Role of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by a pathological hyperinflammatory response which results in a dysregulated immune response. Current advancements in aging research indicates that aging pathways have fundamental roles in dictating healthspan in addition to lifespan. Our review discusses the aging immune system and highlights that senescence and aging together, play a central role in COVID-19 pathogenesis. In our review, we primarily focus on the immune system response to SARS-CoV-2 infection, the interconnection between severe COVID-19, immunosenescence, aging, vaccination, and the emerging problem of Long-COVID. We hope to highlight the importance of identifying specific senescent endotypes (or "sendotypes"), which can used as determinants of COVID-19 severity and mortality. Indeed, identified sendotypes could be therapeutically exploited for therapeutic intervention. We highlight that senolytics, which eliminate senescent cells, can target aging-associated pathways and therefore are proving attractive as potential therapeutic options to alleviate symptoms, prevent severe infection, and reduce mortality burden in COVID-19 and thus ultimately enhance healthspan.

Keywords: COVID-19; SARS-CoV-2; aging; immunosenescence; mortality; sendotypes; senescence; senolytics; severity; vaccination.

Figure 1

Senescence and Immune Dysregulation in COVID-19. SARS-CoV-2 infection and vaccination are both associated with major immunological alterations. These are linked to both aging and senescence. The pathological hyperinflammatory response evident in SARS-CoV-2 infection and the sub-optimal antibody immune responses following vaccination against SARS-CoV-2 may be regulated by novel senescence signatures. Identification of novel senescence signatures in combination with applied machine learning techniques and the Horvath Clock may help to identify novel senescence signatures that may accurately differentiate severe COVID-19 patients from patients with mild to no symptoms (non-severe). It may also identify novel senescence signatures which are implicated in the waning antibody responses evident following vaccination and booster vaccinations. Figure generated using Biorender.com accessed on 17 November 2021.

Figure 2

Hallmarks of Potential Sendotypes for COVID-19. The diagram outlines the hallmarks of potential sendotypes in COVID-19. The hallmarks listed can be used in combination to identify specific senescent endotypes (or “sendotypes”), which can used as determinants of COVID-19 severity and mortality. Indeed, identified sendotypes could be therapeutically exploited for therapeutic intervention via senolytics, to alleviate symptoms, prevent severe infection, and reduce morbidity and mortality in COVID-19. Future studies are required to understand the mechanistic underpinnings of each hallmark and how it would contribute towards specific sendotypes. Figure generated using Biorender.com accessed on 17 November 2021.