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.

衰老是分子病理积累的最确定的危险因素之一