Longevity-associated microbial and evolutionary signatures in the gut of old mice

Abstract

Aging, one of the all-time challenges, is accompanied by several factors, including an increase in inflammation levels and alterations in the intestinal microbiota composition and evolution. Following a period of great fluctuations in the first years of life, the gut microbiota starts to stabilize around age three. This stability continues through adulthood but will inevitably be affected by aging, an important contributor to the loss of homeostasis. On the other hand, gut dysbiosis will also contribute to aging, e.g. by increasing gut permeability and giving rise to systemic inflammation. Nevertheless, how these events impact microbiota evolution and whether they could be involved in pathobiont selection is still unknown. Here we approach this question by comparing microbiota evolution in three sets of mice with different ages: young (6-9 weeks old), old (19 months old), and very old (25 months old). Specifically, previous studies have described the adaptation of a commensal strain of E. coli to the guts of young animals and have shown that it rapidly acquires metabolic-related mutations. In contrast, in the guts of old mice, E. coli adaptation shifts towards stress-related mutations, most likely due to an increase in inflammation and oxidative stress during aging, whereas the rise of metabolic adaptations becomes slower. Yet, to increase both the health and lifespan we need to understand how the (lucky) very old are different and how that impacts E. coli evolution. To tackle this question, we first compared the host environment that E. coli encounters upon colonization of the very old with the two previously studied age groups. For this, we measured the level of frailty, intestinal inflammation and characterized the microbiota composition. We found that the very old animals are the frailest, but do not show higher intestinal inflammation than the old mice. Interestingly, when compared to young and old animals, the very old show an increase in some health-associated bacteria, such as Akkermansia muciniphila, Oscillospira, and several Muribaculaceae members. Moreover, the adaptive pattern of E. coli colonizing the gut of the very old displays more metabolic than stress-related mutations, approaching the profile found in young animals. Together, these data raise the possibility that specific alterations to the microbiota and the gut environment during aging may not be exclusively dysbiotic and may even be associated with longevity. Future studies should try to understand whether only the healthier are able to reach very old age or whether this is a general possibility provided some reversion of dysbiosis occurs.