and potentially lifespan.

As the leader of the pack and the first biotechnology company to hit the clinic with senolytics, Unity was always going to have a harder time than the companies following closely behind. Being the first to do something, to push ahead into the unknown, and to try to become a game changer is rarely easy.

This was evidenced by some disappointing news for Unity Biotechnology last year. The company’s first shot on goal, the drug candidate UBX0101, a MDM2-p53 inhibitor for knee osteoarthritis, unfortunately failed to succeed. Aging biology is complex, results in mice do not always translate, and things do not always go as hoped; this is just the nature of the beast.

A bump in the road but research continues

Thankfully, Unity has continued to persevere and push ahead with other drug candidates in its development pipeline.

UBX1325 for diabetic macular edema is currently in phase 1 clinical study. The drug inhibits Bcl-xL (Bcl-2 family), an alternative pro-survival pathway that senescent cells use to evade apoptosis. The trial is currently enrolling participants and we anticipate that the trial results will be announced sometime around July 2021 or soon after.

UBX1967 is also in their pipeline for eye diseases which may include diabetic macular edema, diabetic retinopathy, and adult macular degeneration. There is currently no timeline for when this might reach clinical trials.

Further out, Unity also has an early pipeline for neurology due to researchers at the Mayo Clinic having discovered a connection between senescent glial cells, tau pathology, and the resulting onset of neurodegenerative diseases in a 2018 study.

An uncertain future

Unity is using a small molecule approach with repurposed cancer drugs and a limiting factor to this could be toxicity. These cancer drugs can be harmful to healthy cells as well as senescent cells which limits the dosage that can be used and makes systemic treatment a challenge.

For example, Bcl-xL inhibitors (including UBX1325) are known to destroy platelets and can cause thrombocytopenia at high dosage. It may be the case that low-dose, localized injections of these drugs are not sufficient to effectively remove senescent cells and the harmful SASP they produce.

Additionally, Unity is using first-generation senolytics based on research that used repurposed cancer drugs like dasatinib and navitoclax or plant flavonols with poor bioavailability, such as quercetin and fisetin. This could be a problem further down the line, as companies hot on their heels are already developing second-generation senolytics that have the potential to be more selective and can be delivered more efficiently via methods such as gene therapy and nanoparticle delivery systems.

That is not to say Unity cannot still succeed here but being leader of the pack is not an easy place to be when the stakes are so high and there are others close behind seeking to innovate on what has gone before.

Siwa Therapeutics

Siwa has been with us as far back as 2006, making it the oldest senolytics company in the field. Founded by Lewis and Misty Gruber, the company is based in Chicago, Illinois. Compared to Unity, the company has a much more modest $1.6 million in funding for their candidate 318H which is currently at the preclinical stage.

Its approach is somewhat more unusual than the typical small-molecule approach used by other companies, as it has chosen to develop an immunotherapy answer to senescent cells, specifically a monoclonal antibody.

Founder Lewis Gruber said in a 2020 interview with Lifespan.io, “It’s just a straight typical monoclonal antibody product, the same sort of immunotherapy that’s used in a variety of cancer therapies.”

SIWA has identified that both senescent and cancerous cells have higher levels of  glycolysis, the first step in the breakdown of glucose to extract energy to be used in cellular metabolism. The 318H monoclonal antibody targets senescent and cancerous cells through an antigen marker of this increased glycolysis that the company has yet to reveal.

In preclinical studies, naturally aged mice treated with 318H saw a 66% reduction of p16INK4a-positive senescent cells and an increase in muscle mass. Muscle mass loss, known as sarcopenia, is typically observed during aging, and its reversal suggests that some level of tissue rejuvenation is occurring due to treatment. SIWA also reports a significant 30% reduction in metastasis in triple-negative breast cancer mouse models.

While SIWA has not yet announced a date for any clinical trials to begin, it has completed tolerability studies in primates and is preparing an Investigational New Drug (IND) application with the FDA. It is likely that 318H will be applied to cancer before age-related diseases.

Senolytic Therapeutics

Based in Barcelona and part of the Life Biosciences group of companies, Senolytic Therapeutics was created in 2017 and co-founded by Dr. Marc Ramis Castelltort and Dr. Manuel Serrano.

Details of what the company is working on are currently somewhat shrouded in mystery, as it has not publicly revealed too much information about its pipeline. However, there is enough available information to make it possible to to piece together at least some of what they are doing.

The company has two senolytic candidates, STX519 and STX43, and based on conference presentations, it seems likely that future clinical trials will be focusing on fibrotic diseases of the liver, lungs and kidneys.

It also has STX255, a monoclonal antibody that targets senescent cell surface proteins and then recruits the immune system to clear senescent cells. STX255 has been licensed out to Swiss biotech company Rejuveron, which is focused on the immune-mediated clearance of senescence cells in the fields of oncology and aging. This twin cancer and senescent cell approach makes sense, as harsh chemotherapy is known to create senescent cells as collateral damage; therefore, removing chemotherapy-induced senescent cells may help to prevent cancer relapse.

The company is also developing a nanoparticle delivery system to provide a more targeted approach and to deliver senolytic payloads to target cell populations.

Conclusion

Senolytic research has exploded in the last few years, and there are now many companies developing these drugs. With some currently in human trials and others close behind, the hope is that before long, one of them will succeed.

Another approach to dealing with these problem cells is not to destroy them, but instead to alter the signals they send, this is known as senomorphics. If successful this would render the cells less inflammatory and harmful.

Which of the two methods for dealing with senescent cells is the most efficient is currently unknown, and both approaches are currently being developed.

Literature

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[2] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.

[3] Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236.

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[9] Zhu, Y., Armstrong, J. L., Tchkonia, T., & Kirkland, J. L. (2014). Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Current Opinion in Clinical Nutrition & Metabolic Care, 17(4), 324-328.

[10] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’Hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[11] Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging cell.

[12] Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354(6311), 472-477.

[13] Palmer, A. K., Tchkonia, T., LeBrasseur, N. K., Chini, E. N., Xu, M., & Kirkland, J. L. (2015). Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes, 64(7), 2289-2298.

[14] Velarde, M. C., & Demaria, M. (2016). Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review. Gerontology.

[15] Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., … & Lowe, V. (2016). Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glw154.

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