Aging, Male Sex, Obesity, and Metabolic Inflammation Create the Perfect Storm for COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) is a novel threat that seems to result from the collusion between a new pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and an existing pandemic of metabolic disease driven by obesity. This Perspective explores the evolving epidemiological, clinical, biological, and molecular evidence to propose an unfolding paradigm in which old age, chronic metabolic disease (such as obesity, type 2 diabetes, and metabolic syndrome), and male biological sex produce a deadly symbiosis of dysregulated immunometabolism and chronic systemic inflammation that intensifies virally induced hyperinflammation associated with SARS-CoV-2 infection. It is intended to inspire new research directions and stimulate funding in this field.

Figure 1

Age, male sex, and excess adiposity interact with SARS-CoV-2 infection to produce the perfect cytokine storm. Obesity, type 2 diabetes, and metabolic syndrome are characterized by excess adipose tissue leading to meta-inflammation with production of proinflammatory cytokines like IL-6 that dysregulate innate immune cells of the lungs. In obesity, hyperleptinemia also acts as a proinflammatory cytokine on lung airway epithelial cells, immune cells, and fibroblasts creating a local inflammatory state. Aging is associated with dysregulation in immune functions and inflammaging with increased systemic proinflammatory cytokines, including IL-6. Male sex is also characterized by an intrinsic propensity to meta-inflammation. Upon SARS-CoV-2 infection, the cumulative effects of old age, male sex, and excess adiposity produce a state of heightened meta-inflammation, which skews immune cells to produce more chemokines and inflammatory cytokines, attracting more inflammatory cells, ultimately leading to a cytokine storm.