Genetic Definition of Mechanisms by which Rapamycin Retards Mammalian Aging

雷帕霉素延缓哺乳动物衰老机制的遗传学定义

• 批准号: 8699620
• 负责人: DAVID E HARRISON
• 金额: $ 36.84万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699620
• 关键词: Address; Adverse effects; Affect; Age; Age-Months; Age-Years; Aging; Albumins; Alleles; Arthritis; Biological Models; Blood; Candidate Disease Gene; Cardiac; Cardiovascular system; Chronic Disease; Clinical Treatment; Complex; Control Groups; Creatinine; Data; Dementia; Detection; Diet; Disease; Drug Targeting; Elderly; Electrocardiogram; Emotional; Face; Financial cost; Genes; Genetic; Genetic Recombination; Genetic Variation; Glucose; Glycosylated hemoglobin A; Health; Health Benefit; Homologous Gene; Human; Hybrids; Immune; Immune system; Inbred Strain; Individual; Insulin; Insulin-Like Growth Factor I; Intervention; Kidney; Life; Life Expectancy; Longevity; Lymphocyte; Malignant Neoplasms; Mammals; Maps; Mediating; Medical; Metabolic; Modeling; Molds; Mus; Names; Natural Selections; Nature; Non-Insulin-Dependent Diabetes Mellitus; One-Step dentin bonding system; Osteoporosis; Outcome; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Population; Process; Recombinant Inbred Strain; Regulation; Renal function; Research; Research Personnel; Resources; Science; Siblings; Sirolimus; Specificity; System; Testing; Time; Variant; Work; density; design; drug metabolism; feeding; gene discovery; healthy aging; inflammatory marker; mTOR protein; mouse model; normal aging; novel; response; urinary

DESCRIPTION (provided by applicant): Rapamycin treatment is the first drug intervention to reliably increase mammalian lifespan by 10% or more. Excitingly, this treatment was effective in heterogeneous mice when initiated at 20 months of age, roughly analogous to human beings at 60 years of age. The 3 independent aims of the current project identify genes regulating health benefits of rapamycin treatment, as well as key genes controlling normal mouse aging. This project is made possible by a revolutionary new mouse model, the diversity outcross (DO), developed by Gary Churchill (Co-Investigator). Compared to other models, the genetic diversity of the DO is more than 4 fold greater, as it was derived from 8 highly diverse inbred strains, including 3 wild-derived M. musculus subspecies. Because the DO is an advanced intercross, it has a high density of recombinations that makes candidate gene identification >10 fold more precise than with a standard F2 or N2 cross. We will initiate treatment in 20-month-old DO mice, because old individuals may respond to treatments differently than young, and to model humans who often would not start treatment until about 60 years of age. Sufficient marker alleles will be tested in each individual mouse to map loci associated with physiological aging (immune, renal, cardiac and metabolic) and lifespan. Dense mapping will identify candidate genes. Aim 1 tests the hypothesis that rapamycin benefits mammalian healthspan (healthy lifespan) via the mTOR pathway. This hypothesis predicts that aging in rapamycin-fed DO mice will be influenced by alleles of mTOR pathway genes. If this hypothesis is verified, we will identify the genes. If this hypothesis is rejected, we will identify alternative loci containing genes, such as drug metabolism genes, that govern rapamycin benefits. Aim 2 tests the hypothesis that the mTOR pathway governs normal aging. This hypothesis predicts that the same genes regulating aging in rapamycin-treated DO mice (Aim 1) also regulate aging in littermate controls. If this hypothesis is verified, we will identify genes with natural variants in the mTOR pathway that provide potential targets for clinical treatments with minimal adverse side effects. If this hypothesis is rejected, we will identify alternative loci containing genes that regulate aging, which would suggest novel mechanisms and novel potential clinical treatments. If, in Aim 1, we do not find genes related to benefits of rapamycin, we will combine Aim 1 and Aim 2 data to confirm and extend detection of key genes regulating normal aging rates. Aim 3 tests the hypothesis that immune, renal, cardiac and metabolic aging, as well as healthspan, are regulated by the same loci. If this hypothesis is verified, we will identify genes that have pleiotropic effects on aging in diverse systems. If this hypothesis is rejected, we will identify genes that regulate aging in each individual system; such specificity in genetic regulation of markers of inflammation could provide the means to decouple benefits of rapamycin treatment from its immune suppressive effects. Whether or not the hypothesis is verified, gene identification will suggest clinical treatments. )

描述(申请人提供)：雷帕霉素治疗是第一个可靠地延长哺乳动物寿命10%或更多的药物干预。令人兴奋的是，这种治疗方法在20个月大的异种小鼠中有效，大致类似于60岁的人类。当前项目的三个独立目标确定了调节雷帕霉素治疗的健康益处的基因，以及控制小鼠正常衰老的关键基因。这个项目是由加里·丘吉尔(共同调查者)开发的革命性的新老鼠模型--多样性杂交(DO)使之成为可能的。与其他模型相比，DO的遗传多样性增加了4倍以上，因为它来自8个高度多样化的近交系，包括3个野生来源的肌肉支原体亚种。由于DO是一种先进的杂交组合，它具有高密度的重组，使候选基因鉴定的精确度比标准的F2或N2杂交高10倍。我们将在20个月大的DO小鼠身上开始治疗，因为老年人对治疗的反应可能与年轻人不同，而且是对通常要到60岁才开始治疗的模型人类。将在每只小鼠身上测试足够的标记等位基因，以定位与生理衰老(免疫、肾脏、心脏和新陈代谢)和寿命相关的基因座。密集的图谱将确定候选基因。目的1验证雷帕霉素通过mTOR途径有益于哺乳动物健康寿命的假说。这一假说预测，喂食雷帕霉素的DO小鼠的衰老将受到mTOR途径基因等位基因的影响。如果这一假设得到证实，我们将识别出这些基因。如果这一假设被拒绝，我们将确定包含控制雷帕霉素益处的基因的替代基因，例如药物代谢基因。目的2验证mTOR通路控制正常衰老的假说。这一假说预测，雷帕霉素处理的DO小鼠(目标1)中调节衰老的相同基因也调节产仔对照组的衰老。如果这一假设得到证实，我们将发现mTOR途径中具有自然变异的基因，为临床治疗提供潜在的靶点，副作用最小。如果这一假设被拒绝，我们将确定包含调节衰老的基因的替代基因，这将提出新的机制和新的潜在临床治疗方法。如果在目标1中，我们没有发现与雷帕霉素益处相关的基因，我们将结合目标1和目标2的数据来确认和扩大对调节正常衰老速度的关键基因的检测。目的3验证免疫、肾脏、心脏和代谢衰老以及健康寿命受相同基因座调控的假设。如果这一假设得到证实，我们将在不同的系统中识别对衰老具有多效性影响的基因。如果这一假设被否决，我们将在每个单独的系统中识别调节衰老的基因；炎症标志物的这种基因调控的特异性可能提供将雷帕霉素治疗的好处与其免疫抑制作用脱钩的手段。无论这一假设是否得到证实，基因识别都将为临床治疗提供建议。)