By: Ranjani Rajenthiran, Assistant Head, Intelligence Exchange, A*STAR

Zara Chung, Communications Lead, Biotech Connection Singapore

Ha Lam, Communications Lead, Biotech Connection Singapore

 

For centuries, mankind has been searching for ways to stop or reverse the effects of ageing. Indeed, losing one’s youthful vigour and zest for life can be daunting. Ageing is a gradual process of physiological decline resulting in a deterioration of health and bodily functions. Cellular deterioration has been shown to be a major risk factor for cancer, diabetes and other age-related diseases, including neurodegenerative disorders. The World Health Organization has estimated that one in six individuals (2.1 billion people) would be 60 years old and above by 2030^[1]. Combating age-related diseases is a rapidly growing field.

 

One of the hallmarks of ageing is cellular senescence, which happens when cells enter cell cycle arrest and no longer divide. Senescent cells that are not cleared from the body remain metabolically active and produce senescence-associated secretory phenotype (SASP). SASP secretion recruits immune cells to eliminate senescent cells to maintain tissue quality. However, the process is not fool-proof. Some senescent cells are able to evade elimination by the immune system. The continued secretion of SASP by these senescent cells then induces senescence in the surrounding normal cells. Over time, senescent cells accumulate in various sites of the body, contributing to functional deterioration and increased risk of age-related diseases.

 

What are senolytics and how can they help?

Senolytics are a class of small molecule drugs that target and selectively kill senescent cells. Compared to traditional anti-ageing treatments that merely target the physical effects of ageing, senolytics directly halt the ageing process. It is no surprise that the market for senolytics in the longevity and anti-senescence domains will have a high projected value of USD 44.2 billion by 2030^[2]. The first senolytic drugs, Dasatinib, Quercetin, Fisetin and Navitoclax, are already in clinical trials for oncology, neurology and ophthalmology.

 

Oncology

Global cancer rates are on the rise, with over 18 million new cases diagnosed in 2020^[4]. In cancers, tumour cells divide uncontrollably. Conventional cancer therapies like radiation therapy and chemotherapy induce tumour cells to enter cellular senescence, whereby they no longer divide. However, some tumour cells have been shown to recover from senescence with an increased ability to divide and higher drug resistance, which accounts for the relapses or increased tumour growth we see in some patients. Senolytics serves as an attractive adjuvant in the treatment of cancers due to their ability to kill senescent cancer cells. They essentially act as a second-line adjuvant in cancer treatment to prevent relapses, and their effects have been studied closely over the past few years.

 

In preclinical research, Navitoclax has been demonstrated to show a high level of success in the clearance of tumour cells. Examples include elimination of senescent lung cancer cells treated with chemotherapy or radiation, and breast cancer cells treated with chemotherapy, radiation or protein inhibitors. In mouse models, clearance of the said senescent tumour cells have led to the reduction of tumour size and increased survival rates.

 

Another senolytic targeting cancer drug is STX255, by Senolytic Therapeutics. While chemotherapy is used to treat cancer, it is known to induce senescence in non-cancerous cells as a side-effect. It is believed that such chemotherapy-induced senescent cells can subsequently lead to cancer relapse. STX255, a monoclonal antibody, targets proteins on the surface of these cells and recruits the immune system to clear the cells. STX255 has been licensed to Rejuveron.

 

Since ageing has been shown to be a significant cancer risk factor, senolytics can potentially prevent cancer or reduce cancer risk, and not just be used as adjuvant therapy.

 

Neurodegenerative Disease

Over the last two decades, efforts to develop novel therapies for neurodegenerative disorders have not made much progress. Given that ageing is the most important risk factor for several neurodegenerative disorders, researchers have sought to develop novel approaches targeting fundamental ageing mechanisms, one of which is cellular senescence.

 

Currently, senolytics targeting neurodegenerative diseases are still at an early stage of development. One disease targeted by senotherapies is Alzheimer’s disease (AD), which affects 6.2 million Americans aged 65 years and older and is projected to reach 13.8 million by 2060 if effective therapeutics are not discovered^[5]. Metformin, Rapamycin, Dasatinib and Quercetin (DQ) are repurposed drugs that have been shown to act as senolytics to downregulate SASP and lower senescent cell burden, thereby displaying beneficial effects in non-clinical models of ageing and AD. These are currently undergoing clinical trials.

 

A senolytic in neuro-inflammatory diseases is Numeric’s NBT-103 compound, which targets transcription factors involved in signalling pathways to control cell cycle, apoptosis and metabolism. In senescent cells, NBT-103 targets a binding site and releases a protein required for cell apoptosis. Numeric is planning a clinical trial for NBT-103 in the first quarter of 2023.

 

Ophthamology

Ophthalmology, specifically age-related macular degeneration (AMD), is another area in which senolytics can provide a therapeutics solution. AMD, which accounts for 8.7% of all blindness globally is estimated to affect 288 million people by 2040^[6]. AMD occurs when ageing damages the macula, a structure in the central retina, resulting in the loss of central vision. (The retina is crucial for vision because it is made up of nervous tissue that transforms light into neuronal signals.)

 

Although AMD is a complex multifactorial disease, it is increasingly recognised that various retinal cells experience senescence as AMD progresses. A senolytic targeting AMD is UBX1325, the most advanced drug candidate developed by Unity Biotechnology and currently being evaluated in a phase 2 clinical trial^[7]. UBX1325 inhibits Bcl-xL, an alternative pro-survival pathway that senescent cells use to evade apoptosis.

