Figure 2. Factors that increase the fatality risk of COVID-19. Epigenetic dysregulation, immune defects, advanced biological age, and other factors increase the risk of cytokine storm and COVID-19 fatality. Tightly controlled activation of the innate immune system is essential for viral recognition and clearance. Cytokine storm is the result of sustained activation of the inflammatory signaling cascade and can result in hypercoagulation in small blood vessels, which leads to tissue damage, DIC and multi-organ failure. Inflammaging and immunosenescence contribute to the development of cytokine storm. D-dimer, a fibrin degradation product and prognostic of disseminated intravascular coagulation (DIC), and elevated levels of the cytokine, IL-6, are associated in the clinic with increased fatality. Epigenetic dysregulation of the immune system and of the renin-angiotensin system (R)AS may increase fatality risk. A variety of biological clocks have been shown to predict human health and longevity more accurately that chronological age. An individual with a biological age greater than their chronological age is thought to be undergoing accelerated aging, which may increase the risk of COVID-19 fatality. Individuals with comorbidities such as cardiovascular disease, diabetes, obesity and COPD, are at greater risk for COVID-19 fatality. Conversely, individuals who live healthy lifestyles and consume geroprotectors such as metformin, resveratrol and NAD+ boosters may have a decreased risk of fatality. Created with BioRender.