Aging Intervention Studies

衰老干预研究

• 批准号: 9147279
• 负责人: Julie Mattison
• 金额: $ 67.35万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9147279
• 关键词: Adult; Adverse effects; Aging; Antigens; B-Lymphocytes; Biochemistry; Biological Markers; Blood; Blood Glucose; Brain; Caloric Restriction; Cell model; Cerebrospinal Fluid; Clinical Trials; Disease model; Dopamine; Dose; Drug Compounding; Energy Metabolism; Enzymes; Functional disorder; Glucose; Goals; Hour; Human; Immune response; Intervention; Intervention Studies; Intervention Trial; Longevity; Macaca mulatta; Metabolic; Metabolic syndrome; Metabolism; MicroRNAs; Mitochondria; Monkeys; Muscle; Muscle Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Parkinson Disease; Parkinsonian Disorders; Peptide Hydrolases; Pharmaceutical Preparations; Physiological; Plasma; Population; Process; Rattus; Regulation; Resveratrol; Rodent; Rodent Model; Role; Sampling; Serum; Signal Transduction; Specific qualifier value; Supplementation; Testing; Time; Translations; Triglycerides; Vaccinated; Vaccination; clinical risk; effective therapy; gastric inhibitory polypeptide receptor; glucagon-like peptide; influenzavirus; inhibitor/antagonist; liver function; nonhuman primate; novel; programs; response; rituximab; sarcopenia

Within this program several studies are on-going Old monkeys were treated with Rituximab to deplete the B cell population. Once B cells were replenished, Rituximab-treated monkeys, and young and old controls were vaccinated against the influenza virus. Plasma samples were collected to assess the antigen response to the vaccination. Analysis is on-going. Inhibition of PI3K signaling has been shown to increase energy expenditure, protect from obesity and metabolic syndrome, and increase longevity in rodent models. In our study, obese monkeys were treated daily for 3 months with an oral dose of a PI3K inhibitor resulting in decreased adiposity, and lowered serum glucose and triglyceride levels, without any detectable side effects. Dipeptidyl protease-4 (DPP-4) inhibitors also known as gliptins - are widely used in the effective treatment of type 2 diabetes to safely regulate blood glucose levels. DPP-4 is the key enzyme responsible for the metabolism of the endogenous incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) whose elevated levels in brain, were hypothesized to provide neurotrophic/neuroprotective actions in cellular and rodent models of Parkinsons disease (PD). On evaluating several DPP-4 inhibitors, brain and plasma incretin levels were, indeed, substantially elevated in rodents, and this resulted in amelioration of Parkinsonism and elevations in brain dopamine levels in a well-characterized rodent PD model. In the current study, we evaluated sitagliptin in nonhuman primates to assess whether translational doses elevate systemic (plasma) and central (CSF) incretin levels, as achieved in rats, to (i) cross-validate our studies across species and (ii) de-risk clinical translation of this drug as a new treatment for PD. Twenty adult rhesus monkeys (Macaca mulatta) were given 1 of 4 drug conditions (Control, 5, 20, or 100 mg/kg) daily for 6 days. On day 6, an oral glucose load was given to stimulate incretin release. Blood and cerebral spinal fluid samples were collected at specified time points during the subsequent 24 hours. Active incretin levels were observed in both plasma and CSF with all 3 doses. The intermediate dose (20 mg/kg) induced the greatest response. DPP4 inhibition in the plasma was dose-dependent. An inverted U dose-response relationship on incretin levels in both plasma and CSF was evident with the high dose providing less activitylikely due to compensatory mechanisms at the level of incretin synthesis/secretion. The current results validate those from rat studies and lay the groundwork for dose selection for repositioning sitagliptin in a potential clinical trial in PD. To better understand muscle dysfunction and factors contributing to sarcopenia, we are assessing muscle and mitochondria function of young and old monkeys in comparison to young and old humans. Several samples have been collected and the analysis is on-going.

在该计划中，一些研究正在进行 用利妥昔单抗治疗旧猴子，以耗尽B细胞群体。补充B细胞后，利妥昔单抗处理的猴子，年轻和旧对照对流感病毒接种疫苗。收集血浆样品以评估对疫苗接种的抗原反应。分析正在进行中。 抑制PI3K信号传导已被证明可以增加能量消耗，防止肥胖和代谢综合征，并增加啮齿动物模型中的寿命。在我们的研究中，每天用口服剂量的PI3K抑制剂治疗肥胖的猴子3个月，导致肥胖降低，血清葡萄糖和甘油三酸酯水平降低，而没有任何可检测到的副作用。 二肽基蛋白酶-4（DPP-4）抑制剂也称为Gliptins-被广泛用于2型糖尿病的有效治疗中，以安全地调节血糖水平。 DPP-4是负责内源性泌尿素，胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性胰岛素多肽（GIP）的主要酶，其在大脑中升高，其升高的脑升高，被认为可提供神经性/神经性疾病的神经性疾病和植物病模型（PARCARPISER）（PARPARCENT SARKINCER SORCERENT SORCERENT SORCERENT SORCERATION）。在评估几种DPP-4抑制剂时，啮齿动物的脑和血浆肠降低素水平实际上显着升高，这导致在良好的啮齿动物PD模型中改善帕金森氏症和脑多巴胺水平的升高。在当前的研究中，我们评估了非人类灵长类动物中的西他列汀，以评估转化剂量升高全身性（等离子体）和中心（CSF）降量蛋白水平，如大鼠所达到的，以（i）跨物种的研究和（ii）对PD的新药物进行跨物种和（ii）临床转换的跨质量。每天6天给出了二十只成年恒河猴（Macaca mulatta）4种药物条件（对照，5、20或100 mg/kg）。在第6天，给出了口服葡萄糖负荷以刺激降血团素的释放。在随后的24小时内，在指定的时间点收集血液和脑脊髓样品。 在所有3剂的血浆和CSF中都观察到活性降直降蛋白水平。中间剂量（20 mg/kg）诱导了最大的反应。血浆中的DPP4抑制作用依赖于剂量。在血浆和CSF中，在降直降蛋白水平上的倒剂剂量反应关系很明显，高剂量由于在肠肠合成/分泌水平上的补偿机制而产生的高剂量较少。当前的结果验证了大鼠研究的结果，并为在PD的潜在临床试验中重新定位剂量的剂量选择奠定了基础。 为了更好地了解肌肉功能障碍和导致肌肉减少症的因素，我们正在评估与年轻人和老年人相比，年轻人和老猴子的肌肉和线粒体功能。已经收集了几个样本，分析正在进行中。