Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil.
Aging (Albany NY). 2024 Mar 20;16(6):4980-4999. doi: 10.18632/aging.205673.
Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice.
Control or CMS121-containing diets were supplied for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism.
The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121.
The diminished lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.
受遗传和环境因素差异的影响，实验小鼠通常会出现体重逐渐增加的现象，最终导致肥胖和代谢失衡。由于神经保护剂 CMS121 对 2 型糖尿病小鼠模型的能量代谢有积极作用，我们研究了 CMS121 抵抗野生型小鼠衰老过程中观察到的代谢变化的潜力。
用含有 CMS121 的或不含 CMS121 的饮食喂养 6 个月，然后在 7 月龄时处死小鼠。分析血液、脂肪组织和肝脏中的葡萄糖、脂质和能量代谢的蛋白质标志物。
CMS121 饮食可使体重增加减少 40%，并改善葡萄糖和脂质指标。用 CMS121 处理后，肝脏中的 caspase 1、caspase 3 和 NOX4 水平降低，表明肝脏炎症状态较低。用 CMS121 处理的脂肪组织中转录因子 Nrf1 和 TFAM 水平升高，以及线粒体电子传递复合物、GLUT4 水平升高和静息代谢率升高。代谢组学分析显示，用 CMS121 处理的小鼠血浆中短链酰基辅酶 A 和丁酸盐代谢物的浓度升高。
与乙酰辅酶 A、酰基辅酶 A 和丁酸盐代谢物水平升高相关的脂肪生成减少，不仅有助于保护外周系统，还有助于保护衰老的大脑。通过模拟生酮饮食的作用，CMS121 有望用于治疗肥胖症和糖尿病等代谢疾病，因为这些饮食很难长期遵循。
