Department of Integrative Physiology, University of Colorado Boulder, 1725 Pleasant St, 354 UCB, Boulder, CO, 80309, USA.
Department of Health and Exercise Science and the Center for Healthy Aging, Colorado State University, Fort Collins, CO, USA.
Geroscience. 2021 Feb;43(1):377-394. doi: 10.1007/s11357-020-00257-2. Epub 2020 Aug 29.
Aging is associated with declines in cognitive performance, which are mediated in part by neuroinflammation, characterized by astrocyte activation and higher levels of pro-inflammatory cytokines; however, the upstream drivers are unknown. We investigated the potential role of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) in modulating neuroinflammation and cognitive function with aging. Study 1: In middle-aged and older humans (65 ± 7 years), plasma TMAO levels were inversely related to performance on NIH Toolbox Cognition Battery tests of memory and fluid cognition (both r = 0.07, p < 0.05). Study 2: In mice, TMAO concentrations in plasma and the brain increased in parallel with aging (r = 0.60), suggesting TMAO crosses the blood-brain barrier. The greater TMAO concentrations in old mice (27 months) were associated with higher brain pro-inflammatory cytokines and markers of astrocyte activation vs. young adult mice (6 months). Study 3: To determine if TMAO independently induces an "aging-like" decline in cognitive function, young mice (6 months) were supplemented with TMAO in chow for 6 months. Compared with controls, TMAO-supplemented mice performed worse on the novel object recognition test, indicating impaired memory and learning, and had increased neuroinflammation and markers of astrocyte activation. Study 4: Human astrocytes cultured with TMAO vs. control media exhibited changes in cellular morphology and protein markers consistent with astrocyte activation, indicating TMAO directly acts on these cells. Our results provide translational insight into a novel pathway that modulates neuroinflammation and cognitive function with aging, and suggest that TMAO might be a promising target for prevention of neuroinflammation and cognitive decline with aging.
衰老是认知表现下降的原因之一，部分原因是神经炎症，其特征是星形胶质细胞激活和促炎细胞因子水平升高；然而，其上游驱动因素尚不清楚。我们研究了肠道微生物群衍生代谢物三甲胺 N-氧化物（TMAO）在调节衰老过程中神经炎症和认知功能中的潜在作用。研究 1：在中年和老年人（65±7 岁）中，血浆 TMAO 水平与 NIH 工具包认知电池测试的记忆和流体认知测试的表现呈负相关（两者 r=0.07，p<0.05）。研究 2：在小鼠中，血浆和大脑中的 TMAO 浓度随着衰老而平行增加（r=0.60），表明 TMAO 穿过血脑屏障。老年小鼠（27 个月）的 TMAO 浓度较高与大脑中促炎细胞因子和星形胶质细胞激活标志物的水平较高有关，与年轻成年小鼠（6 个月）相比。研究 3：为了确定 TMAO 是否独立引起认知功能的“衰老样”下降，用 TMAO 补充年轻小鼠（6 个月）的饮食 6 个月。与对照组相比，TMAO 补充组在新物体识别测试中表现较差，表明记忆和学习能力受损，并且神经炎症和星形胶质细胞激活标志物增加。研究 4：与对照培养基相比，用 TMAO 培养的人星形胶质细胞在细胞形态和蛋白标志物上发生变化，表明 TMAO 直接作用于这些细胞。我们的研究结果为调节衰老过程中神经炎症和认知功能的新途径提供了转化见解，并表明 TMAO 可能是预防神经炎症和认知能力下降的有希望的靶点。
