Aging in COVID-19: Vulnerability, immunity and intervention

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic was first reported in Wuhan, China in December 2019, moved across the globe at an unprecedented speed, and is having a profound and yet still unfolding health and socioeconomic impacts. SARS-CoV-2, a β-coronavirus, is a highly contagious respiratory pathogen that causes a disease that has been termed the 2019 coronavirus disease (COVID-19). Clinical experience thus far indicates that COVID-19 is highly heterogeneous, ranging from being asymptomatic and mild to severe and causing death. Host factors including age, sex, and comorbid conditions are key determinants of disease severity and progression. Aging itself is a prominent risk factor for severe disease and death from COVID-19. We hypothesize that age-related decline and dysregulation of immune function, i.e., immunosenescence and inflammaging play a major role in contributing to heightened vulnerability to severe COVID-19 outcomes in older adults. Much remains to be learned about the immune responses to SARS-CoV-2 infection. We need to begin partitioning all immunological outcome data by age to better understand disease heterogeneity and aging. Such knowledge is critical not only for understanding of COVID-19 pathogenesis but also for COVID-19 vaccine development.

Keywords: Aging; Anti-IL-6 therapy; COVID-19; Cytokine storm; Immunopathology; Immunosenescence; Inflammaging; SARS-CoV-2; Vaccination.

Fig. 1

The Johns Hopkins Coronavirus Resource Center webpage. This webpage “Global Map” was taken from its website (https://coronavirus.jhu.edu/map.html) at the time shown at the left lower corner. The website tracks confirmed COVID-19 cases and death across the globe real time. It can be further drilled down to a country or territory for more detailed information. The website also provides other useful information about the ongoing pandemic.

Fig. 2

ACE2 as the key human cellular receptor for SARS-CoV-2, its role and underlying molecular mechanisms in the pathogenesis of COVID-19. In addition to viral entry, binding to ACE2 of SARS-CoV-2 in concert with S-protein priming by TMPRSS2 and subsequent endocytosis result in dysregulation of the angiotensin system, leading to the loss of ACE2-mediated systemic health protection. These molecular events also upregulate ADAM17-mediated proteolytic cleavage of not only ACE2 itself, which further dysregulates the angiotensin system, but also its primary substrate releasing TNF-α along with IL-6 and other cytokine mediators, leading to cytokine storm. TMPRSS2: transmembrane serine protease 2; ADAM17: a disintegrin and metalloproteinase 17. From Gheblawi M, et al. Circulation Research 2020;126:1457–1475 with permission.

Fig. 3

Nation-wide data on number of hospitalizations (A), ICU admissions (B), and deaths (C) of COVID-19 patients by age group and sex reported up to May 7, 2020 in France. From Salje H, et al. Science 10.1126/science.abc3517 (2020) with permission.

Fig. 4

Percentages of hospitalizations (light blue bar), ICU admissions (blue striped bar), and deaths (white bar) of COVID-19 patients by age group in the US. Adapted from the CDC, https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm.

Fig. 5

The immune hypothesis. This hypothesis encompasses age-related impairment of immune response and protection against SARS-CoV-2 and immunopathology. Immune response includes humoral immunity (i.e., antibody response) and cell-mediated immunity (CMI) (right). While age-related immunosenescence is believed to weaken immune protection, vaccination enhances it. Inflammaging and cytokine storm may lead to Immunopathology (left). Not all immune responses are protective as antibody-dependent enhancement (ADE) in humoral immunity may promote SARS-CoV-2 infection while T_h17 response in CMI may contribute to cytokine storm. Anti-IL-6 therapy with monoclonal antibodies against either IL-6 or IL-6 receptor currently in clinical trials can block cytokine storm and its downstream event and/or suppress T_h17 response. Age-related decrease of physiological reserve in respiratory and other organ systems may also contribute to vulnerability. Together, they lead to disproportionately severe COVID-19 and high mortality in older adults.

Fig. 6

Death curves in Philadelphia and St. Louis during 1918 Spanish flu pandemic (panel A, adapted from Hatchett RJ, et al. Proc. Natl. Acad. Sci. U. S. A. 2007; 104, 7582-7587) and curves of seven-day rolling average of newly confirmed COVID-19 cases in the US (red) and EU (blue) (panel B, Johns Hopkins Coronavirus Resources Center, https://coronavirus.jhu.edu).