Aging: an inevitable road toward gut microbiota pathoadaptation

Laboratory-raised mice live approximately seven times longer and healthier lives compared to their wild counterparts, due to a standardized healthy diet and limited exposure to environmental stressors1. Aging is associated with increased inflammation and microbial dysbiosis2-4. Collectively, these influence microbiota evolution and may contribute to the enrichment in pathobiont frequency observed in old age4. Alternatively, this increase could stem from a decline in colonization resistance5,6, creating favorable conditions for pathobiont invasion. Here, we sought to test whether aging in healthy, controlled conditions, could prevent the selection of age-associated pathobionts. We have followed the adaptive evolution of a commensal strain of Escherichia coli in the guts of mice of advanced age and found that it acquired several mutations common to bacteria colonizing young mice, which were absent in old animals. This, together with the increase in Akkermansia muciniphila in mice of advanced age, suggest healthy aging7,8. However, mutations acquired exclusively in the older were mainly pathoadaptive, tuning the metabolism to oxygen and iron availability, hypermotility, and biofilm formation. In summary, while the evolutionary signature in the guts of very old mice shows youth-like features that may be associated with longevity, the selection of pathoadaptive traits is magnified in very old age. While suggesting that a breach in colonization resistance is not needed to justify the abundance of age-associated pathobionts, our findings raise the question whether specialized bacteria, as opposing to generalists such as E. coli, will display the same ability to evolve pathoadaptive traits. HighlightsO_LIGut commensals face increasingly personalized selective pressures in the aging gut C_LIO_LIEven healthy aging selects for pathoadaptive traits in the gut microbiota C_LIO_LIE. coli s adaptive pattern better reflects the metabolome than microbiota composition C_LI In BriefPathobionts are often enriched in the microbiota of the elderly. Melo-Miranda et al. showed that irrespectively of limiting the opportunity for gut invasion, the strength of selection for pathoadaptation increases with aging. Yet, the gut environment of extreme ages seems to converge, highlighting the discontinuity of the aging process.