Shorter telomere lengths in patients with severe COVID-19 disease

Abstract

The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.

Keywords: COVID-19; SARS-CoV-2; aging; telomeres.

Figure 1

Correlation between HT Q-FISH and PCR and TRF techniques for telomere length measurements. (A) Correlation of telomere length measured by TRF, qPCR and HT Q-FISH in Peripheral blood mononuclear cell (PMBC) samples from 89 individuals. (B, C) Linear regression analysis was used to determine the rate of telomere shortening (B) and the rate of the increase of short telomeres (<3kb) (C) per year in PMBCs. The telomere length data in (B, C) correspond to HT-qFish analysis. The Pearson correlation coefficient and linear regression equation were determined using GraphPad Software.

Figure 2

Telomere shortening and of increase in short telomeres with age in men and women. (A, B) Percentage of short telomeres (<3 kb) in PMBC samples. Mean telomere length (A) and percent of short telomeres (<3kb) (B) in PMBCs from male (blue) and female (red) patients. Linear regression analysis was used to assess the rate of telomere shortening expressed as number of bp loss and the increase of the percentage of short telomeres per year.

Figure 3

Correlation between telomere length, age and COVID-19 severity. (A–D) Pearson correlation analysis between telomere length (A, C, D) or percentage of short telomeres (<3 kb) (B) and age or COVID-19 severity in PMBC samples. In (A, B) telomere length was analysed by HT-QFISH and in (C, D) by TRF and PCR, respectively. The severity score was established by assigning values of 1, 2, 3, 4 for mild, moderate, severe, and acute, respectively (see Materials and Methods). The Pearson r coefficient and the P values are indicated.

Figure 4

Correlation between age and COVID-19 severity and telomere length. (A, B) Person correlation analysis between age and telomere length measured by HT Q-FISH in PMBC samples (A) and with percentage of short telomeres (<3 kb). The severity score was established by assigning values of 1, 2, 3, 4 for mild, moderate, severe and acute, respectively (see Materials and Methods). The Pearson r coefficient and the P values are indicated.

Figure 5

Patients with shorter telomeres develop more severe COVID-19 disease. (A) The telomere lengths of patients were distributed into the quartiles <25% (<11.68 kb), 25-75% (11.68–14.96 kb) and >75% (>14.96 kb) and correlated with COVID-19 severity. (B) The abundance of short telomeres was distributed into the quartiles <25% (<14.73%), 25-75% (14.73-19.32%) and >75% (>19.32%) and correlated with COVID-19 severity. Data represent mean values ±SEM. Statistical significance was assessed using Student’s t test.

Figure 6

Patients with a higher COVID-19 severity score show faster telomere shortening rates. (A, B) Telomere shortening (A) and increase in percent of short telomeres (<3kb) (B) with age in patients diagnosed with mild-moderate and severe-acute COVID-19. Linear regression analysis was used to assess the number of bp loss and of the percent of short telomeres per year (<3 kb) in PMBC of these donors. Statistical significance was assessed using the Mann-Whitney test. (C) Whisker plot representation of telomere length. The between 60-69 and older than 70-year-old were pooled together within the same age group. The patients diagnosed with mild or moderate and those diagnosed with severe or acute were grouped. The telomere length corresponding to individual telomere foci were plotted according to Covid-19 severity groups. The ends of the box are the upper and lower quartiles so that the box spans the interquartile range. The middle line represents the median and bars to standard deviation. The statistical significance was calculated by one way Anova with post tukey test. n= number of foci.