What is cellular senescence?
Aging is often associated with the irreversible process of cellular senescence. Exposure to a range of stress factors, such as DNA damage, oxidative stress or oncogene activation, can induce cells to enter cell cycle arrest. This functions as a protective mechanism to prevent these cells from dividing. This process is particularly crucial when considering the risks of uncontrolled cell growth and therefore the importance of suppressing tumour formation. Senescence is also essential for embryonic development and plays a key role in wound healing and regeneration.
Cellular senescence doesn’t always have beneficial consequences. This is because senescent cells can secrete proinflammatory cytokines. These inflammatory mediators aren’t only associated with chronic inflammation but can also generate an environment that is favourable for tumour growth. Their overall accumulation contributes towards the senescence-associated secretory phenotype (SASP) that may increase one’s risk of developing many age-related diseases. Senescent cells can be eliminated by the body’s immune system. This clearance ability unfortunately reduces with age as a consequence of the process of immunosenescence.
Senotherapeutics refer to the therapeutic strategies that target cellular senescence. These can be subdivided into senomorphics that inhibit the proinflammatory secretory phenotype of senescent cells or senolytics that work by inducing apoptosis. This form of programmed cell death is exploited to selectively kill senescent cells. Senescent cells may be differentiated from healthy cells by their high expression of anti-apoptotic factors. The development of senolytic drugs to target cellular senescence provides hope for the treatment of several age-related diseases
How is Covid-19 linked to cellular senescence?
SARS-CoV-2 mortality rates have been directly correlated with the age of patients. This means that older age groups have been categorised as the most vulnerable throughout the course of the Covid-19 pandemic. A recent research article published in Science explored the use of senolytic drugs for reducing coronavirus mortality in elderly mice. Camell et al. demonstrated how these pharmacological agents improve the survival of older mice infected with mouse hepatitis virus (MHV). Infection with this mouse b-coronavirus was used to simulate the impact of a SARS-CoV-2 infection in humans.
Cox and Lord’s article, also published in Science magazine, summarises the findings of this paper. They highlight the link between cellular senescence and aging as the elimination of senescent cells has been shown to increase lifespan. The findings have pinpointed the effects of viral infection in increasing the formation of senescent cells exhibiting SASP. Therefore, the severity of a SARS-CoV-2 infection is associated with an individual’s proportion of senescent cells. This explains why patients with large amounts of senescent cells, such as the elderly or those suffering from chronic conditions, have formed such a huge proportion of Covid-19 deaths across the world.
Could senolytic drugs also be used to treat Covid-19 infections?
The discovery of the link between cellular senescence and the severity of a Covid-19 infection has opened up the potential for the use of senolytic drugs across several stages of a SARS-CoV-2 infection. This ranges from initial infection to long Covid patients suffering from the prolonged effects of this viral infection. Several senotherapeutics exist but Fisetin is an example that is currently undergoing clinical trials to assess whether this senolytic drug would be a safe option for treating Covid-19 patients.
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