The understanding of how aging contributes to dementia remains obscure. To address this problem, a chemical biology approach was used employing CAD031, an Alzheimer’s disease (AD) drug candidate identified using a discovery platform based upon phenotypic screens that mimic toxicities associated with the aging brain. Since CAD031 has therapeutic efficacy when fed to old symptomatic transgenic AD mice, the chemical biology hypothesis is that it can be used to determine the molecular pathways associated with age-related disease by identifying those that are modified by the compound. Here we show that when CAD031 was fed to rapidly aging SAMP8 mice starting in the last quadrant of their lifespan, it reduced many of the changes in gene, protein, and small molecule expression associated with mitochondrial aging, maintaining mitochondria at the younger molecular phenotype. Network analysis integrating the metabolomics and transcription data followed by mechanistic validation showed that CAD031 targets acetyl-CoA and fatty acid metabolism via the AMPK/ACC1 pathway. Importantly, CAD031 extended the median lifespan of SAMP8 mice by about 30%. These data show that specific alterations in mitochondrial composition and metabolism highly correlate with aging, supporting the use AD drug candidates that limit physiological aging in the brain.

对衰老如何导致痴呆症的理解仍然模糊不清。为了解决这个问题，使用了一种化学生物学方法，采用 CAD031，这是一种阿尔茨海默氏病 (AD) 候选药物，使用基于模拟与大脑老化相关毒性的表型筛选的发现平台确定。由于 CAD031 在喂食老年有症状的转基因 AD 小鼠时具有治疗功效，因此化学生物学假设是它可用于通过识别被该化合物修饰的分子途径来确定与年龄相关疾病相关的分子途径。在这里，我们表明，当 CAD031 被喂给从生命最后一个象限开始的快速衰老的 SAMP8 小鼠时，它减少了许多与线粒体衰老相关的基因、蛋白质和小分子表达的变化，维持线粒体处于较年轻的分子表型。整合代谢组学和转录数据的网络分析以及随后的机制验证表明，CAD031 通过 AMPK/ACC1 通路靶向乙酰辅酶 A 和脂肪酸代谢。重要的是，CAD031 将 SAMP8 小鼠的平均寿命延长了约 30%。这些数据表明，线粒体组成和代谢的特定改变与衰老高度相关，支持使用限制大脑生理衰老的 AD 候选药物。