Underlying Vulnerabilities to the Cytokine Storm and Adverse COVID-19 Outcomes in the Aging Immune System

Older adults are far more vulnerable to adverse health outcomes and mortality after contracting COVID-19. There are likely multiple age-related biological, clinical, and environmental reasons for this increased risk, all of which are exacerbated by underlying age-associated changes to the immune system as well as increased prevalence of chronic disease states in older adults. Innate immune system overactivity, termed the cytokine storm, appears to be critical in the development of the worst consequences of COVID-19 infection. Pathophysiology suggests that viral stimulation of the innate immune system, augmented by inflammatory signals sent from dying cells, ramps up into a poorly controlled outpouring of inflammatory mediators. Other aging-related changes in cells such as senescence as well as higher prevalence of chronic disease states also likely ramp up inflammatory signaling. This in turn drives downstream pathophysiological changes to pulmonary, cardiovascular, skeletal muscle, and brain tissues that drive many of the adverse health outcomes observed in older adults. This article provides an overview of the underlying etiologies of innate immune system activation and adaptive immune system dysregulation in older adults and how they potentiate the consequences of the COVID-19-related cytokine storm, and possible uses of this knowledge to develop better risk assessment and treatment monitoring strategies.