A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin

Abstract

We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.

Keywords: Aging; COVID-19; Geroscience; Immunity; Metformin.

Fig. 1

Geroscience and immune resilience: acute and long-term health. Metformin use (blue line) initiated prior to acute illness like COVID-19 (left most panel) may improve resilience resulting in fewer events like hospitalization (dotted line), briefer recovery time, and improved return to baseline health compared to non-use (black line). Greater long-term health effects could be observed as improved response to vaccine and prevention or delay of age-related diseases and geriatric syndromes

Fig. 2

Metformin alleviates chronic proinflammatory immune signaling and restores immune response. Metformin’s cellular mechanisms include weak inhibition of complex I of the mitochondrial electron transport chain, activation of the energy sensor AMP-activated protein kinase, inhibition of the heteromultimeric protein kinase mTORC1, and suppression of elevated proinflammatory cytokines production. Converging evidence also implicates the gut microbiome which further alleviates inflammation and phagosome-lysosome fusion which induces phagocytosis of neutrophils to reduce pathogen burden. The collective result is a dampened broad proinflammatory cytokine signaling and improved immune cell activation