COVID-19 is an emergent disease of aging

Abstract

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is known to preferentially target older subjects and those with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in all countries tested, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to antiviral approaches, by approaches that target the aging process.

Keywords: COVID-19; age-related diseases; gene expression; lifespan; pneumonia; viral infection.

FIGURE 1

Age is a major risk factor for COVID‐19. (a) Confirmed cases of COVID‐19 in Italy. Data are through June 23, 2020. (b) Deaths in Italy. Men are in dark blue, and women in light blue. (c) Case fatality rate in men and women across age groups. (d) Mortality rate exponentially increases with age. Case fatality rate as a function of age for indicated countries. Linear regression of log of case fatality rate on age is shown by light lines. Men are shown in dark blue and women in light blue. Combined cases (men + women) are shown in black for indicated countries. mrdt—mortality rate doubling time. (e) COVID‐19 mortality as a function of the median age of the country. The countries discussed in the study are labeled

FIGURE 2

Conditions contributing to deaths involving COVID‐19. (a) Percentage of deceased patients diagnosed with the corresponding comorbidity in the United States as of June 22, 2020. (b–c) Age‐related percentages for (b) circulatory diseases and (c) respiratory diseases. Other diseases are shown in Figure S5

FIGURE 3

Pneumonia as an aging‐related disease. (a) Incidence of pneumonia (green) and deaths with pneumonia as the primary cause (red) across age groups in the UKB cohort. (b) Case fatality rate as a function of age in UKB. Linear regression of log of case fatality rate on age is shown by a light line. (c) Risk factors associated with death from pneumonia. Logistic regression odds ratio (OR) for UKB phenotypes. Phenotypes with p‐value < 0.05 marked in blue. (d) Mortality rate of COVID‐19 (red), pneumonia (purple), influenza (green), and all‐cause mortality (blue), in the United States from Feb 1, 2020, to June 27, 2020. (e) Mortality rate of pneumonia, COVID‐19, and other infectious diseases in Spain. COVID‐19 deaths recorded from Feb 11, 2020, to May 10, 2020 (89 days). The mortality rate for the rest of causes corresponds to the 5‐year average (2014 to 2018) normalized to a period of 89 days. All panels combine men + women

FIGURE 4

Age‐related changes in SARS‐CoV‐2 receptor (ACE2) gene expression. Expression of (a) ACE2 and (b) TLR7 mRNAs in human lung samples. TPM (Transcripts Per Million) corresponds to normalized RNA‐seq expression. p‐values were calculated using the Mann‐Whitney test; ns—not significant, *p < 0.05, **p < 0.01. (c) Distribution of genome‐wide correlations between age and expression of genes in the lung. ACE2 is one of top genes whose expression increases with age. GTEx was used for these analyses. Cases on ventilator immediately before death were excluded