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.

项目概要 寿命、健康寿命以及调节它们的机制通常因性别而异。这是 对于人类来说尤其如此——在每个现代社会和历史时期，女性始终比男性长寿。 性别对潜在的衰老调节干预措施的反应也有所不同，并且许多 研究报告称，仅对一种性别具有显着的延长寿命或健康的作用。迄今为止，已发现 6 种化合物 经 NIA 干预测试计划评估已成功延长小鼠和所有动物的寿命 对一种性别的影响比对另一种性别的影响更大。令人惊讶的是，鉴于它们几乎无处不在，性别差异对 延长寿命的遗传或药物干预措施基本上未被研究。虽然这样 差异本身就很有趣，并且可能对衰老的发展很重要 阻碍对人类的干预，性别差异也可以用作填补我们理解空白的工具 衰老的具体机制。如果通过基因或基因来操纵生化网络的某些部分 药理学靶向——仅影响一种性别的健康和寿命，然后通过检查它是如何影响的 操纵以特定性别的方式影响下游目标，我们可以了解特定成分如何 网络影响健康和寿命。因此，对延缓衰老干预措施的性别特异性反应 可用于更深入地了解衰老的基本机制。这 该提案利用了一种独特的小鼠模型，即四核心基因型（FCG），其中性染色体 补体与性腺性别无关。本研究的总体假设是机制 可以揭示和评估小鼠健康和长寿干预措施对性别特异性的影响 通过研究 FCG 小鼠的健康状况和延长寿命干预措施的下游效应器。我们 建议使用 17α-雌二醇 (17α-E2) 来评估这一假设，它仅延长男性的寿命，通过 遵循具体目标 (SA)。 SA1 将检验新陈代谢、炎症反应和 mTOR 和相关通路中的特定节点对激素和性的反应不同 使用经过 17α-E2 治疗和手术去势的 FCG 小鼠进行染色体操作以揭示这些 性别特异性效应。 SA2 将使用急性应激源（肺炎链球菌感染）来进行调查 SA1 中观察到的性别特异性反应是否可以预测健康状况和生存率的改善 涉及炎症和免疫功能的临床相关挑战，这是衰老的标志。