CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline

Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f−/− and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging. [Display omitted] •CD300f−/− mice show reduced lifespan, but no specific cause of death is identified•This is associated with inflammaging, senescence, frailty, and cognitive decline•CD300f−/− mice exhibit microglial aging states and sex-dependent metabolic changes•Absence of CD300f reduces macrophage immunometabolic fitness in a sex-dependent way Evans et al. report that the absence of CD300f myeloid cell immune receptor in male and female mice induces a reduced lifespan. Animals display diverse aged-related conditions such as inflammaging, frailty, cognitive decline, brain senescence markers, microglial aging phenotypes, and reduced macrophage metabolic fitness, as well as sex-dependent metabolic alterations.