Reactive electrophiles in human aging and longevity

反应性亲电子试剂在人类衰老和长寿中的作用

• 批准号: 9162248
• 负责人: Mohit Jain
• 金额: $ 11.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9162248
• 关键词: Age; Age-Years; Aging; Aldehydes; Analytical Chemistry; Biological; Biological Aging; Biological Assay; Biology of Aging; Blood; Caenorhabditis elegans; Cardiovascular Diseases; Cell physiology; Cellular Metabolic Process; Cessation of life; Chemistry; Chronic; Communication; Coupled; DNA; Data; Dedications; Development; Development Plans; Diet; Disease; Drug Metabolic Detoxication; Electrons; Enzymes; Equilibrium; Exhibits; Family; Family Study; Family member; Framingham Heart Study; Funding; General Population; Goals; Human; Individual; Investigation; Ketones; Laboratories; Life; Link; Lipid Peroxidation; Lipids; Longevity; Lower Organism; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Measures; Mediating; Mentorship; Modeling; Nature; Nerve Degeneration; Oxidation-Reduction; Oxygen; Participant; Pattern; Persons; Pharmaceutical Preparations; Phylogenetic Analysis; Physicians; Plasma; Population; Proteins; Reaction; Reactive Oxygen Species; Research; Research Personnel; Risk Factors; Role; Sampling; Science; Scientist; Signal Transduction; Source; Staging; Stress; Toxic Environmental Substances; Training; Work; age related; base; career; clinical epidemiology; cohort; fly; genome-wide; healthy aging; human disease; insight; interest; microbiota; novel; proband; skills; small molecule; theories; tool development

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.

项目概要 尽管进行了深入的研究，决定人类长寿和健康老龄化的因素仍然存在 目前的衰老理论在很大程度上是一个谜，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因素和防御有害因素的保护机制 – 是生物衰老的关键决定因素。 然而，相应的保护机制仍然未知。最近的工作已经确定了反应性。 亲电体以及负责其解毒的酶对生物衰老至关重要。 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，包括大分子靶标，例如蛋白质、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。 来自外源性暴露，例如饮食来源、微生物群、环境毒素和 代谢药物，或来自内源性细胞代谢过程，包括脂质过氧化和其他反应 越来越多的证据表明，蠕虫、苍蝇和低等哺乳动物中的活性氧会引发这种现象。 反应性亲电子试剂增加与有限的寿命和增强的亲电子试剂解毒作用相关 迄今为止，特定反应性亲电子试剂的测量受到限制。 目前尚不清楚特定的反应性亲电子试剂是否会影响生物衰老和与年龄相关的 我们的实验室最近开发了基于高通量质谱的新型方法。 我们拥有从人血浆中选择性提取和测量反应性亲电子试剂的方法。 将这些方法应用于人群，并在其中发现了独特的反应性亲电化合物 血浆在全基因组统计阈值上与渐进的实际年龄高度相关。 本次GEMSSTAR申请，申请人旨在全面探讨反应性亲电子试剂的作用 具体来说，拟议的研究将确定是否具有超长寿命的家庭。 免受反应性亲电子试剂的影响，并表现出与年轻个体相当的亲电子模式 生物年龄以及循环反应性亲电子试剂是否可以作为长寿和健康的预测因素 申请人是一位早期医学科学家，有着致力于科学追求的记录。 该 GEMSSTAR 应用程序利用了申请人的跨学科科学技能。 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，同时启动申请人的长期独立性 从事转化衰老研究的职业生涯。