Biological Aging Contributions to Molecular Pathology and Neurodegeneration

衰老是分子病理学和骨质疏松症积累的最公认的危险因素之一。 1%的老年人缺乏分子病理的神经退行性变。随着个人年龄的增长，有一种 神经原纤维tau缠结(NFT)与淀粉样β蛋白斑块(Aβ)共存的风险增加 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 NFTs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 在性质上和在没有β分子病理的情况下，与神经病理诊断一致的 原发性年龄相关性脊椎病(部分)。因此，目前还不清楚为什么大多数老年人会患上 NFT病理(即部分或AD)和不同程度的严重程度，而只有部分 个体也会发生Aβ病理(即，在AD中)。到目前为止，绝大多数的衰老研究都定义了 按时间顺序(即出生年限)计算的与年龄相关的病理风险。然而，这一比率 衰老的实际“生物学”方面似乎因个体而异，有些个体表现出 加速(生物年龄大于实际年龄)或延迟(生物年龄)的衰老特征 年龄小于他们的实际年龄)。该提案的首要目标是评估以下三个来源 非神经功能衰竭和β分子病理的风险和严重程度潜在的生物衰老机制及其相关 神经退行性变。首先，DNA甲基化(MDNA)，或“表观遗传时钟”，可以可靠地测量到 按时间顺序预测年龄以及加速或延缓衰老。第二，端粒是重复的DNA 保护染色体末端的序列和相关蛋白质随着细胞分裂和年龄的增加而缩短 大多数人体组织，包括大脑。第三，我们将评估单核苷酸多态(SNPs) 与寿命缩短和端粒长度缩短有关，有助于识别不良生物学因素的风险因素 衰老促进早期干预并精确确定新疗法的候选遗传机制 接近了。总之，我们建议将mDNA和最短端粒长度分析(TESLA)与 互补性SNP关联测试，以评估加速衰老(生物学年龄较大)的假设 会增加分子病理和神经退行性变的风险。我们将评估 特征性良好的部位和AD尸检证实的生物老化-样品和活体结构MRI和 18F-Flotaucipir(Tau)和18F-florbetaben(Aβ)的PET分子标记在衰老控制中的作用 阿尔茨海默病中心(ADC)和合作的ADC。通过研究生物衰老的机制 NFT和Aβ病理学，这项建议解决了国立卫生研究院的优先事项，以提高我们对阿尔茨海默氏症的理解 大脑老化背景下的疾病“。相当大比例的老龄化人口有不同程度的 分子病理学和这项研究将有助于建立生物异质性 脑老化影响病理性堆积和神经退行性变的发展和进展。

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.