The Association Between Aging, Inflammation, and Clinical Outcomes in Acute Respiratory Distress Syndrome

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ABSTRACT Acute Respiratory Distress Syndrome (ARDS) is a highly fatal condition characterized by diffuse pulmonary infiltrates and severe hypoxemia. The outcomes of ARDS are significantly worse in older adults, a finding that has been underscored by the ongoing COVID-19 pandemic. ARDS is known to be more severe with advanced biological age, as demonstrated by the relationship between telomere length and severity of ARDS. Aging is characterized by inflammation and cellular senescence, two processes which may mechanistically explain worse outcomes seen in older adults with ARDS. Recently, two inflammatory subphenotypes have been described in ARDS. The hyperinflammatory subphenotype has a higher mortality, similar to that of older adults. A considerable overlap exists in the protein biomarkers which define the hyperinflammatory subphenotype and those which circumscribe the age defining process of senescence, suggesting that age may play a role in the biological heterogeneity of ARDS. Furthermore, inflammation and cellular senescence are both canonical age- related processes. The proposed research will test the relationships between aging, inflammation, and outcomes in ARDS and determine whether biological age differs between the two previously defined inflammatory subphenotypes of ARDS. Finally, this work will attempt to define novel senescent subphenotypes of ARDS and establish the degree to which these subphenotypes overlap with the already defined inflammatory subphenotypes. This work will be performed in two distinct cohorts, a COVID-19 and non-COVID-19 cohort allowing for additional analysis regarding whether the relationship between age, inflammation, and outcomes is differentially expressed in COVID-19 versus non-COVID-19 ARDS. This work will contribute significantly to a deeper mechanistic understanding of ARDS and will support predictive enrichment in ARDS clinical trials which will contribute to more effective therapies for older adults with ARDS.