Senotherapy: the science of winding back the ageing clock

By Jia Hua Wang

Global life expectancy has increased markedly within the past century due to enhanced access to healthcare and improved healthcare services. By 2050, it is estimated that one sixth of the world’s population will be aged 65 or above (United Nations, 2020). However, as ageing remains one of the major risk factors in diseases, the increased life expectancy of humans is accompanied by the increased prevalence of age-related diseases (ARDs) such as cardiovascular and neurodegenerative diseases and cancer. Currently, ARDs are among the leading causes of death and morbidity worldwide (Kim & Kim, 2019). In view of the health issues surrounding ageing, many studies are now focusing on anti-ageing strategies with hopes of slowing down ageing and reducing or delaying the onset of ARDs. Consequently, current research has evolved to place greater emphasis on maintaining better health during ageing, which corresponds to a better quality of life in old age (Shetty et al., 2018).

Ageing is a familiar aspect of biology, yet it is not well-understood due to its inherent complexity. For example, ageing can occur at different rates for different individuals and for different tissues within the body. In this case, ageing refers to biological ageing (or senescence) and should be clearly distinguished from chronological ageing. While chronological age is how age is primarily defined, biological age is influenced by genetic and environmental factors and is, thus, a more reliable proxy for ageing (Jylhävä, Pedersen & Hägg, 2019). Presently, there exist many evolutionary theories attempting to ascertain the specific causes of ageing. Current understanding suggests that ageing is caused not by active genetic programming, but by evolutionary limitations in somatic maintenance which result in an accumulation of damage at the molecular and cellular level (Kowald & Kirkwood, 2016). As such, organisms with long lifespans are genetically determined to make greater investments in cellular maintenance and repair than short-lived ones. This results in slower accumulation of damage but comes with certain evolutionary trade-offs (Kirkwood, 2005). 

At the cellular level, senescence can be induced by telomere shortening (replicative senescence) or by the accumulation of multiple developmental, stress-associated, or DNA damage induced cues (stress-induced premature senescence). Some known stressors include oncogene activation, increased levels of reactive oxygen species (ROS), and ultraviolet radiation (Myrianthopoulos, 2018). Senescent cells (SCs) are characterised by a typically irreversible cell cycle arrest and exhibit a multitude of diverse phenotypical features. These include tolerance against apoptosis, modified cellular morphology and altered chromatin organization (Docherty et al., 2020). Normally, cells enter acute cellular senescence in response to stressors, resulting in repair or clearance by the immune system (e.g. macrophages, neutrophils, or natural killer cells). Acute SCs thus occur transiently as a defence mechanism against uncontrolled growth and malignant transformation (Zeng, Shen & Liu, 2018). Beyond tumour suppression, they are also responsible for key physiological functions such as tissue repair, wound healing, and embryonic development (Docherty et al., 2020).

Notably, current studies indicate that chronic senescence can evolve from acute SCs as a result of impaired immune-mediated clearance, coupled with a gradual build-up of cellular stress and damage (Docherty et al., 2020). While unable to proliferate, chronic SCs are still metabolically active and possess altered transcriptomes and secretomes. The resulting senescence-associated secretory phenotype (SASP) includes pro-inflammatory cytokines, chemokines, tissue-damaging proteases, and growth factors (van Deursen, 2014). By secreting these bioactive signals, chronic SCs exert deleterious effects on the neighbouring tissue microenvironment. Persistence of chronic SCs and their subsequent accumulation in tissues over time exacerbate these effects which ultimately promote ageing and ARDs. This is supported by consistent findings of SCs at pathological sites (Myrianthopoulos, 2018). Furthermore, the injection of SCs in mice is sufficient to induce age-related conditions like osteoarthritis (Xu et al., 2017).  

To combat ageing and its associated diseases, different classes of approaches are currently in development and range from clinical procedures to lifestyle changes. Particularly, pharmaceutical interventions that target SCs, or senotherapeutics, are gaining traction and these can be further classified into senolytics and senomorphics. Senolytics selectively eliminates SCs while senomorphics inhibit SASP and suppress senescence indirectly (Myrianthopoulos, 2018). Potential candidates for senolytics may include inhibitors of anti-apoptotic proteins such as Bcl-2 and Bcl-xL as they target the anti-apoptotic pathways that SCs are reliant on for survival (Kim & Kim, 2019). Currently, there are several classes of senolytic agents reported, of which most are natural compounds such as quercetin, fisetin, and piperlongumine (Shetty et al., 2018). Senomorphics, however, aim to modulate SCs without killing them. This can be achieved by interfering with senoinflammation and senescence-related signalling pathways  (Kim & Kim, 2019). Finally, geroprotectors may also be employed to slow down cellular senescence by targeting its stressors. For example, telomerase activators and antioxidants, which reduce oxidative stress from ROS, both possess geroprotective properties (Moskalev et al., 2017). 

As SCs are specifically targeted by senotherapeutics, robust identification of cellular senescence is key. Currently, the few biomarkers utilized include increased production/activity of cyclin-dependent kinase (CDK) inhibitors p16INK4a and p21CIP1, senescence-associated β-galactosidase (SA-β-gal), and lipofuscin, a nondegradable ageing by-product (Myrianthopoulos, 2018). However, no single biomarker is found to be specific to SCs and the presence of any biomarker alone is insufficient to confirm senescence (Docherty et al., 2020). 

In summary, senotherapy is a relatively new but fast-growing field. While many senotherapeutics show considerable promise in combating ageing and ARDs, their long-term efficacy and potential side effects remain unclear due to the lack of extensive clinical trials. Moving forward, it is also important to pay close attention to the ethical implications of intervening with ageing, and to understand the complexity of the impact it has on different industries and stakeholders within society.

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