Healthspan and lifespan extension by fecal microbiota transplantation in progeroid mice

The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease or cancer, but its precise role in aging remains to be elucidated. Here, we characterize the gut microbiome profile of accelerated aging and show that its external modulation is sufficient to extend healthspan and lifespan. We found that two different mouse models of progeria present with intestinal dysbiosis, which is characterized, among other alterations, by an increment in proteobacteria, cyanobacteria and a loss in verrucomicrobia, whereas long-lived humans (i.e., centenarians) exhibit a remarkable increase in verrucomicrobia and a reduction in proteobacteria. Fecal microbiota transplantation proved to be effective to enhance healthspan and lifespan in both progeroid mouse models and, more importantly, the solely transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Our results demonstrate that intestinal dysbiosis is a phenotype associated with accelerated aging and its correction provides health benefits. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial outcome of reestablishing a healthy microbiome. Our results suggest the existence of a link between gut aging and the microbiota, and can help to gain insight into the rationale for microbiome-based interventions against age-related diseases. Mouse sequence data have been deposited in ENA (https://www.ebi.ac.uk/ena) under accession number PRJEB34214EGA study EGAS00001003656

肠道菌群（gut microbiome）正逐渐成为多种代谢、免疫及神经内分泌通路的关键调控因子。肠道菌群失调已被证实与肥胖、2型糖尿病、心血管疾病、非酒精性脂肪性肝病（non-alcoholic fatty acid liver disease）乃至癌症等重大疾病存在关联，但其在衰老过程中的确切作用仍有待阐明。本研究对加速衰老模型的肠道菌群特征进行了表征，并证实通过外部调控肠道菌群即可有效延长健康寿命与总寿命。我们发现，两种不同的早衰症小鼠模型均存在肠道菌群失调现象，其特征除其他改变外，还包括变形菌门（proteobacteria）、蓝细菌门（cyanobacteria）丰度升高，以及疣微菌门（verrucomicrobia）丰度降低；而长寿人群（即百岁老人）则表现为疣微菌门丰度显著升高、变形菌门丰度降低。粪便菌群移植（fecal microbiota transplantation）被证实可有效改善两种早衰样小鼠模型的健康寿命与总寿命；更重要的是，仅移植疣微菌门的嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila）即可发挥有益作用。本研究结果证实，肠道菌群失调是与加速衰老相关的表型，纠正该失调可带来健康益处。此外，对回肠内容物的代谢组学分析显示，次级胆汁酸（secondary bile acids）的恢复可能是重建健康菌群所带来益处的潜在机制。本研究结果揭示了肠道衰老与菌群之间存在关联，可为理解基于菌群干预衰老相关疾病的理论依据提供新的见解。小鼠测序数据已提交至ENA（https://www.ebi.ac.uk/ena），登录号为PRJEB34214，EGA研究编号为EGAS00001003656