A New Translational Rat Model for Evaluating Anti-Aging Interventions

我们建议发展一个可持续的衰老研究基础设施，一个新的和独特的遗传学 可用于评估可能延长寿命和健康的异种实验大鼠模型 干预措施。在干预性衰老研究中，大鼠比小鼠有许多优势，包括 与人类相似的生理学和病理生理学、更复杂的认知和更大的遗传多样性 与标准小鼠品系进行比较。灵感来自于UM-HET3小鼠所使用的干预测试 计划中，我们的大鼠模型(OKC-HETb/w)也将是4个基因异质性的F2后代的群体 不同的近亲繁殖品系。与UM-HET3小鼠显著不同的是，我们的育种计划利用了 与小鼠相比，大鼠的线粒体基因组多样性要高出一半 携带BN株线粒体(OKC-HETb)的另一半携带WKY株线粒体(OKC-HETb)。 HETW)。这些线粒体基因组模仿了人类线粒体的巨大多样性，因为它们的差异在95%左右 核苷酸涉及13个线粒体蛋白编码基因中的11个，5个tRNA和两个核糖体亚基。我们的 初步数据显示，OKC-HETb和OKC-HETw大鼠对运动耐力、握力 力量，以及对17α-雌二醇的反应性。作为原则证明，我们将在OKC-HETb/w大鼠和 抗衰老干预(17α-雌二醇)，此前发现仅能延长雄性小鼠的寿命。一个 我们项目的有趣结果将是验证这种性别特异性是否也在我们的大鼠模型中出现。 在这个项目的R21阶段，我们将生产OKC-HETb/w大鼠和(1)表征基于能量学的 在标准和应激(HFD)条件下，两性在整个动物和细胞水平的健康分析 在两种线粒体基因型中，(2)确定17α-雌二醇的剂量，该剂量将产生可比较的血液水平 那些在研究中发现的有效延长寿命的剂量以及17α-雌二醇对 饮食诱导肥胖小鼠的代谢参数，以及(3)为研究人员提供组织作为 以及新老OKC-HETb/w。在R33阶段，我们将使用在R21阶段获得的信息来： (1)测定17α-雌二醇对男女长寿和年龄相关病理的影响 线粒体基因分型和(2)确定17α-雌二醇对大鼠衰老相关改变的长期影响。 代谢和健康参数，同样，在两性和两种线粒体基因类型中。

We propose to develop as sustainable aging research infrastructure, a new and unique genetically heterogeneous laboratory rat model that can be used to evaluate putative life- and health-extending interventions. The rat has numerous advantages over the mouse for interventional aging research including more human-like physiology and pathophysiology, more cognitive sophistication, and greater genetic diversity compared with standard mouse strains. Inspired by the UM-HET3 mice used by the Interventions testing program, our rat model (OKC-HETb/w) will also be populations of genetically heterogeneous F2 descendants of 4 divergent, inbred strains. A significant difference from the UM-HET3 mice, our breeding scheme takes advantage of the rat’s substantial mitochondrial genomic diversity compared with the mouse to create a population half of which carries the BN strain mitochondria (OKC-HETb), the other half carries the WKY strain mitochondria (OKC- HETw). These mitochondrial genomes mimic great human mitochondrial diversity in that they differ at 95 nucleotides involving 11 of 13 mitochondrial protein-coding genes, 5 tRNA’s and both ribosomal subunits. Our preliminary data show that the OKC-HETb and OKC-HETw rats respond differently to exercise endurance, grip strength, and responsiveness to 17α-estradiol. As a proof of principle, we will evaluate in the OKC-HETb/w rat an anti-aging intervention (17α-estradiol) that was previously found to enhance the longevity of male mice only. An intriguing outcome of our project will be to verify whether or not, this sex-specificity is also seen in our rat model. In the R21 phase of this project we will produce the OKC-HETb/w rats and (1) characterize energetics-based health assays at whole animal and cellular levels under standard and stressed (HFD) conditions in both sexes in both mitochondrial genotypes, (2) determine the dose of 17α-estradiol that will yield blood levels comparable to those found at effective life-extending doses in the ITP study and the short-term effects of 17α-estradiol on metabolic parameters in diet-induced obese mice of both sexes, and (3) provide investigators with tissues as well as young and old OKC-HETb/w. In the R33 phase, we will use the information gained in the R21 phase to: (1) determine the effect of 17α-estradiol on the longevity and age-related pathology in both sexes and both mitochondrial genotypes and (2) determine the long-term effects of 17α-estradiol on age-related changes in metabolic and health parameters, again, in both sexes and both mitochondrial genotypes.