A Four Core Genotype (FCG) Approach to Investigating Sex Differences in Health and Longevity

研究健康和长寿性别差异的四核心基因型 (FCG) 方法

• 批准号: 9504206
• 负责人: STEVEN N. AUSTAD
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9504206
• 关键词: Acute; Adipose tissue; Affect; Aging; Androgens; Animal Model; Biochemical; Biology of Aging; Castration; Cell Culture Techniques; Complex; Developed Countries; Developing Countries; Development; Diptera; Disabled Persons; Discrimination; Elderly; Estradiol; Estrogens; Exhibits; FRAP1 gene; Female; Gene Expression; Genes; Genetic; Genotype; Gonadal Hormones; Gonadal Steroid Hormones; Growth Factor; Health; Hormonal; Hospitals; Human; Infection; Inflammation; Inflammatory Response; Intervention; Knowledge; Learning; Life; Liver; Longevity; Metabolism; Mitochondrial Proteins; Modernization; Mus; Ovary; Pathway interactions; Performance; Pharmacology; Ploidies; Progestins; Reporting; Sex Characteristics; Sex Chromosomes; Societies; Streptococcus pneumoniae; Stress; Sum; System; Testing; Testis; Transgenes; Translations; United States; Visit; Woman; Women' s Health; Work; Y Chromosome; autosome; clinically relevant; dosage; enantiomer; health difference; healthspan; immune function; improved; in vivo; insight; interest; mTOR inhibition; male; men; mitochondrial metabolism; mouse model; novel; programs; response; senescence; sex; sry Genes; stressor; tool; trait; virtual

Project Summary Lifespan, healthspan, and the mechanisms that modulate them often vary between the sexes. This is particularly true of humans—women consistently outlive men in every modern society and historical period. The sexes also vary in their response to potentially senescence-modulating interventions and numerous studies have reported a significant life- or health-extending effect in one sex only. To date, 6 compounds evaluated by the NIA Intervention Testing Program have successfully extended lifespan in mice and all affected one sex more than the other. Surprisingly, given their near ubiquity, sex differences in response to lifespan-extending genetic or pharmacological interventions have gone largely unstudied. While such differences are of interest in their own right and are likely to be important for the development of senescence- retarding interventions in humans, sex differences can also be used as a tool to fill gaps in our understanding of specific mechanisms of aging. If manipulation of parts of a biochemical network—either by genetic or pharmacological targeting—affects health and longevity in one sex only, then by examining how that manipulation affects downstream targets in a sex-specific manner we can learn how specific components of the network impact health and longevity. Thus, sex-specific responses to senescence-retarding interventions can be used to provide a deeper understanding of the fundamental mechanisms involved in aging. This proposal exploits a unique mouse model, the Four Core Genotypes (FCG), in which sex chromosome complement is independent of gonadal sex. The overarching hypothesis of this study is that mechanisms underlying the sex-specific effects of health and longevity interventions in mice can be revealed and evaluated by investigating the health and downstream effectors of life-extending interventions in the FCG mice. We propose to evaluate this hypothesis using 17α-estradiol (17α-E2), which extends lifespan in males only, via the following Specific Aims (SAs). SA1 will test the hypothesis that metabolism, inflammatory response and specific nodes in the mTOR and associated pathways are differentially responsive to hormonal and sex chromosome manipulations using the FCG mice treated with 17α-E2 and surgical castration to uncover these sex-specific effects. SA2 will use an acute stressor, infection with Streptococcus pneumoniae, to investigate whether the sex-specific responses observed in SA1 are predictive of improved health and survival under a clinically relevant challenge involving inflammation and immune function, hallmarks of aging.

项目摘要 寿命，健康范围以及调节它们的机制在性别之间通常会有所不同。这是 人类尤其如此 - 妇女在每个现代社会和历史时期都始终超过男人。 性别的反应也有所不同 研究报告说，仅在一种性别中具有重大的寿命或健康延伸作用。迄今为止，6种化合物 通过NIA干预测试计划评估的小鼠和所有人都成功地延长了寿命 对一种性别的影响比另一种性别更大。令人惊讶的是，鉴于它们几乎普遍存在，性别差异 延长寿命的遗传或药理干预措施在很大程度上未被研究。而这样 差异本身就是感兴趣的，对于衰老的发展很重要 - 延迟对人类的干预措施，性别差异也可以用作填补我们理解空白的工具 衰老的特定机制。如果操纵生化网络的一部分 - 药理靶向 - 仅在一种性别中影响健康和寿命，然后检查如何 操纵以特定于性别的方式影响下游目标，我们可以学习特定组成部分 该网络影响健康和寿命。那是对害虫干预措施的性别特定反应 可用于对衰老所涉及的基本机制有更深入的了解。这 提案利用独特的鼠标模型，即四种核心基因型（FCG），其中性别染色体 补体独立于性腺性别。这项研究的总体假设是机制 可以揭示和评估健康和寿命干预措施的性别特异性影响 通过研究FCG小鼠寿命延长干预措施的健康和下游影响。我们 提出使用17α-雌二醇（17α-e2）评估这一假设的建议，该假设仅通过男性延长寿命 遵循特定目标（SAS）。 SA1将检验代谢，炎症反应和 MTOR和相关途径中的特定节点对荷尔蒙和性别的响应有所不同 使用用17α-E2治疗的FCG小鼠和手术cast割的染色体操纵，以发现这些 性别特定的效果。 SA2将使用急性应激源，肺炎链球菌感染，研究 在SA1中观察到的性别特定反应是否可以预测改善的健康和生存 临床相关的挑战参与炎症和免疫学功能，衰老的标志。