A systems biology approach to explain sex differences in aging

解释衰老性别差异的系统生物学方法

• 批准号: 10625366
• 负责人: Daniel Edward Promislow
• 金额: $ 5.81万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625366
• 关键词: Address; Affect; Age; Aging; Biological; Biological Assay; Biology; Cessation of life; Clinical Research; Complex; Country; Data; Diagnosis; Disease; Drosophila genome; Drosophila genus; Environment; Female; Future; Genes; Genetic; Genetic Models; Genetic Variation; Genetic study; Genome; Genotype; Goals; Human; Individual; Intervention; Laboratory Study; Life Expectancy; Light; Link; Longevity; Measures; Methods; Modeling; Molecular; Organism; Outcome; Ovary; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Prevention; Prognosis; Proteome; Proteomics; Publishing; Research; Research Personnel; Resistance; Risk; Role; Sex Bias; Sex Chromosomes; Sex Differences; Shapes; Sirolimus; Specificity; Stress; Study models; Systems Biology; Testing; Testis; Thinking; Transgenic Organisms; United States National Institutes of Health; Variant; Woman; Work; age effect; age related; biological sex; design; dimorphism; disease diagnosis; disorder risk; endophenotype; epigenome; falls; genetic predictors; genetic resource; healthspan; healthy aging; high dimensionality; human male; improved; innovation; male; men; metabolome; metabolomics; microbiome; mortality risk; novel; novel strategies; pharmacologic; precision medicine; prevent; reference genome; response; sex; sex determination; sexual dimorphism; small molecule; therapy design; trait; transcriptome; translational goal; translational potential; translational study; treatment response

ABSTRACT The risk of mortality is higher for human males than females at all ages and in almost every country, and this same pattern holds in most other mammalian species as well. In studies of genetic, environmental or pharmacological interventions designed to ameliorate the effects of aging, the responses are frequently sex- biased, and in some cases, benefits are limited to just one sex. Researchers have been encouraged by NIH’s “Sex As a Biological Variable” (SABV) initiative to consider the effect of sex in aging-related laboratory and clinical studies. However, the focus has been on sexual dimorphism due to dichotomous differences (e.g., XY versus XX sex chromosomes). This typological approach can successfully determine if sex affects outcome, but fails to address why these sex differences occur. This gap in existing approaches represents a critical unmet need in the field of aging research. Recent published studies and preliminary work from our lab show that the effects of sex on complex traits are far from dichotomous, falling along a continuum. In fruit flies, for example, both the magnitude and direction of difference between males and females in lifespan vary among genotypes. Preliminary data suggest the same is true for the sex-specific response to treatments designed to improve healthy aging in lab organisms. This shift from a dichotomous to continuous perspective on the effects of sex reflects an important conceptual innovation. Based on these findings, the central hypothesis tested here is that biological sex differences fall along a continuum shaped by sex interacting with the underlying genotype, and that the mechanisms contributing to this continuum are discoverable. The primary goal of this proposal is to use a systems biology approach with metabolomic profiling to discover the molecular mechanisms that underlie genotype-dependent effects of sex on aging and age-related traits. As in much of our prior work, we use the Drosophila Genome Reference Panel, a powerful model of natural genetic variation. We combine this genetic resource with profiles of the metabolome, which measures the small molecules that make up the structural and functional building blocks for all traits. To test our central hypothesis, we explore two questions. First, we use measures of metabolome profiles, including measures within each sex and the difference between sexes, to predict and explain genetic variation in sex differences for lifespan and stress resistance in Drosophila. Second, we test the ability of the metabolome to predict and explain sex differences in response to rapamycin, a drug found to extend healthy lifespan in diverse lab organisms. We employ proteomic and transgenic approaches to validate putative mechanisms for sex differences suggested by metabolomics. The long-term goal of this research is to lay the groundwork for improved sex-specific disease prediction, prognosis, diagnosis, treatment and prevention in human populations.

抽象的 几乎在每个国家，所有年龄段的人类死亡风险都高于女性，这 在遗传、环境或其他大多数哺乳动物物种的研究中也存在同样的模式。 旨在改善衰老影响的药物干预措施，其反应往往是性别- 美国国立卫生研究院鼓励研究人员享受有偏见的福利，而且在某些情况下，福利仅限于一种性别。 “性别作为生物变量”（SABV）倡议考虑性别对衰老相关实验室和 然而，临床研究的重点是由于二分差异（例如 XY）引起的性别二态性。 与 XX 性染色体）这种类型学方法可以成功确定性别是否影响结果，但是 未能解决这些性别差异发生的原因。现有方法中的这一差距代表了一个关键的未满足问题。 我们实验室最近发表的研究和初步工作表明，衰老研究领域的需求。 性别对复杂性状的影响远不是二元的，例如在果蝇中，是连续的。 男性和女性寿命差异的大小和方向因基因型的不同而不同。 初步数据表明，对于旨在改善的治疗的性别特异性反应也是如此。 实验室有机体的健康衰老从二分法到连续性的影响的转变。 基于这些发现，这里测试的中心假设反映了这一点。 生物性别相互作用的差异属于由性别与潜在基因型形成的连续体，并且 该提案的主要目标是使用有助于发现这一连续体的机制。 采用代谢组学分析的系统生物学方法，以发现潜在的分子机制 与我们之前的大部分工作一样，我们使用性别对衰老和年龄相关特征的基因型依赖性影响。 果蝇基因组参考面板，一个强大的自然遗传变异模型，我们结合了这种遗传变异。 具有代谢组概况的资源，可测量构成结构和结构的小分子 为了检验我们的中心假设，我们首先探讨两个问题。 代谢组谱的测量，包括每个性别内的测量以及性别之间的差异，以 预测并解释果蝇寿命和应激抵抗力的性别差异的遗传变异。 我们测试代谢组预测和解释对雷帕霉素（一种药物）反应的性别差异的能力 发现可以延长不同实验室生物体的健康寿命。我们采用蛋白质组学和转基因方法来研究。 验证代谢组学提出的性别差异的假定机制。这是其长期目标。 研究旨在为改善性别特异性疾病预测、预后、诊断和治疗奠定基础 和人群预防。