Assessing lifespan and aging phenotypes resulting from FoxO3 induction using mouse models

使用小鼠模型评估 FoxO3 诱导产生的寿命和衰老表型

• 批准号: 10015317
• 负责人: Jesse B Owens
• 金额: $ 28.68万
• 依托单位: KUAKINI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015317
• 关键词: Age; Aging; Animal Model; Apoptosis; Biological Assay; Biological Models; Caloric Restriction; Cardiovascular Diseases; Cardiovascular Physiology; Cell Cycle Arrest; Cell physiology; Cells; Center for Translational Science Activities; Centers of Research Excellence; DNA; Development; Disease; FOXO3A gene; Future; Gene Transfer Techniques; Genes; Genetic; Genetic Enhancement; Genome; Genotype; Goals; Heart; Human; Individual; Inflammation; Intervention; Knowledge; Lead; Length; Life; Literature; Longevity; Low Prevalence; Malignant Neoplasms; Medical center; Memory; Metabolism; Mus; Oxidative Stress; Phenotype; Play; Population; Reporting; Research; Resistance; Role; Signal Transduction; Single Nucleotide Polymorphism; Stress; Survivors; System; Testing; Therapeutic; Time; Tissues; Transgenic Animals; Translating; age related; cohort; comparative; dietary restriction; dosage; experimental study; fly; gain of function; glucose tolerance; healthspan; healthy aging; human data; improved; innovation; longevity gene; loss of function; mouse model; neuromuscular; novel; phenotypic data; prevent; programs; promoter; protective effect; stem cells; synergism; telomere; transcription factor; vector; working group

PROJECT SUMMARY The genetic contribution to longevity in humans is estimated to be >25% and may be much higher in populations with larger numbers of exceptional survivors. Activation of the DAF-16/FoxO3 transcription factor was required in experiments that increased the lifespan of flies by >50% and worms by six-fold. Environmental signals such as caloric restriction and oxidative stress trigger FoxO3 to upregulate target genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis which may play a preventative role for age-related diseases. Protective single-nucleotide polymorphisms (SNPs) in FOXO3 are strongly associated with exceptional longevity in humans. Surprisingly, mouse studies incorporating extra copies of FoxO3 have not yet been performed. It is currently unclear if FoxO3 is capable of increasing lifespan in mice analogous to what has been observed for other known longevity genes. There is a need to correct this gap in knowledge because identifying FoxO3 as a target gene in mice would be an important advance for developing future aging interventions. The long-term research goal is to identify candidate targets for enhancing longevity in model systems so that these discoveries can be translated to human therapies. The objective for the proposal is to demonstrate a clear relation between FoxO3 and longevity in mouse models. The central hypothesis is that increased dosage of FoxO3 will improve healthspan in mice and mimic aging phenotypes seen in humans with the protective genotype. This hypothesis has been formed on the basis of studies demonstrating FoxO3's role in human longevity, as well as reports showing that FoxO3 provides resistance to oxidative stress, protects against cancer, and is required for the life- extending effect of dietary restriction in mice, among other longevity-supporting effects. This hypothesis will be tested by pursuing three specific aims: 1) Generate mouse models for longevity-associated genes and assay gain and loss of function of FoxO3 at key timepoints in the mouse lifespan; 2) Determine if increased expression of FoxO3 improves aging phenotypes in mouse models; and 3) Establish correlations between FoxO3 mouse models and the Kuakini Honolulu Heart Program (Kuakini HHP) human cohort. FOXO3 is one of only two genes (the other being APOE) that have been replicated consistently for association with longevity in humans. The proposed research is innovative because the applicants will analyze novel mouse lines capable of activating or deactivating FoxO3 when desired. This will be the first time that genetic enhancement of FoxO3 will be assayed for improvements to healthspan and lifespan in mice. The approach is significant because studying FoxO3 could extend lifespan and healthspan in mice, and therefore lead to a better understanding of human longevity. Ultimately, this may lead to potential therapeutic approaches to help humans live longer and healthier lives.

项目摘要 据估计，基因对人类寿命的贡献大于25%，在成年人中可能更高。 有大量特殊幸存者的群体。转录因子β 16/FoxO 3的激活 在实验中，果蝇的寿命增加了50%以上，蠕虫的寿命增加了6倍。 热量限制和氧化应激等环境信号触发FoxO 3上调靶向 参与应激抗性、代谢、细胞周期阻滞和凋亡的基因，这些基因可能发挥作用， 预防与年龄有关的疾病。FOXO 3中的保护性单核苷酸多态性（SNP）是 与人类的长寿密切相关。令人惊讶的是，在小鼠研究中， FoxO 3的复制还没有进行。目前尚不清楚FoxO 3是否能够增加 小鼠的寿命类似于其他已知的长寿基因。有必要 纠正这一知识差距，因为在小鼠中鉴定FoxO 3作为靶基因将是重要的 促进未来老龄化干预措施的发展。长期研究目标是确定候选人 提高模型系统寿命的目标，以便这些发现可以转化为人类 治疗该提案的目的是证明FoxO 3和寿命之间的明确关系， 小鼠模型。核心假设是增加FoxO 3的剂量将改善小鼠的健康寿命 并模仿在具有保护基因型的人类中看到的衰老表型。这一假说已经形成 基于研究表明FoxO 3在人类长寿中的作用，以及报告显示， FoxO 3提供抗氧化应激，预防癌症，并为延长生命所必需。 饮食限制对小鼠的影响，以及其他长寿支持作用。这一假设将得到检验 通过追求三个具体目标：1）产生长寿相关基因和测定增益的小鼠模型 以及在小鼠寿命的关键时间点FoxO 3的功能丧失; 2）确定是否增加的表达 FoxO 3改善小鼠模型中的衰老表型;以及3）建立FoxO 3 小鼠模型和Kuakini檀香山心脏计划（Kuakini HHP）人类队列。FOXO 3是仅有的 两个基因（另一个是APOE）一直在复制，与长寿有关， 人类这项研究具有创新性，因为申请人将分析新的小鼠品系。 能够在需要时激活或去激活FoxO 3。这将是第一次， 将测定FoxO 3的增强对小鼠健康寿命和寿命的改善。的方法 是重要的，因为研究FoxO 3可以延长小鼠的寿命和健康寿命，因此导致 更好地了解人类寿命。最终，这可能会导致潜在的治疗方法， 帮助人类活得更长更健康。