It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.

已经确定衰老是认知缺陷的主要危险因素，并且越来越明显的是，胰岛素抵抗是另一个因素。胰岛素抵抗和痴呆之间联系的生物学合理性与了解疾病病因学相关，并为减轻疾病负担的预防工作奠定基础。在本研究中，在 SAMP8 小鼠（衰老小鼠模型）中发现外周和中枢胰岛素抵抗并伴有认知缺陷。此外，在 SAMP8 小鼠中观察到明显的外周炎症状态，随后出现神经炎症，这可能是由于较高的细胞因子通过老化破坏的血脑屏障泄漏到大脑中所致。而且，衰老诱导的肠道菌群失调会产生更高的 TMAO，这也可能导致外周和中枢炎症张力以及在 SAMP8 小鼠中观察到的认知缺陷。所有这些改变都被 DMB 逆转，DMB 是一种降低 TMAO 水平的治疗方法。从该项目获得的数据表明，微生物失调和 TMAO 分泌增加可能是衰老、胰岛素抵抗和痴呆之间的关键联系。因此，导致 TMAO 水平降低的药物干预，例如 DMB，可以为未来治疗神经退行性疾病开辟一条新途径。从该项目获得的数据表明，微生物失调和 TMAO 分泌增加可能是衰老、胰岛素抵抗和痴呆之间的关键联系。因此，导致 TMAO 水平降低的药物干预，例如 DMB，可以为未来治疗神经退行性疾病开辟一条新途径。从该项目获得的数据表明，微生物失调和 TMAO 分泌增加可能是衰老、胰岛素抵抗和痴呆之间的关键联系。因此，导致 TMAO 水平降低的药物干预，例如 DMB，可以为未来治疗神经退行性疾病开辟一条新途径。