Short Telomeres and a T-Cell Shortfall in COVID-19: The Aging Effect

Abstract

The slow pace of global vaccination and the rapid emergence of SARS-CoV-2 variants suggest recurrent waves of COVID-19 in coming years. Therefore, understanding why deaths from COVID-19 are highly concentrated among older adults is essential for global health. Severe COVID-19 T-cell lymphopenia is more common among older adults, and it entails poor prognosis. Much about the primary etiology of this form of lymphopenia remains unknown, but regardless of its causes, offsetting the decline in T-cell count during SARS-CoV-2 infection demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. We have built a model that captures the effect of age-dependent TL shortening in hematopoietic cells and its effect on T-cell clonal expansion capacity. The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity plummets by more than 90% over the next ten years. The collapse coincides with the steep increase in COVID-19 mortality with age. HCTL metrics may thus explain the vulnerability of older adults to COVID-19. That said, the wide inter-individual variation in HCTL across the general population means that some younger adults with inherently short HCTL might be at risk of severe COVID-19 lymphopenia and mortality from the disease.

Significance statement: Declining immunity with advancing age is a general explanation for the increased mortality from COVID-19 among older adults. This mortality far exceeds that from viral illnesses such as the seasonal influenza, and it thus requires specific explanations. One of these might be diminished ability with age to offset the development of severe T-cell lymphopenia (a low T-cell count in the blood) that often complicates COVID-19. We constructed a model showing that age-dependent shortening of telomeres might constrain the ability of T-cells of some older COVID-19 patients to undertake the massive proliferation required to clear the virus that causes the infection. The model predicts that individuals with short telomeres, principally seniors, might be at a higher risk of death from COVID-19.

Fig. 1.. Age-dependent T-cell telomere length (TL) and its relation to T-cell clonal expansion.

a displays age-dependent TL before (▬) and after (▬) clonal expansion. Naïve T-cell clonal expansion shortens telomeres by Δ, where Δ_max is T-cell telomere shortening resulting from expansion to form the maximal clonal size (MCS). The telomeric brink (TL_B) of 5 kb is TL that increases the risk of cessation of replication. TL₂₀ is TL at 20 years, TL_O is telomeric onset, which indicates the shortest T-cell TL that enables attaining MCS. X_O is age of onset of clonal expansion limitation. b displays T-cell clonal expansion size vs age from onset X_O. Circle areas depict relative clonal size in 2-year intervals after X_O. Light blue circle is MCS.

Fig. 2.. Population distribution of T-cell TL at age 20 (TL₂₀), T-cell TL shortening with age, and age-dependent change in T-cell clone size (CS).

a displays the TL₂₀ distribution, showing mean TL = 7.3 kb (▬), long TL (mean + SD) = 7.9 kb (▬), and short TL (mean – SD) = 6.7 kb (▬). b displays age-dependent change in T-cell for mean, long and short TL₂₀. Past the telomeric onset (TL_O = 6.4 kb), TL is insufficient to produce MCS because a full clonal expansion drops TL below the telomeric brink (TL_B = 5 kb). The TL_O is reached at different ages of onset (X_O), i.e., an older age for T-cells with long T-cell telomeres and younger with T-cells with short telomeres. The age-dependent T-cell TL shortening (0.03 kb/year) for T cells with mean, long and short telomeres at TL₂₀ is shown by the lines. c shows that the T-cell CS is partitioned by the X_O into plateau and slope regions. T cells with mean, long or short TL₂₀ achieve MCS on the CS plateau, but their CS exponentially collapses (slope) once their TLs shorten below TL_O of 6.4 kb and exceed X_O (at different ages).

Fig. 3.. Shifts by age in naïve T-cell TL distribution and relative frequency (0 to 10) of T-cell clone size (CS) in the population.

a displays the shift in TL₂₀ distribution (Fig. 2a) resulting from age-dependent shortening of 0.03 kb/year. It depicts TL < TL_O (6.4 kb) by blue bars (█) and TL > TL_O by red bars (█). b displays relative frequency of CS’s generated by naïve T-cell clonal expansion corresponding to the categories of TL below or above TL_O. It shows that maximal CS (MCS) of ~ 10⁶ cells occurs in individuals with naïve T-cell TL > TL_O, while limited CS (LCS) occurs in those with naïve T- cell TL ≤ TL_O. At age 20, naïve T cells of nine out of ten individuals can generate MCS. At age 70, naïve T cells of less than two out of ten individuals can generate MCS, and seven out of ten generate clone sizes that are less than 0.1 MCS. At age 50 the population is approximately equally divided between the MCS and LCS groups.

Fig. 4.. Steps linking mean limited clone size (LCS) to COVID-19 mortality and general mortality Hazards ratios₂₀ in the population.

a displays data based on COVID-19 mortality (●) and non- COVID-19 mortality (●), and corresponding exponential fitted relationships for Hazards ratios₂₀ (▬ and ▬). b displays the relationship of mean LCS in units of 10⁶ cells with age, generated with Eq. 2, using the TL₂₀ distribution of Fig. 2a. c displays the relationships of Hazards ratios₂₀ generated from COVID-19 mortality and non-COVID-19 mortality plotted against mean LCS obtained from b. The top of the panel also displays age. The divergence between the COVID-19 and non-COVID-19 mortalities occurs at mean LCS of ~ 0.13 × 10⁶ T cells. At the corresponding age, 50 years, the population is about evenly divided into the LCS and MCS sub-populations (Fig. 3b). After this age, the majority of the population is in the LCS subpopulation, which is susceptible to COVID-19 mortality, whereas the MCS group is not.