Pro-inflammatory responses are potentiated in response to stress and play a role in age-related pathology and cognitive decline. We have undertaken an extensive littermate-controlled mouse phenotyping study to characterize the consequences of toll-like receptor 4 (TLR4) deletion in young and aged mice. Our study includes behavioral tests, next-generation microbiome sequencing, complete blood counts, clinical chemistries, serum glucocorticoid and cytokine levels, histology of all tissues, and assessments of function in immune cells isolated from stressed and unstressed animals. Deletion of TLR4 improves memory in both young and old mice, alters social motivation, reduces anxiety-like behavior, and changes behavioral and immune responses to acute stress. TLR4 deletion also leads to chronic intermittent seizures in some animals. Basal and stress-induced changes in serum and splenocyte secreted cytokines associated with stress and depressive-like behavior (IL-6 and IL-10, specifically) differ between wild-type and TLR4 knockout mice. Correlations between serum cytokines and circulating leukocytes also differ. Abundance of specific gut microbes also differ significantly between wild-type and TLR4 KO littermates who have lived long-term in the same cage. TLR4 functions in different tissues may offer mechanistic insight to the differences observed. Ongoing studies are delineating the roles of specific cell types and downstream pathways underlying the observed phenotype. Our results highlight the need for interdisciplinary work that will help elucidate how animals integrate information across multiple systems to coordinate adaptive responses.