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

项目摘要 寿命、健康寿命以及调节它们的机制往往因性别而异。这是 人类尤其如此-在每个现代社会和历史时期，妇女的寿命始终比男子长。 两性对潜在的衰老调节干预措施的反应也各不相同， 研究报告指出，只有一种性别的人具有显著的延长寿命或健康的效果。迄今为止， 通过NIA干预测试计划评估，成功延长了小鼠的寿命， 对一种性别的影响大于另一种。令人惊讶的是，考虑到它们几乎无处不在， 延长寿命的遗传或药物干预在很大程度上没有得到研究。虽然这种 差异本身就很重要，可能对衰老的发展很重要- 虽然性别差异阻碍了对人类的干预，但它也可以作为一种工具，填补我们理解的空白。 衰老的具体机制。如果通过基因或其他手段操纵生物化学网络的一部分， 药理学靶向--仅影响一种性别的健康和寿命，然后通过研究这如何影响 操纵以性别特异性的方式影响下游靶点，我们可以了解 网络影响健康和寿命。因此，延缓衰老干预措施的性别特异性反应 可以用来提供对衰老的基本机制的更深入的理解。这 一项提案利用了一种独特的小鼠模型，即四个核心基因型（FCG），其中性染色体 补体与性腺性别无关。这项研究的首要假设是， 可以揭示和评估小鼠健康和长寿干预措施的性别特异性效应 通过研究FCG小鼠的健康和下游效应延长寿命的干预措施。我们 我建议使用17α-雌二醇（17α-E2）来评估这一假设，它只延长男性的寿命，通过 具体目标（SA）。SA 1将检验代谢、炎症反应和 mTOR和相关通路中的特定节点对激素和性别有不同的反应， 使用17α-E2和手术去势处理的FCG小鼠进行染色体操作， 性别特异性效应SA 2将使用急性应激源，肺炎链球菌感染，以调查 在SA 1中观察到的性别特异性反应是否可以预测在一个治疗方案下的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，衰老的标志。

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.