 

 

Figure 1: Market potential of therapeutics in different clinical indications

 

The future of senolytics

The study of senolytics is still relatively new and operates on a completely new mechanism as a therapeutic. Senolytics indubitably hold huge promise in their applications towards multiple age-related indications. Apart from the previously discussed fields, skin biology is an emerging application for senolytics. The skin is the largest organ of the human body and functions as a physical barrier to protect the body from the external environment, including infection from bacteria or viruses, and protection from chemicals, temperature changes and UV rays. The ageing process remodels the skin, resulting in very visible effects of skin thinning, loss of cellularity and wrinkles. Aged skin also has reduced regenerative capacity, negatively impacting wound healing. In today’s cosmopolitan context, factors such as air pollution, UV exposure and smoking exacerbate and accelerate skin ageing.

 

Existing anti-wrinkle treatments such as retinoids have side effects including peeling, breakouts, redness and constrained effective periods. Senolytics provide an alternative with minimal side effects and longer-term efficacy due to their inherent ability to stave off the skin’s ageing process. In mouse models, Fisetin has been demonstrated to reduce UVB-associated phenotypes, including epidermal thickness, skin inflammation and skin wrinkles^[8].

 

Apart from skin biology, there remain many other applications for senolytics that are currently in the early stages of research. However, the nascency of senolytics research also means that there are many challenges and concerns that have yet to be addressed.

 

The challenges to overcome

Firstly, most senolytic research has been established in mice models and other preclinical models. Translation to the clinical level is not always successful and involves myriad considerations such as dosing, toxicity and the complexity of individual reactions to the drugs administered. Variability in efficacy is a huge concern that has been observed for the senolytic Navitoclax^[9]. Navitoclax has widely variable activity as a senolytic across different types of senescent cancer cells. Much more research is required to understand the factors that affect this variability in efficacy.

 

Another challenge in the administration of senolytics would be measuring efficacy in eliminating senescent cells in the human body. Currently, there is no consensus-based recommendations or FDA-recognised gerodiagnostics to standardise the results of senolytics administrations in clinical trials. Some researchers are looking at the detection of specific SASPs secreted by senescent cells as an indication of the volume of senescent cells in the body. The focus currently would be to measure factors present in body fluids such as urine, saliva, blood or cerebrospinal fluid for the development of non-invasive detection. The lack of a gold standard measurement to determine the efficacy of senolytics is something that needs to be overcome for regulatory bodies to objectively determine their stance on various drugs.

 

Finally, senescent cells are not always bad. Senescent cells play essential fundamental roles in the human body. This includes processes like cellular reprogramming, regulation of embryonic development, wound healing, resolution of fibrosis and tumour suppression. However, the build-up of senescent cells over time can cause adverse effects such as cancer and chronic inflammation. Senolytics should not target the complete elimination of all senescent cells in our body. Instead, they should be viewed as a tool to combat age-related complications caused by harmful effects of the build-up of senescent cells. Hence, senolytics that target tissue-specific expression of senescence biomarkers need to be developed and carefully evaluated. A more personalised medical approach could be taken to combine existing disease-specific therapies with senolytics for safer and more desired outcomes as the field of senolytics continues to progress and grow.

 

In conclusion, it is critical to understand that safety and efficacy measures of senotherapeutics are still being evaluated. Without carefully monitoring and controlling clinical trials and being attentive to areas of concern, serious unexpected side effects could emerge. Each indication where senolytics is applied requires stringent and careful preclinical and clinical studies, and the determination of the appropriate dosage and mode of administration of the best senolytic agent to use alongside.

 

[1] World Health Organization (2022), Ageing and Health, WHO. Retrieved (25 October 2022) from https://www.who.int/news-room/fact-sheets/detail/ageing-and-health#:~:text=­By%202030%2C%201%20in%206,will%20double%20(2.1%20billion).

[2] Biospace (2022), Longevity and Anti-senescence Therapy Market Size to Reach $44.2 BN by 2030, Biospace. Retrieved (date) from https://www.biospace.com/article/longevity-and-anti-senescence-therapy-market-size-to-reach-44-2-bn-by-2030/?keywords=senescent+cells+aging

[3] Kobbe, C. (2019). Targeting senescent cells: approaches, opportunities, challenges. Aging (Albany NY), 11(24): 12844-12861

[4] Ferlay, J. et al. (2021). Cancer statistics for the year 2020: An overview, Int J Cancer.

[5] Alzheimer’s disease facts and figures (2021), Alzheimer & Dementia, 17(3):327-406

[6] Wong, W.L. et al. (2014). Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis, The Lancet, 2(2), 106-116.

[7] Spark, J. (2022). Unity Biotechnology completes enrollment in phase 2 envision study of UBX1325 in wet age-related macular degeneration, Unity Biotechnology. Retrieved (25 October 2022) from https://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-completes-enrollment-phase-2-envision-study.

[8] Wu, P.Y. (2017). Fisetin Regulates Nrf2 Expression and the Inflammation-Related Signaling Pathway to Prevent UVB-Induced Skin Damage in Hairless Mice. Int J Mol Sci,18(10):2118.

[9] Carpenter, V.J. (2021). Senolytics for Cancer Therapy: Is All That Glitters Really Gold? Cancers (Basel), 13(4):723.