Post-intensive care syndrome (PICS), characterized by physical and mental/cognitive symptoms occurs in some intensive care unit (ICU) survivors.  We developed a mouse model of PICS by combining acute lung injury (ALI) with lower limb immobilization in both young and aged mice. Clinically, these animals exhibited characteristics of PICS including disuse muscle atrophy, signs compatible with depression, and pulmonary and systemic inflammation. Single cell transcriptomic analysis in brain demonstrated the effect of ageing in several cell types, specially microglia and endothelial cells and analysis of treatment effect showed that aged mice is more susceptible to changes in gene expression by the induction of ALI. Shared upregulated genes in aged and young treated mice were identified. Our data indicates that the combination of ALI and immobilization induces gene programs in brain associated with depression or neurodegenerative disorders and differentially affects young and aged individuals.