Senolytics is an umbrella term that has a lot going on underneath – it’s time to get a handle on senotherapeutics.

Cellular senescence – the zombie state in which cells forget to die – is one of the nine hallmarks of aging. Disrupting the formation of senescent cells in tissues can lengthen healthspan and reduce the risk of age-related disease. Therapies that try to ensure cells follow the usual pathway of moving from senescence into apoptosis (cell death), or clear them away while they are going about their nefarious business of pumping out toxic chemicals while simultaneously encouraging other, healthy, cells to join the dark side of senescence, are called senolytics. But is that term serving the field?

Longevity.Technology: There is much research that suggests a direct link between senescent cells and longevity and therefore there is commensurate interest in finding therapies that leverage that connection. The word senolytic, which means disintegration of senescence, is used to describe those therapies, but at Longevity.Technology we are of the opinion that this term does a disservice to the range of senotherapeutic strategies employed in tackling senescence. So buckle up – it’s a school day!

Senotherapeutics target a pathological cell fate, not a single aberrant pathway or molecule. This means there are multiple steps within the biological process of cellular senescence that could potentially lead to therapeutic efficacy, giving senotherapeutic technologies flexibility and versatility.

Senotherapeutics can either kill the senescent cells (senolytics), block the SASP phenotype (senomodulators), reactivate immune cell clearance (senescence-associated immunomodulators) or block the damage that is causative of the senescent phenotype in the first place (senoblockers). Each method comes with its own opportunities and challenges and, ultimately, could be used in combination to tackle cellular senescence.

Senotherapeutics hold tremendous potential to ameliorate a wide range of pathological features along the continuum of the aging process. From early-stage damage (primary hallmarks) that drives senescence to later stage consequences of senescence pathology that manifest as chronic diseases such as osteoporosis, pulmonary fibrosis, insulin resistance, Alzheimer’s disease, macular degeneration and cardiovascular disease. So, let’s find out more about the difference senotherapeutic strategies currently in development.

Senolytics

Senolytics target cellular pathways that make senescent cells vulnerable to death, namely, senescent cell anti-apoptotic pathways (SCAP). There are multiple pathways that can be targeted to accomplish this, with the overall strategy of releasing the “molecular brakes” on the cellular suicide pathway (apoptosis) within senescent cells. Notably, senescent cells have up-regulated pro-survival pathways to protect them from their pro-apoptotic senescence-associated secretory phenotype (SASP) profile. This is akin to a car in which the acceleration pedal represents pro-survival pathways and the brake pedal represents pro-apoptosis pathways. Senescent cells have a foot on each pedal, allowing the acceleration (pro-survival pathways) to prevail.

Senolytics that help ease pressure on the acceleration pedal make senescent cells more sensitive to the foot that is pressing on the brakes (pro-apoptosis signalling) and subsequent cell death – this is a therapeutic opportunity to interfere with pro-survival pathways and make them vulnerable to their own pro-apoptotic signalling [1].

One of the major advantages of senolytics is the opportunity for intermittent dosing. Studies within multiple model systems have shown that monthly administration of senolytics is just as effective as daily in alleviating multiple chronic diseases [2], meaning therapies could be safer and more cost effective when brought to market.

However, just killing senescent cells may not always be enough: they need to be recognised and cleared away by the immune system to prevent secondary necrosis; combinatorial therapies that pair senolytics with immunomodulators to prevent undesirable side effects and maximise therapeutic efficacy could be the solution.

Senomodulators

Modulating the aberrant signalling cascade driven by the SASP has also been shown to mitigate the progression of chronic diseases and improve health [3]. Senomodulators defuse or “defang” senescent cells without killing them. They do this via targeting the aberrant (SASP) signalling network that drives the accumulation of senescent cells across the body. This can be done through disrupting the pathways that generate SASP or preventing their secretion. A relevant metaphor for this treatment paradigm would be to think of senescent cells like a viral infected host.

Damage accumulation (virus) pushes cells into a senescent (sick) state and these cells can go on to infect other cells within the body through SASP signalling (akin to sneezing around other humans). Senomodulators are akin to putting personal protective equipment, such as a mask, on senescent cells in order to prevent SASP propagation and spread of senescence.

The SASP contains over 100 different molecules that can be targeted (alone or in conjunction) to influence the behaviour of senescent cells. One of the major advantages of senomodulating strategies is their unparalleled selectivity which has led to the development of precision senostatics. Precision senostatics offer the opportunity for selective targeting of specific senescent populations based on their unique SASP signatures, as well as selectively targeting SASP molecules to allow senescent cells to maintain their physiological and reparative functions while defusing any toxic effects.

Senomodulators require a more continuous treatment regimen to maintain senescent cells in their defused state. Chronic treatment with any medication is generally more costly and can give rise to unwanted side effects.

Senoblockers

Senoblockers inhibit formation of senescent cells via clearing away various cellular damages that eventually lead to senescence phenotype. The main goal of senoblockers is to prevent the molecular signalling cascade that propagates further senescence. These technologies include genetic reprogramming and blocking the low grade chronic inflammation that accompanies aging and can lead to senescence. Senoblocker technologies hold significant promise as geroprotectors that prevent the progression (or onset) of senescence-associated chronic diseases. By suppressing the emergence of pathological senescence, senoblockers address the root of the problem and can avoid many of the potential challenges posed by other senotherapeutic technologies.

Senoblocker technologies share similar challenges with senomodulators and senolytics in their need for a continuous treatment regimen and the potential to disrupt the functional role of senescent cells in the body. Furthermore, success with senoblocker technologies is contingent upon gaining a better understanding of the various factors that give rise to senescence and propagate its pathogenic effects. As such, senoblockers presently represent the most fringe technology being developed in the senotherapeutics market.

Senescence-associated immunomodulators

Senescence-associated immunomodulators improve recognition and clearance of senescent cells by the immune system. This typically involves enhancing the functionality of our body’s Natural Killer cells to influence the turnover rate of senescent cells. The most promising research on senescent associated immunomodulators builds on strategies applied in the field of oncology that focus on checkpoint inhibitors and blocking decoy receptors that help senescent cells evade immune surveillance [4].

The threshold theory of senescent cell burden postulates that once senescent cell abundance crosses a certain threshold, it exceeds the capacity of the immune system to keep up with clearance and aging is accelerated. This theory implicates immune system clearance of senescent cells as the critical step (in an otherwise beneficial process) that leads to pathology [2]. Senescence-associated immunomodulators have the advantage of tapping into our bodies’ natural defence systems to restore a healthy balance of senescent cell density without compromising their physiological roles within the body. These therapies also hold tremendous promise for disease prevention, but this is contingent upon advances in biomarker discovery that would allow precise tracking of senescent cell density in humans.

The efficacy of immunotherapies can be unpredictable and, over time, cells can develop resistance to drug treatment. Biomarkers for the precise recognition and clearance of pathogenic senescent cells need to be developed, and immunotherapy drugs are often very costly.

Intrigued by the exciting and developing senotherapeutics field? Our market intelligence report on senotherapeutics is now available – order your copy here and watch out for more senotherapeutics-related articles coming soon.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939651/
[2] https://onlinelibrary.wiley.com/doi/full/10.1111/joim.13141
[3] https://pubmed.ncbi.nlm.nih.gov/33823141/
[4] https://link.springer.com/article/10.1007%2Fs00018-020-03746-x