Age-dependent disease tolerance to SARS-CoV-2 infection

Trikha Rastogi, S.; Mesquita, M.; Fonseca, D. M.; Salazar, S.; Cardoso, S.; Faisca, P.; Drotleff, B.; Alenquer, M.; Lone, J.-C.; Miguel, V.; Sancho, D.; Herrero, L.; Paixao, T.; Amorim, M. J.; Jentho, E.; Graca, L.; Kitoko, J. Z.; Soares, M. P.

doi:10.64898/2026.06.27.734955

bioRxiv · 10.64898/2026.06.27.734955

Age-dependent disease tolerance to SARS-CoV-2 infection

Trikha Rastogi, S.·Mesquita, M.·Fonseca, D. M.·Salazar, S.·Cardoso, S.·Faisca, P.·Drotleff, B.·Alenquer, M.·Lone, J.-C.·Miguel, V.·Sancho, D.·Herrero, L.·Paixao, T.·Amorim, M. J.·Jentho, E.·Graca, L.·Kitoko, J. Z.·Soares, M. P.

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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 SummarySARS-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.

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Trikha Rastogi, S., Mesquita, M., Fonseca, D. M., Salazar, S., Cardoso, S., Faisca, P., Drotleff, B., Alenquer, M., Lone, J.-C., Miguel, V., Sancho, D., Herrero, L., Paixao, T., Amorim, M. J., Jentho, E., Graca, L., Kitoko, J. Z., Soares, M. P.. 2026-06-30. Age-dependent disease tolerance to SARS-CoV-2 infection. https://doi.org/10.64898/2026.06.27.734955

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