Immunometabolic Resistors of Aging in Long-Lived Golden Spiny Mice 2309529

Abstract Introduction Investigating long-lived wild rodents closely related to laboratory mice on the evolutionary scale presents an opportunity to uncover dormant pathways that combat inflammaging. Spiny mice (Acomys) are known for their exceptional regenerative capabilities, but their lifespan and resilience to aging remain unexplored. Methods We established cohorts of two Acomys species (A. russatus and A. dimidiatus), originating from a colony at Tel Aviv University Zoological Research Garden, and laboratory mice (Mus musculus) across their lifespans (0.5 to 4.5 years for Acomys and 0.5 to 2.5 years for Mus). We conducted behavioral tests and histological analyses of immune-metabolic organs. Bulk or single-nucleus RNA sequencing analysis was utilized in young and aged Mus and Acomys. Aged M. musculus were randomly assigned to receive either a vehicle or clusterin (50 µg/kg) for 2 weeks. Results We reveal that A. russatus, maintained in a non-pathogen-free environment, outlives M. musculus significantly both in the wild (>4 years) and in captivity (>5 years). We observe that A. russatus resists age-associated functional decline and exhibits a greater repair capacity with minimal thymic involution and splenic cellular senescence compared to its congener, A. dimidiatus, or M. musculus. Furthermore, aged A. russatus does not exhibit cellular and molecular immune aging hallmarks, such as the accumulation of age-associated B cells and exhausted T cells, nor inflammatory cytokine production. Notably, clusterin expression is significantly elevated in diverse immune cells in A. russatus, unlike in M. musculus. Interestingly, clusterin administration to aged mice improves healthspan, suppresses the accumulation of B cells and regulatory T cells, and reduces inflammatory cytokine production, mirroring the exceptional aging resilience observed in A. russatus. Conclusion A. russatus biology unveils therapeutically actionable targets that may enhance functional capacity and maintain immunometabolic homeostasis during aging. Funding Source National Research Foundation of Korea grant RS-2024-00412002 Yale University Waldemar Von Zedtwitz endowed chair Yale University School of Medicine’s intramural funding Israel Science Foundation grant 2129/20 Topic Categories Veterinary and Comparative Immunology (VET)