Molecular Aging of the Human Brain: Genetic Modulation and Functional Outcomes

描述(由申请人提供)：在过去的一个世纪里，医疗干预和生活条件的改善极大地延长了人类的平均寿命。因此，情绪和认知健康已成为老年生活质量的一个主要决定因素，也是一个未得到满足的挑战。事实上，如果成功衰老是可以实现的，对许多人来说，情绪低落往往是衰老的早期症状，也是导致衰老螺旋式下降的重要因素，其中包括认知和运动能力的进一步下降。在神经退行性疾病的症状前阶段也可以观察到情绪低落，这表明情绪调节在从活力到虚弱的转变中可能选择性地脆弱。然而，这一假说很难检验，因为在老年人中，分子变化和功能衰退之间的相关性在逻辑上是复杂的，而且由于没有方法识别具有更高生物风险的个人。在这里，我们建议通过平行的死后和活体研究来识别与生物和功能衰老有关的“基因调节器”。我们对生物衰老的分析是基于这样一个事实，即大脑衰老与强劲的分子、细胞和结构变化有关，为此我们已经确定了一组特定的基因，这些基因的表达随年龄而变化。衰老的这一分子标志包含许多神经精神和神经退行性疾病相关基因，这些基因在促病方向上受到影响，这表明衰老可能会促进疾病的各个方面。值得注意的是，我们发现分子年龄--这里定义的年龄是通过个体的基因表达谱预测的年龄--可以偏离实际年龄。例如，携带假定长寿基因(Sirtuin 5)的DNA变体的个体显示出较老的分子年龄，这可能是由于线粒体相关基因转录随年龄增长而加速下降。因此，我们假设，携带与大脑分子年龄较大相关的“危险”等位基因的受试者将表现出更高的情绪和其他低功能症状的发生率，反之，携带“保护性”等位基因的受试者可能经历更成功的衰老。为了验证这一假设，我们将系统地识别与死后个体(n~300)大脑分子年龄较大或较年轻相关的遗传变异(目标1)。然后，我们将评估这些已确定的“风险”或“保护性”遗传因素的存在对老年人体内相应功能结果的预测程度，这体现在两项老龄化流行病学研究的受试者的情绪、认知和运动年龄依赖的变化上：心血管健康(n=5,888)和健康老龄化与身体成分(n=3,075)研究(目标2)。在这项研究结束时，我们将实现(I)识别生物和功能衰老的稳健遗传标记，以及(Ii)更详细地表征情绪、认知和运动功能之间的生物/功能联系。这将提供(Iii)基于证据的假说来监测老年人的关键功能区域，以及(Iv)为合理的实验设计以调查成功的衰老提供生物学线索。

DESCRIPTION (provided by applicant): Improvements in medical interventions and living conditions have dramatically increased the average human lifespan over the last century. As a result, emotional and cognitive fitness has become a major determinant, and unmet challenge, to the quality of life during old age. Indeed, if successful aging is achievable, for numerous individuals, low mood is too often an early symptom and significant contributor to the downward spiral of aging, which includes further cognitive and motor declines. Low mood is also observed in presymptomatic stages of neurodegenerative disorders, together suggesting that mood regulation may be selectively vulnerable at the vigor-to-frailty transition. However, this hypothesis has been difficult to test, as correlations between molecular changes and functional declines are logistically complex to assess in elderly individuals, and, since means to identify individuals at higher biological risk are not available. Here, we propose to identify "genetic modulators" that associate with both biological and functional aging, by performing parallel postmortem and in vivo studies. Our assay for biological aging is based on the fact that brain aging associates with robust molecular, cellular and structural changes, for which we have identified a specific set of genes with age-dependent expression changes. This "molecular signature" of aging contains many neuropsychiatric and neurodegenerative disease-related genes, which are affected in disease-promoting directions, suggesting that aging may promote aspects of diseases. Notably, we show that molecular age - defined herein as the age that is predicted by the gene expression profile in that individual - can deviate from chronological age. For instance, individuals carrying a DNA variant in a putative longevity gene (Sirtuin 5) display older molecular ages, potentially through accelerated age-dependent declines in mitochondrial-related gene transcripts. Thus, we hypothesize that subjects carrying "risk" alleles associated with older brain molecular age will display higher incidence of mood and other low function symptoms, and conversely that subjects carrying "protective" alleles may experience greater successful aging. To test this hypothesis, we will systematically identify genetic variants associated with older or younger brain molecular ages in postmortem individuals (n~300) (Aim 1). We will then assess the extent to which the presence of these identified "risk" or "protective" genetic factors predicts corresponding functional outcomes in vivo in elderly individuals, as manifested by mood, cognitive and motor age-dependent changes in subjects from two epidemiological studies of aging: the Cardiovascular Health (n=5,888) and Health Aging and Body Composition (n=3,075) studies (Aim 2). At the end of this study, we will have achieved (i) the identification of robust genetic markers for biological and functional aging, and (ii) a more detailed characterization of biological/functional links between mood, cognition and motor functions. This will provide (iii) evidence-based hypotheses to monitor critical functional domains in old age, and (iv) biological leads for rational experimental design to investigate successful aging.