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: 8183883
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183883
• 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; Disease; Drug Delivery Systems; 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; 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; Disease; Drug Delivery Systems; 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. ) PUBLIC HEALTH RELEVANCE: In the US, two of the most critical medical issues we face are the emotional and financial costs related to ill health in the elderly, which is increasing as the "baby boomer" population ages. In addition to the humanitarian benefits of postponing disease, increases in healthy lifespan will have enormous financial benefits for the US. Dietary rapamycin in mice, started at 20 months of age, increased their healthy lifespan by 15% - equivalent to increasing life expectancy of 60- year-old humans by 10 years. The current study will identify genes whose alleles regulate effects of rapamycin and healthy aging in general. This information will target pathways for interventions to retard aging and extend healthy lifespan in human beings.

描述（由申请人提供）：雷帕霉素治疗是可靠地将哺乳动物寿命可靠的第一种药物干预措施提高10％或更多。令人兴奋的是，这种治疗在20个月大时开始时在异质小鼠中有效，大致类似于60岁的人类。当前项目的3个独立目标确定了调节雷帕霉素治疗健康益处的基因，以及控制正常小鼠衰老的关键基因。由加里·丘吉尔（Gary Churchill）（共同投资者）开发的革命性新老鼠模型（DO）使该项目成为可能。与其他模型相比，DO的遗传多样性大于4倍以上，因为它来自8种高度多样化的近交菌株，包括3个野生衍生的Musculus subspecies。因为DO是一种高级间交叉，所以它具有高度的重组密度，使候选基因识别> 10倍比标准的F2或N2交叉更精确。我们将在20个月大的DO小鼠中开始治疗，因为老年人可能对治疗的反应与年轻人的反应不同，并且对人类的对象进行了模型，而人类通常要等到60岁左右才能开始治疗。将在每只小鼠中测试足够的标记等位基因，以绘制与生理衰老（免疫，肾脏，心脏和代谢）和寿命相关的基因座。密集的映射将识别候选基因。 AIM 1检验了雷帕霉素通过MTOR途径使哺乳动物HealthSpan（健康寿命）受益的假设。该假设预测，雷帕霉素喂养的DO小鼠的衰老将受到mTOR途径基因等位基因的影响。如果该假设得到验证，我们将识别基因。如果拒绝了该假设，我们将确定含有含有雷帕霉素益处的药物代谢基因的替代基因座。 AIM 2检验了MTOR途径控制正常衰老的假设。该假设预测，在雷帕霉素处理的DO小鼠中调节衰老的相同基因（AIM 1）也调节同窝窝控制中的衰老。如果验证了该假设，我们将在MTOR途径中鉴定具有自然变异的基因，这些基因为具有最小不良副作用的临床治疗提供了潜在的靶标。如果该假设被拒绝，我们将确定含有调节衰老的基因的替代基因座，这将暗示新的机制和新型的潜在临床治疗。如果在AIM 1中，我们找不到与雷帕霉素益处相关的基因，我们将结合AIM 1和AIM 2数据，以确认和扩展调节正常衰老率的关键基因的检测。 AIM 3检验了以下假设：免疫，肾脏，心脏和代谢衰老以及健康状态受到同一基因座的调节。如果验证了该假设，我们将确定对各种系统中衰老具有多效影响的基因。如果该假设被拒绝，我们将确定调节每个单个系统衰老的基因。炎症标志物的遗传调节中的这种特异性可以提供使雷帕霉素治疗的益处与免疫抑制作用相结合的手段。是否验证了该假设，基因鉴定将暗示临床治疗。 ） 公共卫生相关性：在美国，我们面临的两个最关键的医学问题是与老年人健康状况不佳有关的情感和财务成本，随着“婴儿潮一代”的人口年龄，这一情况正在增加。除了延迟疾病的人道主义益处外，健康寿命的增加还将为美国带来巨大的经济利益。小鼠饮食中的雷帕霉素从20个月大开始，将其健康的寿命提高了15％ - 相当于增加60岁的人的预期寿命增加了10年。当前的研究将确定其等位基因调节雷帕霉素和健康衰老的作用的基因。该信息将针对干预措施延迟衰老并延长人类健康的寿命。