Leonard Hayflick revealed in the 1960s that cultured human diploid cells had limited proliferative ability, with cells ceasing to multiply after serial passage in vitro. This was the first time the term "cellular senescence" was used to describe a permanent condition of cell cycle halt.
Hayflick is now regarded as one of history's most influential biologists, even though his study and results at the time were contentious because they contradicted Alexis Carrel's earlier notion that cells are eternal. Hayflick entirely disproved this orthodoxy, which had been held for 60 years, and as a result, the "Hayflick Limit" was born.
Dasatinib (D, an FDA-approved tyrosine kinase inhibitor), Quercetin (Q, a flavonoid found in many fruits and vegetables), Navitoclax, A1331852, and A1155463 (Bcl-2 pro-survival family inhibitors), and Fistein have all been tested as senolytic agents (F, a flavonoid). Cardiac glycosides, such as digoxin, which is currently used to treat irregular heartbeats associated with atrial fibrillation, have also been shown to have broad senolytic activity. Such senolytic compounds have been shown to work by temporarily limiting the pro-survival linkages that protect senescent cells from apoptosis while not negatively affecting proliferating or quiescent, differentiated cells.
Currently, no such senescence-aging-related biomarker signatures have been identified for coronavirus disease 2019 (COVID-19) risk stratification. Such novel biomarker signatures will inevitably improve clinical outcomes for patients by allowing for early intervention and stratification.
Because COVID-19 research is still in its early stages, more research is needed to explore, identify, and validate potential novel stratification signatures that have robust clinical utility in identifying the risk of severe infection versus non-severe infection and helping recognize patients who are more likely to require ICU admission versus those who can be treated in non-intensive care wards. A review published in Cells discussed characteristics of cellular senescence, the role of senescence in cancer, and the role of the telomere clock in aging.
COVID-19 research is now working on discovering and verifying prognostic, diagnostic, and predictive markers that are more robust and reliable than current inflammatory markers using proteomics and transcriptome analysis. Researchers are also attempting to determine whether the presence of specific biomarkers makes a patient more vulnerable to a more severe infection.
The discovery of such biomarkers could aid in predicting the severity of an infection and, as a result, in determining the level of medical intervention that would be far more effective and could be given to the patient much more quickly. For example, long pentraxin 3 (PTX3) is an independent, strong prognostic signal for predicting death in COVID-19 and is a superior biomarker compared to traditional inflammatory markers, according to a recent study.
Another study, on the other hand, refuted this finding, claiming that PTX3 is no more helpful than other markers and that there are more relevant inflammatory pathway indicators. Another study found that patients with COVID-19 have greater Growth Differentiation Factor 15 (GDF-15) levels and that higher levels are linked to a worse result. This biomarker, once again, was found to be superior to commonly used cardiovascular and inflammatory indicators.
Several differently expressed proteins that are unique to COVID-19 severity have also been discovered in other research. Telomere shortening is linked to senescence, as previously stated. A recent study found that patients with shorter telomeres have a higher probability of acquiring severe COVID-19 diseases, reinforcing the concept that senescence is associated with COVID-19.
China was the first country to report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in its population. COVID-19's case fatality ratio (CFR) appears to grow with age, according to early data from China. The CFR for patients aged 40 years or less was reported to be less than 0.4%, increasing to 8% for patients in their 70s, and then to a staggering 14.8% for patients aged 80 years and above [141,149].
In its COVID-19 CFR data, Italy reported the same severe effect of aging, with the CFR being less than 0.4% for patients aged 40 years or less, increasing to 12.8% for patients in their 70s, and then to 20.2% for patients in their 80s and above.
Furthermore, Italy's overall CFR was substantially higher than China's, at 7.2% vs. 2.3%, which could be explained by the fact that Italy has one of the world's greatest numbers of senior persons. Similar findings have been reported from many nations, demonstrating the strong link between COVID-19 CFR and aging, with the CFR for COVID-19 increasing exponentially with age. The median age of patients seriously ill with COVID-19 was 63 years old, according to a separate retrospective analysis of 1591 patients in Italy.
COVID-19 data released by the US Centers for Disease Control and Prevention (CDC) on September 15, 2021, shows that the older age group of 65 years and above accounted for 77.7% of COVID-19 deaths, while the younger age group of 45 years or less accounted for only 3.3%, highlighting age as a major determinant factor in COVID-19 mortality once again.
To further understand why some people develop more severe COVID-19 than others and to uncover particular elements of the aged immune system, such as novel sendotypes (senescent endotypes) that predispose the elderly to more severe clinical consequences, including mortality, more research is needed.
It will also be intriguing to see if senescence plays a complicating role in fading immune responses, particularly in the elderly, and if senolytic treatments could ameliorate immune response declines after vaccination. It would also be interesting to see if senescence has a role in patients' susceptibility to long COVID.