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: 10263957
• 负责人: Jesse B Owens
• 金额: $ 9.01万
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263957
• 关键词: Age; Aging; Animal Model; Apoptosis; Biological Assay; Biological Models; Caloric Restriction; Cardiovascular Diseases; Cardiovascular Physiology; Cell Cycle Arrest; 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 cell function; 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.

项目概要 据估计，遗传因素对人类长寿的贡献>25%，并且在人类中可能更高。 拥有大量特殊幸存者的人群。 DAF-16/FoxO3 转录因子的激活 实验中需要将苍蝇的寿命延长 50% 以上，将蠕虫的寿命延长六倍。 热量限制和氧化应激等环境信号触发 FoxO3 上调靶标 参与应激抵抗、新陈代谢、细胞周期停滞和细胞凋亡的基因可能发挥着重要作用 对与年龄相关的疾病具有预防作用。 FOXO3 中的保护性单核苷酸多态性 (SNP) 是 与人类的超长寿命密切相关。令人惊讶的是，小鼠研究结合了额外的 FoxO3 的副本尚未执行。目前尚不清楚 FoxO3 是否能够增加 小鼠的寿命与在其他已知长寿基因中观察到的寿命类似。有必要 纠正这一知识差距，因为将 FoxO3 识别为小鼠的靶基因将是一个重要的 为开发未来的老龄化干预措施取得进展。长期研究目标是确定候选者 提高模型系统寿命的目标，以便这些发现可以转化为人类 疗法。该提案的目的是证明 FoxO3 与长寿之间的明确关系 鼠标模型。中心假设是增加 FoxO3 的剂量将改善小鼠的健康寿命 并模仿具有保护性基因型的人类中观察到的衰老表型。这个假设已经成立 基于证明 FoxO3 在人类长寿中的作用的研究以及表明 FoxO3 可抵抗氧化应激，预防癌症，并且是延长生命所必需的 饮食限制对小鼠的影响，以及其他长寿支持作用。这个假设将被检验 通过追求三个具体目标：1) 生成长寿相关基因和检测增益的小鼠模型 FoxO3 在小鼠寿命关键时间点的功能丧失； 2) 确定表达是否增加 FoxO3 可改善小鼠模型的衰老表型； 3) 建立 FoxO3 之间的相关性 小鼠模型和 Kuakini 檀香山心脏计划 (Kuakini HHP) 人类队列。 FOXO3 是唯一的之一 两个基因（另一个是 APOE）已被一致复制，与长寿相关 人类。拟议的研究具有创新性，因为申请人将分析新的小鼠品系 能够在需要时激活或停用 FoxO3。这将是基因首次 将检测 FoxO3 的增强是否能改善小鼠的健康和寿命。方法 意义重大，因为研究 FoxO3 可以延长小鼠的寿命和健康寿命，从而导致 更好地了解人类的长寿。最终，这可能会带来潜在的治疗方法 帮助人类活得更长久、更健康。