SUMMARY The familiar assertion that older persons are more likely to die from COVID-19 because of their declining immunity is factual but also reductive. This project seeks to generate more specific insight into the high COVID- 19 mortality among older adults by focusing on the role of T-cell telomere length (TL) in the lymphopenia that often develops in patients infected with SARS-CoV-2. The central hypothesis posits that COVID-19 patients with short telomeres are more likely to develop severe T-cell lymphopenia, less likely to normalize their T- cell count during the course of the disease, and therefore less likely to clear the virus and recover. It is directly relevant to aging because TL shortens with age, and older age poses a heightened risk of severe disease after infection with SARS-CoV-2. The work will also explore the potential role of T-cell TL in suppressing the innate immune response, a major contributor to the “cytokine storm” that is largely mediated by pro-inflammatory monocytes. The project will study 417 adults hospitalized with COVID-19, half of whom with a severe form of the disease indicated by admission to the ICU. Blood samples will be collected on admission (time point T1), at day 3 (time point T2) and at day 7 (time point T3). All-cause mortality will be determined up to 30 days after T1. As very short telomeres, not mean telomere length, undermine cell viability, T-cell TL parameters will be quantified by the novel Telomeres Shortest Length Assay (TeSLA), a method that detects and measures short telomeres, including those below the range detectable by standard methods. Aim 1 will examine the relation of T-cell TL parameters at T1 with mortality. It will test the hypothesis that short T-cell TL at T1 predicts mortality, and that T-cell lymphopenia at T2 is a mediator of this relationship. Aim 2 will probe deeper into the relation between T- cell TL parameters at T1 and mortality, testing the hypothesis that older age drives the pathway examined in Aim 1. The findings of these two aims will generate new knowledge about the relation between aging, T-cell TL parameters and T-cell lymphopenia, and test models that postulate causal effects of these factors on all-cause mortality in COVID-19. Aim 3, an exploratory aim, will examine the relation of T-cell TL parameters with selected cytokine levels and monocyte subsets in blood samples donated by 50 participants in Aims 1 and 2. This aim represents the first step of examining the role of T- cell TL in the innate immune response to infection by SARS- CoV-2. Findings of the study have the potential to transform understanding of the causes of COVID-19 lymphopenia, elucidate the mechanism underlying the relationship between older age and COVID-19 mortality, and motivate development of new treatments. They may also be relevant to understanding adaptive responses of older adults to vaccination against SARS-CoV-2. Finally, insight generated by this project will be important for not only the present pandemic but also outbreaks and pandemics by other β-coronaviruses that will almost certainly happen in the future.

PROJECT NARRATIVE This project will generate insight into the high mortality from COVID-19 among older adults by examining the role of T-cell telomere length in the T-cell lymphopenia that often develops in patients infected with SARS-CoV-2.