Age-dependent disease tolerance to SARS-CoV-2 infection
Year: 2026
Type: preprint
Abstract: ABSTRACT Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations. One-Sentence Summary SARS-CoV-2 infection induces adipose tissue lipolysis to release fatty acids that drive myelopoiesis and monocyte production for lung protection and COVID-19 disease tolerance, but this protective circuit declines with age, increasing disease severity in the elderly.
Authors: Sonia Trikha Rastogi, Miguel Mesquita, Diogo Martins Fonseca, Sara Salazar, Silvia Cardoso, Pedro Faisca, Bernhard Drotleff, Marta Alenquer, Jean-Christophe Lone, Veronica Miguel, David Sancho, Laura Herrero, Tiago Paixão, Maria João Amorim, Elisa Jentho, Luis Graça, Jamil Zola Kitoko, Miguel P. Soares
Institutions: Gulbenkian Institute for Molecular Medicine, University of Lisbon, European Molecular Biology Laboratory, Universidade Católica Portuguesa, Spanish National Centre for Cardiovascular Research, Instituto de Salud Carlos III, Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7166806332