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

人脑的分子老化：基因调节和功能结果

基本信息

批准号：
9109227
负责人：
ETIENNE L SIBILLE
金额：
$ 17.2万
依托单位：
CENTRE FOR ADDICTION AND MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-09 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109227
关键词：
Affect Age Aging Alleles Autopsy Biological Biological Aging Biological Assay Biological Markers Biological Process Body Composition Brain Brain-Derived Neurotrophic Factor Cell physiology Code Cognition Cognitive Cognitive aging Complement Complex Copy Number Polymorphism Custom DNA DNA copy number Databases Development Disease Elderly Emotional Enrollment Epidemiologic Studies Experimental Designs Functional disorder Future Gene Expression Profile Genes Genetic Genetic Markers Genetic Variation Genotype Health Human IGF1 gene Incidence Individual Intervention Left Life Life Expectancy Link Longevity Mediator of activation protein Medical Mitochondria Modeling Molecular Molecular Profiling Monitor Moods Motor Nerve Degeneration Neurodegenerative Disorders Neuropeptides Outcome Prefrontal Cortex Quality of life Recruitment Activity Research Design Risk Rosa Sampling Single Nucleotide Polymorphism Sirtuins Somatostatin Staging Symptoms Testing Transcript United States Variant age related aging brain base cardiovascular health cohort data reduction evidence base experience fitness frailty functional decline functional outcomes genetic variant genome-wide analysis in vivo longevity gene middle age mood regulation neuropsychiatry prevent risk variant

项目摘要

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.

描述（由申请人提供）：在过去的世纪，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，也是一个尚未解决的挑战。事实上，如果成功的衰老是可以实现的，对于许多人来说，情绪低落往往是一种早期症状，也是衰老螺旋式下降的重要因素，包括进一步的认知和运动能力下降。在神经退行性疾病的症状前阶段也观察到情绪低落，这表明情绪调节可能在活力到虚弱的过渡中选择性地脆弱。然而，这一假设一直难以检验，因为在老年个体中评估分子变化和功能下降之间的相关性在逻辑上是复杂的，并且因为无法获得识别具有较高生物风险的个体的方法。在这里，我们建议通过进行平行的死后和体内研究来确定与生物和功能衰老相关的“遗传调节剂”。我们的生物衰老检测是基于这样一个事实，即大脑衰老与强大的分子，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与年龄相关的表达变化。这种衰老的“分子标记”包含许多与神经精神和神经退行性疾病相关的基因，这些基因在促进疾病的方向上受到影响，这表明衰老可能促进疾病的某些方面。值得注意的是，我们表明，分子年龄-在此定义为通过该个体中的基因表达谱预测的年龄-可以偏离实际年龄。例如，在推定的长寿基因（Sirtuin 5）中携带DNA变体的个体显示出较老的分子年龄，可能是通过加速与年龄相关的基因转录的下降。因此，我们假设携带与较老的脑分子年龄相关的“风险”等位基因的受试者将显示出更高的情绪和其他低功能症状的发生率，相反，携带“保护”等位基因的受试者可能会经历更成功的衰老。为了验证这一假设，我们将系统地识别与死后个体（n~300）中较老或较年轻脑分子年龄相关的遗传变异（目的1）。然后，我们将评估这些确定的“风险”或“保护”遗传因素的存在在多大程度上预测老年人体内相应的功能结果，如两项老龄化流行病学研究受试者的情绪，认知和运动年龄依赖性变化所表现的那样：心血管健康（n= 5，888）和健康老化和身体成分（n= 3，075）研究（目标2）。在本研究结束时，我们将实现（i）确定生物和功能老化的强大遗传标记，以及（ii）更详细地描述情绪，认知和运动功能之间的生物/功能联系。这将提供（iii）以证据为基础的假设，以监测关键的功能域在老年，和（iv）合理的实验设计，以调查成功的老化的生物线索。