Calorie restriction increases the sensitivity of progeroid Ercc1^Δ/- mice to acute (neuro)inflammation

Hospitalized elderly patients frequently suffer from delirium, especially in the context of sepsis-associated encephalopathy. Current treatments of delirium are merely symptomatic. Calorie restriction (CR) is both a promising strategy to protect against sepsis and has beneficial effects on aging-induced neurodegeneration. In this study, we investigated whether six weeks of 30% CR had protective effects on lipopolysaccharide (LPS) induced (neuro)inflammation in wild-type (WT) and progeroid mice deficient in the DNA excision-repair gene Ercc1 (Ercc1^Δ/-). While CR did not affect the LPS-induced inflammatory response in WT mice, CR exaggerated the peripheral inflammatory response in Ercc1^Δ/- mice, as evidenced by an increase of pro-inflammatory serum cytokines (TNF-α, IL-1β, and IFN-γ) and kidney injury marker Ngal. Neuroinflammatory effects were assessed by RNA-sequencing of isolated microglia. Similarly, CR did not affect microglia gene expression in WT mice, but increased neuroinflammation-associated gene expression in Ercc1^Δ/- mice. In conclusion, CR increases the peripheral and brain inflammatory response of Ercc1^Δ/- mice to a systemic inflammatory stimulus.