Study of young and old mice at different times of the day through a 24 hour timeseries.
Aging-related dysmetabolism encompasses the decline in metabolic homeostasis, involving circadian dysregulation, reprogrammed cellular signaling pathways, and insulin resistance. Interventions such as caloric restriction and time-restricted feeding improve lifespan and metabolic health in model organisms. Studies in young mice demonstrate that these dietary strategies appear to exert their beneficial effects partly through modulation of the gut microbiome and bile acid dynamics. However, the impact of aging on the microbiome, its functions, and bile acid signaling remains poorly understood, and the potential for modulating microbial functions to enhance health span is still underexplored. Here we show that aged mice exhibit increased deconjugation of taurine-conjugated bile acids and elevated microbial bile salt hydrolase (BSH) expression, traits that are also observed in human centenarians, and appear to be protective adaptations. We found that aging-related dysmetabolism and bile acid changes occurred in the setting of dysregulated circadian behaviors and gene expression, along with altered luminal microbial bile acid biotransformations and bile acid pools. Since analyses from human centenarian studies demonstrated the same results, they suggest that these microbial functions and their related bile acid pool changes are protective. Thus, we used engineered native bacteria to further increase luminal BSH activity in already aged mice. This functional manipulation of the gut microbiome led to a decrease in fat mass, increase in lean mass with a concomitant increase in fatty acid oxidation, modulation of ileal inflammatory pathways, and a modest effect on insulin response. These findings indicate that the increased BSH activity and the consequent bile acid deconjugation, previously seen as potential markers of dysbiosis, might actually play a protective role in aging. This insight challenges the prevailing notion that all aging-related changes in microbial activities are detrimental and highlights their potential to maintain metabolic health and longevity.