Post-COVID syndrome is connected to a sustained senescence-associated inflammatory response

Over two hundred million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)  since its emergence in 2019.  A significant number of them have also suffered a post-acute coronavirus disease (COVID-19) syndrome, in which symptoms and/or complications even after the virus can no longer be detected. The severity of COVID-19 and post-covid syndrome in the elderly indicates a possible relationship between this infection and aging.

One of the possible connections is cellular senescence – a state of irreversible cell-cycle arrest that can be induced by various factors. Senescent cells are non-dividing, immortalized, and tend to accumulate during the aging process, developing senescence-associated secretory profile (SASP). In SASP, they produce a range of pro-inflammatory factors, including inflammatory cytokines, chemokines, growth factors, and enzymes. Though the primary mechanism of cellular senescence is tumor suppression, the accumulation of senescent cells has been solidly connected to the aging and onset of aging-related inflammatory diseases.

These mechanisms prompted Tsuji and colleagues to examine the relationship between SARS-CoV-2 and cellular senescence, for which they set up several in vitro and in vivo experiments. They infected human lung diploid fibroblast cells (common subject in senescence studies) with SARS-CoV-2. During these experiments, the signs of cellular senescence were observed on day 9 of SARS-CoV-2 administration, which is consistent with previous reports on the senescent-inducing effect of certain viral infections. Interestingly, most of these cells no longer expressed SARS-CoV-2 protein, and its RNA was almost nondetectable by PCR. This indicated that the senescent phenotype could be indirectly prompted both in the infected and neighboring cells. Further cell experiments demonstrated that the infection indeed facilitates the production of senescence-promoting cytokines, TNF-α (tumor necrosis factor), and p16 (cyclin-dependent kinase inhibitor 2A). In the healthy organisms these proteins are involved in a variety of cellular signaling processes that influence cell growth and division.

Next, Tsuji et al. explored the hypothesis that inflammatory response connected to SASP serves as one of the primary reasons for post-covid syndrome in the series of experiments on Syrian hamsters and mice. They demonstrated not only that the expression levels of p16 and SASP factors remain high even at days 14 and 45 after SARS-CoV-2 but also that application of a senolytic drug (ABT-263) resulted in decreasing signs of senescence-connected inflammation in mice.

These findings imply that senolytic drugs may be beneficial in treating post-acute COVID-19 syndrome. However, the authors caution that a more detailed analysis is needed to determine an actual possible use in the clinical practice.

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