Gut Biogeography Accentuates Sex-Related Differences in the Murine Microbiome.

Recent studies have highlighted the influence of factors such as sex and sex-linked hormones on microbiome composition, raising concerns about the generalizability of findings. Here, we explore whether gut geography, specifically the upper and lower gastrointestinal tract (GI), contributes to sex-linked microbiome differences in mice. We collected microbial samples throughout the length of the GI from male and female C57B6/J mice at 6- and 8-weeks old, and conducted 16S rRNA sequencing. Our findings revealed significant sex-related differences, with Clostridium_sensu_stricto_1 more abundant in the male colon, while females exhibited higher levels of Dubosiella newyorkensis across all organs at 6 weeks. We also observed decreased Shannon alpha diversity in the small intestine compared to the lower GI, and this diversity decreased further at 8 weeks. Interestingly, our results suggest that age mitigates sex-related, but not gut geography-related differences in beta diversity, with implications for experimental outcomes and treatment strategies. This study underscores the dynamic nature of microbial diversity, influenced by sex, age, and GI localization, emphasizing the need for a more comprehensive understanding of microbiome dynamics in experimental research and clinical interventions.

Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms.

Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using homologous recombination and related each to emerging models of receptor tyrosine kinase structure and function. Three mutations when combined as trans-heterozygotes extended lifespan while retarding growth and fecundity. These genotypes reduced insulin-stimulated Akt phosphorylation, suggesting they impede kinase catalytic domain function. Among these genotypes, longevity was negatively correlated with egg production, consistent with life-history trade-off theory. In contrast, one mutation (InR353) was located in the kinase insert domain, a poorly characterized element found in all receptor tyrosine kinases. Remarkably, wild-type heterozygotes with InR353 robustly extended lifespan without affecting growth or reproduction and retained capacity to fully phosphorylate Akt. The Drosophila insulin receptor kinase insert domain contains a previously unrecognized SH2 binding motif. We propose the kinase insert domain interacts with SH2-associated adapter proteins to affect aging through mechanisms that retain insulin sensitivity and are independent of reproduction.