Late-in-life treadmill-training mitigates gut microbiome imbalances and cardiovascular disease risk in mice

Primary aging associates with an imbalanced gut microbiome and cardiovascular disease (CVD) risk in mice and humans. Strong evidence from clinical and pre-clinical studies supports that habitual physical exercise improves cardiovascular function and intestinal health in adults. Here we tested the hypothesis that exercise training, even when initiated late-in-life, re-establishes a beneficial and cooperative intestinal microbiome to an extent that associates with reduced risk for CVD. At 21-months of age, male C57BL/6 mice started a progressive resistance treadmill-training program 6-days per week (Old+ETR) for 12-weeks. Twenty-one month old (Old) and 4-month old (Adult) male mice remained sedentary. First, reductions in exercise capacity and soleus muscle citrate synthase activity displayed by Old vs. Adult mice were restored in Old+ETR animals. Next, systolic function (fractional shortening, FS), diastolic function (E/A ratio), and overall left-ventricular function (myocardial performance index, MPI) otherwise depressed in Old vs. Adult mice were normalized in Old+ETR animals. Third, elevated trimethylamine (TMA) and TMA N-oxide (TMAO), and heightened inflammatory markers [e.g., interferon (IFN)-g and keratinocyte-derived chemokine (KC)], observed in Old vs. Adult mice were lowered in Old+ETR animals. Importantly, the abundance of beneficial microbial features, including Bacteroides, Muribaculaceae, Parabacteroides, and the Rikenellaceae RC9 gut group, otherwise depressed by aging, was normalized in Old+ETR mice. Finally, the Rikenellaceae RC9 gut group positively correlated with FS, and Parabacteroides negatively correlated with IFN-γ. These findings support that late-in-life exercise training beneficially remodels the gut microbiome to an extent that associates with reduced CVD risk in male mice.