Reactive electrophiles in human aging and longevity

项目总结 尽管进行了深入的调查，但决定人类长寿和健康衰老的因素仍然存在 在很大程度上是一个谜。目前的衰老理论表明，两种相互竞争的影响之间的平衡- 改变细胞功能的破坏性因素和防御有害因素的保护机制 -是生物老化的关键决定因素。这些关键破坏因素的性质和 然而，相应的保护机制仍不清楚。最近的研究发现了反应性 亲电体以及负责解毒的酶对生物老化至关重要。反应性 亲电体代表与内源细胞高度反应的小分子代谢物。 亲核试剂，包括蛋白质、DNA和脂类等大分子靶标，从而共价和 不可逆转地改变靶功能、信号转导和细胞完整性。反应性亲电体可能是 来自外源暴露，如饮食来源、微生物区系、环境毒素和 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 是由活性氧引发的。在蠕虫、苍蝇和低等哺乳动物身上积累的证据表明 相关的反应性亲电体增加，寿命有限，并增强了电泳剂的解毒作用 具有超长寿命的机械装置。到目前为止，对特定反应性亲电剂的测量一直是有限的。 目前尚不清楚特定的反应性亲电体是否影响生物衰老和与年龄相关的 人类的疾病。我们实验室最近开发了一种新型的高通量质谱学 从人血浆中选择性提取和测定活性亲电体的方法。我们有 在人类群体中应用了这些方法，并在 在全基因组统计阈值上与进展性年龄高度相关的血浆。在……里面 本次GEMSSTAR申请，申请人旨在全面探索反应性亲电体的作用 在人类衰老过程中。具体地说，拟议的研究将确定异常长寿的家庭是否 不受活性亲电体的保护，并显示出可与年轻个体相媲美的电泳性图案 生物学年龄以及循环中的反应性亲电体是否可作为长寿和健康的预测因子 衰老。申请人是一名早期内科医生兼科学家，有致力于科学研究的记录。 和发现力。此GEMSSTAR应用程序利用申请者的跨学科科学技能 强大的机构支持、指导和全面的专业发展计划 对衰老机制的前所未有的洞察，同时推出申请人的长期独立 从事翻译性老龄化研究。

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.