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: 10200670
• 负责人: Corey T McMillan
• 金额: $ 74.99万
• 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/10200670
• 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.

衰老是分子病理学积累的最确定的风险因素之一， <1%的老年人缺乏分子病理学。随着年龄的增长， 与β淀粉样蛋白斑块（Aβ）同时发生的神经元tau蛋白缠结（NFT）风险增加， 阿尔茨海默病（AD）神经病理学标准。然而，几乎所有>50岁的成年人都有 可能以与AD相似的空间分布发生但通常不太严重的NFT的病理学证据 在本质上和在没有Aβ分子病理学的情况下，与神经病理学诊断一致， 原发性年龄相关性tau蛋白病（PART）。因此，目前尚不清楚为什么大多数老年人发展 NFT病理学（即，无论是在部分或AD）和不同程度的严重性，而只有一部分 个体也发展为Aβ病理（即，在AD中）。迄今为止，绝大多数衰老研究已经定义了 按时间顺序测量的年龄相关的病理风险（即，自出生以来）。然而， 衰老的实际“生物学”方面似乎因人而异，有些人表现出 加速老化（生物学年龄大于实际年龄）或延迟老化（生物学 年龄小于实际年龄）。本提案的总体目标是评估三个来源， NFT和Aβ分子病理学的潜在风险和严重程度的生物学衰老机制以及相关的 神经变性首先，DNA甲基化（mDNA），或“表观遗传时钟”，可以可靠地测量， 预测实际年龄以及加速或延迟老化。其次，端粒是重复的DNA 保护染色体末端并随着细胞分裂和衰老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，我们将评估单核苷酸多态性（SNP） 与寿命缩短和端粒长度缩短相关，以帮助确定不良生物学行为的风险因素。 衰老，以促进早期干预，并查明候选的遗传机制，为新的治疗 接近。总之，我们建议使用mDNA和最短端粒长度分析（TeSLA）连同沿着， 补充SNP关联测试以评估加速老化（生物学年龄更大）的假设 比实足年龄）将增加分子病理学和神经变性的风险。我们将评估 在充分表征的PART和AD尸检确认样本和体内结构MRI中的生物老化， 18F-floretaucipir（tau）和18F-florbetaben（Aβ）的PET分子标记物在我们的NIA资助的衰老对照中的应用 阿尔茨海默病中心（ADC）和合作ADC。通过研究生物衰老机制 NFT和Aβ病理学，该提案提出了NIH的优先事项，以提高我们对阿尔茨海默氏症的理解 《脑老化背景下的疾病》。很大一部分老龄化人口有不同程度的 分子病理学，这项研究将有助于建立机制，通过这种机制，生物学中的异质性， 脑老化影响病理积累和神经变性的发展和进展。