Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease

摘要 衰老是阿尔茨海默病（AD）和相关痴呆症（ADRD）的最大风险因素。但 将衰老机制与ADRD联系起来的潜在分子机制尚不清楚。发展 老年保护剂，针对衰老的药物，可用于治疗ADRD，我们开发了一种以神经为中心的 老年科学平台，以确定老年神经保护器（GNP），延长寿命的老年保护器， 同时保护神经元免受多种与年龄相关的毒性。GNP应该是理想的治疗方法 抗抑郁药仅仅增加寿命而不治疗痴呆症，只会延迟疾病发作甚至延长 疾病的持续时间，并因此恶化ADRD问题，这是不断增加的寿命的结果。 我们提出了一个证明GNP，J147的原理，并表明它可以延长寿命，防止记忆丧失，甚至 当在20-24个月大的野生型或有症状的APPswe小鼠中开始治疗时恢复记忆。我们 提出了一个可测试的模型，其中J147通过降低ATP来保护神经元免受持续的蛋白毒性应激 合成酶活性，将能量代谢转向糖酵解，伴随乙酰辅酶A的积累。 乙酰辅酶A积累导致H3 K9组蛋白乙酰化增加并保护突触相关基因 转录漂移的表达-与年龄相关的转录程序恶化-和 从而导致功能衰退。在下面的建议中，我们将通过执行以下操作来详细测试此模型： 在老年野生型小鼠和两种小鼠模型中的神经病理学、电生理学和行为测定 ADRD。我们发现这些效应在进化上是保守的，降低ATP合酶活性 延长M. musculus、D. melanogaster和C.优雅ATP合成酶和年龄- 突触基因的相关转录漂移是从M进化上保守的。musculus到C. elegans 我们将使用C。鉴定控制突触相关基因的染色质重塑因子 以及它如何对线粒体损伤作出反应。我们将验证已确定因素的作用 在控制原代神经元、老年野生型小鼠和 ADRD。最后，我们将扩展我们的GNP概念，以描述由实验室鉴定的老年保护化合物。 干预测试计划（ITP），以保护神经元免受不同年龄相关毒性的影响， 以确定在保护效果上具有互补性的老年保护剂组合。因为ADRD 是具有多种病理学方面的复杂疾病，不太可能通过单一药物解决， 我们预测合理设计的护老组合会比单独的护老组合更有效。 这些研究将为衰老和ADRD如何损害突触功能提供深入的见解 以及如何通过单一GNP或合理GNP组合治疗来解决这一问题。

ABSTRACT Aging is the biggest risk factor for Alzheimer's disease (AD) and related dementias (ADRD). However, the underlying molecular mechanism that link mechanisms of aging to ADRDs are unknown. To develop geroprotectors, drugs that target aging and could be used to treat ADRDs we developed a neuro-centric geroscience platform to identify Gero-Neuro-Protectors (GNP), geroprotectors that extend lifespan and simultaneously protect neurons from multiple age associated toxicities. GNPs should make ideal treatments for ADRDs. Increasing lifespan alone, without treating dementia, will only delay disease onset or even prolong disease duration, and thus worsen the ADRD problem, which is the consequence of ever increasing lifespans. We present a proof of principle GNP, J147 and show that it extends lifespan, prevents memory loss, and even restores memory when treatment is initiated in 20-24 month old wild type or symptomatic APPswe mice. We propose a testable model in which J147 protects neurons from ongoing proteotoxic stress by lowering ATP synthase activity, shifting energy metabolism towards glycolysis accompanied by accumulation of acetyl-CoA. Accumulating acetyl-CoA leads to increased H3K9 histone acetylation and protects synapse related gene expression from transcriptional drift -the age-associated deterioration of transcriptional programs- and consequently from functional decline. In the following proposal we will test this model in detail by conducting neuropathology, electrophysiology and behavioral assays in aged wild type mice and two mouse models of ADRD. We show that these effects are evolutionarily conserved and that lowering ATP synthase activity extends lifespan in M. musculus, D. melanogaster and C. elegans. As both, ATP synthase and the age- associated transcriptional drift of synaptic genes are evolutionarily conserved from M. musculus to C. elegans we will use C. elegans to identify the chromatin remodeling factor that controls synapse related gene expression in aging and how it respond to mitochondrial insults. We will validate the role of the identified factor in controlling chromatin on synaptic promoters in primary neurons, aged wild type mice and mouse models of ADRD. Finally, we will expand our GNP concept to profile geroprotective compounds identified by the intervention testing program (ITP) for their ability to protect neurons from different age-associated toxicities and to identify combinations of geroprotectors that are complementary in their protective effects. Because ADRDs are complex diseases with multiple pathological aspects that are unlikely to be addressable by a single drug, we predict rationally designed combinations of geroprotectors to outperform individual geroprotectors. Together these studies will provide deep insights into how aging and ADRDs compromise synapse function and how this can be addressed by treatment with single GNPs or rational GNP combinations.