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: 10649484
• 负责人: Corey T McMillan
• 金额: $ 73.88万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649484
• 关键词: Acceleration; Address; Adult; Age; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Apoptosis; Autopsy; Biological; Biological Aging; Biological Markers; Birth; Blood; Brain; Cell Aging; Cell Cycle Arrest; Cell division; Chromosomes; Chronology; Cognitive aging; Collaborations; 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; 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 old age (65+); human tissue; improved; in vivo; molecular marker; molecular pathology; neuropathology; 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最明确的危险因素之一， 随着个体年龄的增长，<1% 的老年人缺乏分子病理学的神经退行性疾病。 神经原纤维 tau 缠结 (NFT) 与淀粉样蛋白斑块 (Aβ) 共存的风险增加，与以下一致 然而，几乎所有 50 岁以上的成年人都患有阿尔茨海默病 (AD)。 NFT 的病理证据，其空间分布可能与 AD 类似，但通常不那么严重 在自然界中并且在不存在 Aβ 分子病理学的情况下，与神经病理学诊断一致 因此，目前尚不清楚为什么大多数衰老个体会发生原发性年龄相关性 tau 蛋白病 (PART)。 NFT 病理学（即 PART 或 AD）且严重程度各异，而只有一部分 个体也会出现 Aβ 病理（即 AD），迄今为止，绝大多数衰老研究已经明确了这一点。 时间测量中与年龄相关的病理风险（即出生后的年数）。 衰老的实际“生物学”方面似乎因人而异，有些人表现出 加速衰老（生物年龄大于实际年龄）或延迟衰老（生物年龄）的特征 该提案的总体目标是评估三个来源。 NFT 和 Aβ 分子病理学及相关风险和严重程度的生物衰老机制 首先，可以可靠地测量 DNA 甲基化（mDNA）或“表观遗传时钟”。 预测实际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和年龄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，以帮助识别不良生物学的危险因素 衰老以促进早期干预并查明新疗法的候选遗传机制 我们建议结合使用 mDNA 和最短端粒长度分析 (TeSLA)。 补充性 SNP 关联测试可评估加速衰老（生物年龄较老）的假设 比实际年龄）会增加分子病理学和神经退行性变的风险。 在经过充分表征的 PART 和 AD 尸检确认样本以及体内结构 MRI 和 18F-floretaucipir (tau) 和 18F-florbetaben (Aβ) 在衰老控制中的 PET 分子标记，来自我们 NIA 资助的项目 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 病理学的研究，该提案解决了 NIH 的优先事项，以提高我们“对阿尔茨海默病的理解” 大脑老化背景下的疾病》。 分子病理学和这项研究将有助于建立生物异质性的机制 大脑衰老影响病理积累和神经退行性变的发生和进展。