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Managing senescent cells to drive human longevity:

Senotherapeutics

Contributor

Daragh Campbell

Head of Research (Former)
Market Intelligence Unit, Longevity.Technology
Contributor

Girish Harinath

Scientific Editor
Market Intelligence Unit, Longevity.Technology
  • The rising tides of a Silver Tsunami are an ever-growing concern for economists who predict that an “aging” population combined with increasing healthcare costs and significant loss of healthy-life years will result in an impending economic crisis.
  • Senotherapeutics have the potential to support a new standard of care that could help redefine what we see as “old”.
  • Given the ubiquitous nature of senescence as a hallmark of damaged cells, and the abundance of associated target pathways and technological flexibility to target them, senotherapeutics have the potential to tackle the age-driven incidence rate of chronic disease by addressing the cause rather than the symptom(s).

Cellular senescence

Cellular senescence is a fundamental mechanism activated by cells in response to various stressors including telomere shortening, DNA damage and mitochondrial stress. Senescent cells have in essence lost their ability to multiply, therefore our immune system is tasked with identification and clearance of senescent cells to maintain a balanced turnover rate.

However, as we age, our bodies are less efficient at removing these dysfunctional cells due to factors such as a weakening immune system. When we’re young, senescent cells make up a small percentage of the total biomass of a given organ or tissue. As we age, the senescence burden increases.

When they are not effectively removed the senescent cells secrete senescence-associated secretory phenotype (SASP) factors which propagate the senescent phenotype across cells and tissues of the body. This interferes with tissue homeostasis, regeneration, and contributes to inflammaging and extracellular matrix remodelling to further exacerbate the primary hallmarks of aging. The accumulation of senescent cells is thought to be a key driving force behind many age-related diseases, particularly metabolic and fibrotic conditions.

Clearance of senescent cells has been shown to delay damage accumulation associated with the aging process as well as the onset and progression of several chronic diseases across multiple model organisms (Kaur, 2020).

Senotherapeutics

Senotherapeutics encompasses a range of different methods of clearing senescent cells and include the following:

1. Senolytics: Kill the senescent cells by targeting cellular pathways that make senescent cells vulnerable to death.

2. Senomodulators: Target the SASP signalling network that drives senescent pathologies. Either prevent their secretion or disrupt SASP generating pathways.

3. Senoblockers: Inhibit the formation of senescent cells via clearing away cellular damages that lead to senescence phenotype.

4. Senescence-associated immunomodulators: Improve the recognition and clearance of senescent cells by the immune system.

Spectrum of stress

Each method comes with its own opportunities and challenges, and ultimately could be used in combination with other methods to tackle cellular senescence.

The UN estimates that 1 in 6 people on Earth will be over the age of 65 by 2050. As a result, the incidence of chronic disease will increase at an alarming rate and could lead to an economic crisis if not addressed. The amount of money invested in cancer, cardiovascular disease and Alzheimer’s disease vastly outstrips that of healthy aging, yet age is the leading risk factor for all these diseases.

Senotherapeutics have the potential to tackle the age-driven incidence rate of chronic disease by addressing the cause rather than the symptom(s) and to support a new standard of care that could help redefine aging. There are a number of key factors that will contribute to senotheraputic success in the longevity market and in tackling the aging population crisis.

  • SASP have emerged as a driver of, and promising therapeutic target for, multiple age-related conditions, ranging from neurodegeneration to cancer (Qiu, 2021).
  • They have already shown unparalleled efficacy in preclinical studies.
  • Senotherapeutics hold promise to be incorporated into a single, effective regimen that restores health in the elderly. In doing so, elderly individuals can reduce the number of medications they take and associated risks of cross interaction.
  • Significant opportunities exist for their use as adjuvant therapies and within the cell therapy and organ transplantation market.

Since senescence is a hallmark of aging and has had extremely promising results in delaying the onset and progression of multiple chronic diseases within preclinical trials, industry players within the senotherapeutics market are in a prime position to tap into the significant potential within the longevity economy.

Cellular senescence is particularly aggravating due to the influence of the SASP on driving the system-wide progression of multiple hallmarks of aging (Partridge, 2020). Therefore, addressing senescence before it gets out of hand has significant potential to mitigate the systemic consequences of the aging process. For this reason, senotherapeutic technologies are perfectly positioned as a prophylactic therapy within the longevity market.

Longevity.Technology estimates that the combined annual market value of diseases that could be addressed by senotherapeutics, including macular degeneration, chronic kidney disease, type 2 diabetes and neurodegenerative disease, amounted to more than $127 billion in 2021.

Furthermore, the global longevity therapies market as a whole is projected to grow from US$329.8 million in 2018 to US$644.4 million by 2023 with a compound annual growth rate (CAGR) of 14.3% in the period 2018-2023 (BCC Research, 2019). Key drivers of market growth include increased company funding, progress in aging research and the level of investment from a wealthy aging (Boomer) population (Alix Ventures, 2020).

