Sex-based differences in the gut-metabolism axis in aging and Nrf2-deficient mice

Hallmarks of aging are highly variable among individuals, and sexual dimorphism may contribute to these differences. However, the details are unclear.The gut-metabolism axisin naturally aging wild-type and Nrf2 knockout (KO) mouse models was investigated. In this study, intraperitoneal glucose tolerance tests were performed on 12- and 48-week-old wild-type and Nrf2 KO mice to assess glucose tolerance. Serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein levels were measured using biochemicaltest kits. The estradiol and testosterone levels in the serum were detected using enzyme-linked immunosorbent assays. Liver and adipose tissue morphology were examined using hematoxylin and eosin staining, and gut microbiota composition was analyzed using 16S rDNA sequencing of fecal samples.The results showed that glucose tolerance was significantly impaired in aging male Nrf2 KO mice, and lipid accumulation in hepatic and adipose tissues increased in aging wild-type (WT) miceandaging Nrf2 KO mice of both sexescompared with that in their young counterparts.Aged miceand Nrf2 KO mice exhibited divergent responses in their serum lipid profiles.Notably, female Nrf2 KO mice showed a significantly lowerα-diversity in gut bacterial composition, compared with both male Nrf2 KO mice and female WT controls.In conclusion, the resultsindicatethat aging and Nrf2 deficiency promoted weight gain and tissue lipid accumulation in both sexes but elicited sex-dimorphic differences in blood glucose stability, microbiota composition, and the magnitude of adiposity. Therefore, sex is an important factor contributing to age-related variations in gut microbiota and metabolism.