Biological Aging Contributions to Molecular Pathology and Neurodegeneration

生物衰老对分子病理学和神经退行性变的贡献

• 批准号: 10017140
• 负责人: Corey T McMillan
• 金额: $ 78.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017140
• 关键词: Address; Adult; Age; Age-Years; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Apoptosis; Autopsy; Biological; Biological Aging; Biological Markers; Birth; Blood; Brain; Cell Aging; Cell Cycle Arrest; Cell division; Chromosomes; Chronology; Cognitive aging; DNA Methylation; DNA Sequence; Data; Development; Diagnosis; Early Intervention; Elderly; Epigenetic Process; Funding; Gene Expression; Gene Frequency; Genes; Genetic; Goals; Heterogeneity; Individual; Laboratories; Length; Leukocytes; Longevity; Magnetic Resonance Imaging; Measurement; Measures; Methylation; Nature; Nerve Degeneration; Pathologic; Pathology; Positron-Emission Tomography; Proteins; Research; Resources; Risk; Risk Factors; Sampling; Senile Plaques; Series; Severities; Single Nucleotide Polymorphism; Source; Spatial Distribution; Structure; Tauopathies; Telomere Shortening; Testing; Tissues; United States National Institutes of Health; Work; age related; aging brain; aging population; biobank; cell age; cohort; genetic association; genetic risk factor; genomic locus; healthy aging; human tissue; improved; in vivo; molecular marker; molecular pathology; novel therapeutic intervention; tau Proteins; tau aggregation; telomere; trait

Aging is among the most well-established risk factors for the accumulation of molecular pathology and neurodegeneration with <1% of older adults lacking molecular pathology. As individuals age there is an increased risk of neurofibrillary tau tangles (NFTs) co-occurring with amyloid-beta plaques (Aβ) consistent with Alzheimer's disease (AD) neuropathological criteria. However, nearly all adults >50 years of age have pathological evidence of NFTs which may occur in a similar spatial distribution to AD but typically less severe in nature and in the absence of Aβ molecular pathology, consistent with a neuropathological diagnosis of primary age-related tauopathy (PART). Therefore, it is currently unclear why most aging individuals develop NFT pathology (i.e., either in PART or AD) and in variable degrees of severity while only a proportion of individuals also develop Aβ pathology (i.e., in AD). To date the vast majority of aging research has defined age-related pathological risk in chronological measurements (i.e., years since birth). However, the rates of actual “biological” aspects of aging appear to differ between individuals, with some individuals displaying features of aging that are accelerated (biological age older than their chronological age) or delayed (biological age younger than their chronological age). The overarching goal of this proposal is to evaluate three sources of biological aging mechanisms underlying risk and severity for NFT and Aβ molecular pathology and associated neurodegeneration. First, DNA methylation (mDNA), or “the epigenetic clock”, can be measured to reliably predict chronological age as well as accelerated or delayed aging. Second, telomeres are repetitive DNA sequences and associated proteins that protect chromosome ends and shorten with cell division and age in most human tissues, including brain. Third, we will evaluate single nucleotide polymorphisms (SNPs) associated with reduced longevity and shortened telomere length to help identify risk factors of poor biological aging to facilitate early interventions and pinpoint candidate genetic mechanisms for novel therapeutic approaches. Together, we propose to use mDNA and shortest telomere length analysis (TeSLA) along with complementary SNP association tests to evaluate the hypothesis that accelerated aging (biological age older than chronological age) will increase the risk of molecular pathology and neurodegeneration. We will assess biological aging in well-characterized PART and AD autopsy-confirmed samples and in vivo structural MRI and PET molecular markers of 18F-floretaucipir (tau) and 18F-florbetaben (Aβ) in aging controls from our NIA-funded Alzheimer's Disease Center (ADC) and collaborating ADCs. By investigating the biological aging mechanisms of NFT and Aβ pathology, this proposal addresses a NIH priority to improve our “Understanding of Alzheimer's Disease in the Context of the Aging Brain”. A significant proportion of the aging population has varying levels of molecular pathology and this research will help establish mechanisms by which heterogeneity in biological brain aging impacts the development and progression of pathological accumulation and neurodegeneration.

衰老是分子病理积累和 <1％的老年人缺乏分子病理学的神经变性。随着个人的年龄，有一个 与淀粉样蛋白斑块（Aβ）共同出现的神经原纤维tau缠结（NFTS）的风险增加 阿尔茨海默氏病（AD）神经病理学标准。但是，几乎所有成年人> 50岁都有 NFT的病理证据可能发生在与AD相似的空间分布中，但通常不那么严重 在自然界和没有Aβ分子病理学的情况下，与神经病理学诊断一致 初级年龄相关的tauopathy（部分）。因此，目前尚不清楚为什么大多数老年人会发展 NFT病理学（即部分或AD），严重程度可变，而仅占一定比例 个体还会发展为Aβ病理学（即在AD中）。迄今为止，绝大多数衰老研究已经定义 年龄与年龄相关的病理风险（即出生以来的年份）。但是，比率 衰老外观与个人之间不同的实际“生物学”方面，有些人显示 加速的衰老特征（比年代年龄大的生物年龄）或延迟（生物学 年龄比年龄年龄更小）。该提案的总体目标是评估三个来源 NFT和Aβ分子病理学的风险和严重程度的生物老化机制以及相关的 神经变性。首先，可以将DNA甲基化（MDNA）或“表观遗传时钟”测量到可靠 预测年代年龄以及加速或延迟衰老。其次，端粒是重复的DNA 保护染色体末端并随着细胞分裂而缩短的序列和相关蛋白质 大多数人体组织，包括大脑。第三，我们将评估单个核苷酸多态性（SNP） 与寿命降低和缩短端粒相关，以帮助识别生物学差的危险因素 衰老以促进早期干预措施，并确定新治疗的候选遗传机制 方法。我们一起建议使用mDNA和最短的端粒长度分析（特斯拉）以及 完全SNP关联测试，以评估加速衰老（生物年龄较大）的假设 比年龄年龄更高的年龄）会增加分子病理学和神经退行性的风险。我们将评估 特征良好的部分和广告尸检确认的样品以及体内结构MRI和 从我们的NIA资助 阿尔茨海默氏病中心（ADC）和合作ADC。通过研究生物老化机制 NFT和Aβ病理学，该提案针对NIH的优先级，以提高我们对阿尔茨海默氏症的理解 在衰老大脑的背景下疾病”。大部分的老龄化人口具有不同的水平 分子病理和这项研究将有助于建立生物学异质性的机制 脑老化会影响病理积累和神经退行性的发展和发展。