Investment by location

Number of Senotheraputic Companies by region.  Analysis by Longevity.Technology, according to Pitchbook funding data as of 23 June 2022, based on  6 companies.

USA, Canada and Europe currently dominate the senotheraputics market. The USA and Canada continue have a growing healthcare sector prompting increased research and advancements in the pharmaceutical sector. Another major driver for the large number of senotheraputics companies in North America is the increasing incidence of chronic disease associated with age, as well as a growing demand for anti-aging products. Similarly the rise in interest and number of senotheraputic companies in Europe could also be explained at least in part by the growing aging population within the region which is likely to lead to a large societal and economic burden.

Formations by year

Senthotherapeutic companies founded each year as percentage of total.  Analysis by Longevity.Technology, according to Pitchbook funding data as of 23 June 2022, based on 24 companies.

Senthotherapeutic companies founded  analysis by Longevity.Technology, according to Pitchbook funding data as of 23 June 2022.

The year 2017-2018 saw a large spike in the number of senotheraputic companies entering the market. This is likely attributed to a Peter de Keizer research study which proposed a novel senolytic agent and identified a key target for disruption to senescent cell viability. The research attracted a lot of attention and led to a number of start ups entering the market based on a similar approach.

Capital invested and deal count

Senotherapeutic companies venture capital investment ($M) analysis by Longevity.Technology, according to Pitchbook funding data as of 23 June 2022, based on 24 companies.
Senotherapeutic companies yearly deal count. Analysis by Longevity.Technology, according to Pitchbook funding data as of 23 June 2022, based on 24 companies.

The recent dip in the level of funding of senotherapeutic companies may be attributed in part to  Unity Biotechnology’s lack of success at clinical trial stage, which likely caused cold feet in some investors. The promising biotech company, which attracted big name investors such a Jeff Bezos, saw a 60% drop in its stock in, and one-third of staff being laid off following clinical trial disappointments. This, in combination with the pandemic around the same time was a setback for the senotherapeutic field and likely acted as a deterrent to larger investments in the field.  Nonetheless, the number of deals in the sector remained high through the period to end 2021, suggesting investor interest remains strong, but some caution remains with regard to the potential risks and amounts invested.

Senotherapeutic companies by category

Longevity Senotherapeutic Companies by Category. Analysis by Longevity.Technology, according to Longevity.Technology data as of 22 June 2022, based on 24 companies.

Out of the four key categories of senotherapeutics, senolytics, currently dominates the space. Killing off the damaging senescent cells was an obvious area of initial focus.  However, these cells also have a physiological function in the body and therefore other approaches may be preferable and could dominate the field in the future. The use of senoblockers, senescence-associated immunommodulators and senomodulators are likely to need more research for wider adoption.

Clearly, the senotherapeutics market has tremendous potential to absorb several multibillion-dollar markets. An increasing global geriatric population that may exceed 1 billion within the next 30 years is also one of the major reasons why the senotherapeutic drugs market will experience future growth. However, this growth may be tempered by rules and regulations including FDA approvals as clinical trials continue and the relevant technologies evolve.

Technical Risk

Apart from their role in aging, cell senescence also pays an essential part in certain physiological aspects such as tumour suppression, tissue repair, wound healing and regeneration (Davan-Wetton, 2021). Therefore, unselectively manipulating cellular senescence could compromise physiological integrity and impact patient health. Careful analyses of the potential adverse effects of long-term administration of senotherapeutics is essential for their future successful application.

Market risk

The senotherapeutics market is still relatively new, and although there are several companies developing compounds that successfully address multiple chronic diseases in preclinical studies, there is yet to be a therapeutic that has moved past Phase 3 clinical trials.

The Common Fund Cellular Senescence Network (SenNet) programme supported by the US National Institute of Health (NIH) promises to propel the senotherapeutics industry forward within the next 5-10 years by addressing many of the barriers present today. Although the potential impact of senotherapeutics grows stronger as progress within the industry steadily advances, the likely time frames until clinical trial success suggest investors will need to be patience.

Market adoption

Senotherapeutic technologies hold great potential to utilise the rising tides of the Silver Tsunami and address several multi-billion-dollar chronic disease markets in the process. However, despite it being potentially the “next big thing” in anti-aging research, the field is still in its infancy and some way off reaching a stage of commercialisation.

If and when that point is successfully reached, it will certainly raise many important moral and ethical questions about the consequences of intervening with the aging process and possibly even death.

Senotherapeutics offer a great deal of potential in the Longevity Market especially as the world faces the increasing pressures posed by an aging population. As research into the mechanisms of cell senescence continues and understanding advances, this will lead to improved development of therapeutics that target cellular senescence to improve and extend healthspan.

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