Reactive electrophiles in human aging and longevity

项目摘要 尽管进行了深入的研究，决定人类寿命和健康老龄化的因素仍然存在 很大程度上是个谜当前的衰老理论表明两种相互竞争的影响之间的平衡- 改变细胞功能的损伤因子和防御有害因子的保护机制 - 是生物衰老的关键决定因素这些关键破坏因素的性质和 然而，相应的保护机制仍然未知。最近的研究发现， 亲电体以及负责其解毒的酶对生物衰老至关重要。反应性 亲电体代表与内源性细胞代谢物高度反应的小分子代谢物， 亲核试剂，包括大分子靶标，如蛋白质、DNA和脂质，从而共价和 不可逆地改变靶功能、信号转导和细胞完整性。反应性亲电试剂可以是 来源于外源性暴露，如饮食来源、微生物群、环境毒素， 药物，或来自内源性细胞代谢过程，包括脂质过氧化和其他反应 由活性氧引发在蠕虫、苍蝇和低等哺乳动物中积累的证据 与增加的反应性亲电体相关，寿命有限，亲电体解毒增强 具有超长寿命的机械装置。迄今为止，特定反应性亲电试剂的测量是有限的 目前还不清楚特定的反应性亲电体是否会影响生物衰老和年龄相关的衰老。 人类的疾病。我们的实验室最近开发了新的高通量质谱， 用于从人血浆中选择性提取和测量反应性亲电体的方法。我们有 将这些方法应用于人类群体，并发现了不同的反应性亲电化合物， 在全基因组统计阈值处与进行性年龄高度相关的血浆。在 在GEMSSTAR申请中，申请人旨在全面探索反应性亲电试剂的作用 在人类衰老过程中。具体来说，拟议中的研究将确定长寿家庭是否 保护免受反应性亲电体的影响，并表现出与年轻人相当的亲电模式。 生物学年龄以及循环反应性亲电体是否可作为长寿和健康的预测因子 衰老申请人是一名早期的物理学家和科学家，有献身于科学事业的记录 和发现该GEMSSTAR应用程序利用了申请人的跨学科科学技能， 强有力的机构支持，指导和全面的专业发展计划，以摆脱 对衰老机制的前所未有的洞察力，同时启动申请人的长期独立 从事转化老化研究。

PROJECT SUMMARY Despite intensive investigation, the factors dictating human longevity and healthy aging continue to remain largely a mystery. The current theory of aging suggests that the balance between two competing influences – damaging factors that alter cellular function and protective mechanisms that defend against deleterious factors – is the key determinant of biological aging. The nature of these critical damaging factors and the corresponding protective mechanisms, however, still remain unknown. Recent work has identified reactive electrophiles as well as the enzymes responsible for their detoxification as critical to biological aging. Reactive electrophiles represent small molecule metabolites that are highly reactive with endogenous cellular nucleophiles, including macromolecular targets such as proteins, DNA and lipids, thereby covalently and irreversibly altering target function, signal transduction and cellular integrity. Reactive electrophiles may be derived from either exogenous exposures, such as dietary sources, microbiota, environmental toxins, and drugs, or from endogenous cellular metabolic processes, including lipid peroxidation and other reactions triggered by reactive oxygen species. Accumulating evidence in worms, flies, and lower mammals have associated increased reactive electrophiles with limited lifespan and enhanced electrophile detoxification mechanisms with exceptional longevity. To date, measures of specific reactive electrophiles have been limited and it remains unknown whether specific reactive electrophiles influence biological aging and age-associated diseases in humans. Our laboratory has recently developed novel high throughput mass spectrometry based approaches for selective extraction and measure of reactive electrophiles from human plasma. We have applied these approaches in human populations and have found distinct reactive electrophile compounds in plasma that are highly associated at genome-wide statistical thresholds with progressive chronologic age. In this GEMSSTAR application, the Applicant aims to comprehensively explore the role of reactive electrophiles in human aging. Specifically, proposed studies will determine whether families with exceptional longevity are protected from reactive electrophiles and exhibit electrophile patterns comparable to individuals of a younger biological age as well as whether circulating reactive electrophiles serve as predictors of longevity and healthy aging. The Applicant is an early stage physician-scientist with a track record of dedication to scientific pursuits and discovery. This GEMSSTAR application leverages the Applicant's trans-disciplinary scientific skills with strong institutional support, mentorship, and a comprehensive Professional Development Plan to shed unprecedented insight into the mechanisms of aging while launching the Applicant's long-term independent career in translational aging research.