Calorie restriction increases the sensitivity of progeroid Ercc1Δ/- mice to acute (neuro)inflammation

V A Reitsema; L Schreuder; E Gerrits; B J L Eggen; M Goris; J D Laman; S E de Rooij; E M Wesseling; H R Bouma; R H Henning

doi:10.1007/s11357-024-01347-1

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

Geroscience. 2024 Sep 17. doi: 10.1007/s11357-024-01347-1. Online ahead of print.

Authors

V A Reitsema^#¹, L Schreuder^#^{2

3}, E Gerrits³, B J L Eggen³, M Goris¹, J D Laman^{3

4}, S E de Rooij^{2

5}, E M Wesseling³, H R Bouma^{6

7

8}, R H Henning¹

Affiliations

¹ Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
² Department of Internal Medicine, University Center for Geriatric Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³ Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴ Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁵ Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁶ Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [email protected].
⁷ Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [email protected].
⁸ Department of Acute Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. [email protected].

^# Contributed equally.

PMID: 39287878
DOI: 10.1007/s11357-024-01347-1

Abstract

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.

Keywords: Calorie restriction; Delirium; Encephalopathy; Fasting; Sepsis.