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 对于人类来说尤其如此--在每个现代社会和历史时期，女性的寿命都一直高于男性。 两性对潜在的调节衰老的干预措施的反应也不同，许多 研究报告称，只有一种性别有显著的延长寿命或健康的效果。到目前为止，有6种化合物 通过NIA干预测试计划评估，成功地延长了小鼠和ALL的寿命 对某一性别的影响比对另一性别的影响更大。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在很大程度上还没有研究过。尽管如此， 差异本身就是利益所在，而且可能对衰老的发展很重要。 性别差异阻碍了对人类的干预，也可以作为一种工具来填补我们理解上的空白 衰老的特定机制。如果对生化网络的部分进行操纵--无论是通过遗传还是通过 药物靶向--只在一种性别中影响健康和寿命，然后通过检查 操纵以性别特有的方式影响下游靶点，我们可以了解到 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 可以用来更深入地了解衰老的基本机制。这 Proposal利用了一种独特的小鼠模型，即四种核心基因类型(FCG)，在该模型中，性染色体 补体与性腺性别无关。这项研究的首要假设是，机制 可以揭示和评估健康和长寿干预措施对小鼠的性别特异性影响 通过调查FCG小鼠的健康和延寿干预的下游效应。我们 建议使用17α-雌二醇(17α-E2)来评估这一假说，它只在男性中延长寿命，通过 遵循特定目标(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别的反应不同 用17α-E_2处理的胎鼠的染色体操作和手术去势来揭示这些 性别特有的影响。SA2将使用一种急性应激源-肺炎链球菌感染-来调查 在SA1中观察到的性别特异性反应是否预示着在 与临床相关的挑战，涉及炎症和免疫功能，这是衰老的标志。

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.