Genetic Definition of Mechanisms by which Rapamycin Retards Mammalian Aging

描述（由申请人提供）：雷帕霉素治疗是第一种能够可靠地将哺乳动物寿命延长10%或更多的药物干预。令人兴奋的是，这种治疗在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3个独立目标确定了调节雷帕霉素治疗的健康益处的基因，以及控制正常小鼠衰老的关键基因。这个项目是由一个革命性的新的小鼠模型，多样性异交（DO），由加里丘吉尔（共同研究员）开发。与其他模型相比，DO的遗传多样性是4倍多，因为它来自8个高度多样的近交系，包括3个野生来源的M。亚种肌因为DO是一种高级互交，它具有高密度的重组，使得候选基因鉴定比标准F2或N2杂交精确>10倍。我们将在20个月大的DO小鼠中开始治疗，因为老年人对治疗的反应可能与年轻人不同，并且模型人类通常直到60岁左右才开始治疗。将在每只小鼠中检测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。密集作图将识别候选基因。目的1检验雷帕霉素通过mTOR途径有益于哺乳动物健康寿命（健康寿命）的假设。这一假说预测，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。如果这一假设得到证实，我们将确定基因。如果这一假设被拒绝，我们将确定替代基因座含有基因，如药物代谢基因，管理雷帕霉素的好处。目的2检验mTOR通路控制正常衰老的假设。这一假说预测，在雷帕霉素处理的DO小鼠（目的1）中调节衰老的相同基因也调节同窝对照小鼠的衰老。如果这一假设得到验证，我们将鉴定出mTOR通路中具有天然变异的基因，这些基因为临床治疗提供了潜在的靶点，且副作用最小。如果这一假设被拒绝，我们将确定含有调节衰老基因的替代基因座，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的益处相关的基因，我们将结合联合收割机目标1和目标2的数据来确认和扩展调节正常衰老率的关键基因的检测。目的3检验免疫、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，我们将确定基因，有多效性的影响老化在不同的系统。如果这一假设被拒绝，我们将确定在每个系统中调节衰老的基因;炎症标志物的遗传调节的这种特异性可以提供将雷帕霉素治疗的益处与其免疫抑制作用分离的方法。无论假说是否被证实，基因鉴定将为临床治疗提供建议。) 公共卫生相关性：在美国，我们面临的两个最关键的医疗问题是与老年人健康状况不佳相关的情感和经济成本，随着“婴儿潮”人口的老龄化，这一成本正在增加。除了推迟疾病的人道主义利益外，健康寿命的增加将为美国带来巨大的经济利益。从20个月大的小鼠开始，饮食中的雷帕霉素将其健康寿命延长了15% -相当于将60岁的人类预期寿命延长了10年。目前的研究将确定其等位基因调节雷帕霉素和健康衰老的影响的基因。这些信息将针对干预措施的途径，以延缓衰老和延长人类的健康寿命。

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.