A systems biology approach to explain sex differences in aging

摘要 几乎在每个国家，在所有年龄段，男性的死亡风险都高于女性， 同样的模式也适用于大多数其他哺乳动物物种。在遗传、环境或 药物干预旨在改善衰老的影响，反应往往是性别- 有偏见，在某些情况下，福利仅限于一种性别。美国国立卫生研究院的研究人员受到鼓舞， “性别作为一种生物变量”倡议，在与衰老有关的实验室中考虑性别的影响， 临床研究。然而，由于二分差异（例如，XY 相对于XX性染色体）。这种类型学方法可以成功地确定性是否影响结果， 没有解释为什么会出现这种性别差异。现有方法中的这一差距是一个关键的未得到满足的问题， 在老龄化研究领域的需求。最近发表的研究和我们实验室的初步工作表明， 性别对复杂性状的影响远非二分法，而是沿着一个连续体下降。例如，在果蝇中， 男性和女性寿命差异的大小和方向因基因型而异。 初步数据表明，对于旨在改善性别差异的治疗， 实验室生物体的健康衰老。这种从二分法到连续视角的转变， 这是一个重要的概念创新。基于这些发现，这里测试的中心假设是， 生物学上的性别差异沿着一个由性别与潜在基因型相互作用形成的连续体， 这种连续性的机制是可以解释的。该提案的主要目的是利用 代谢组学分析的系统生物学方法，以发现 性别对衰老和年龄相关性状的基因型依赖效应。与我们之前的许多工作一样，我们使用 果蝇基因组参考面板，一个强大的自然遗传变异模型。我们将这种基因联合收割机 资源与代谢组学的概况，它测量的小分子组成的结构和 所有特征的功能性基础为了验证我们的核心假设，我们探讨两个问题。首先利用 代谢组特征的测量，包括每种性别内的测量和性别间的差异， 预测和解释果蝇寿命和抗应激性性别差异的遗传变异。第二、 我们测试代谢组预测和解释对雷帕霉素反应的性别差异的能力， 在不同的实验室生物中发现可以延长健康寿命。我们采用蛋白质组学和转基因方法， 验证代谢组学提出的性别差异的假定机制。其长期目标是 研究的目的是为改善性别特异性疾病的预测、预后、诊断和治疗奠定基础。 和预防。

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.