"Mitochondrial biogenesis and the decline of hypoxia, oxidative stress and toxin tolerance with age"

“线粒体生物发生以及缺氧、氧化应激和毒素耐受性随着年龄的增长而下降”

• 批准号: 250649-2012
• 负责人: Willmore, William
• 金额: $ 2.04万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=570930
• 关键词: Mitochondrial; biogenesis; decline; hypoxia; oxidative

The Canadian population is aging. Seniors make up the fastest-growing age group and, in 2010, an estimated 4.8 million Canadians were 65 years of age or over (14.1% of the population) and that number is expected to double in the next 25 years to reach 10.4 million (23.5% of the population). Understanding the environmental factors that influence the molecular basis of aging will be crucial for healthy aging of Canadians in the near future. My NSERC Program investigates the biochemical aspects of aging, examining the molecular mechanisms of senescence and how environmental factors can either contribute to or inhibit the aging process in cells. Aging itself is associated with a high incidence of ischemic diseases (cardiac arrest, stroke) and the elderly lose the ability to cope with factors linked to these diseases including a) insufficient oxygen (hypoxia), b) oxidative stress (the production of reactive oxygen species (ROS)) and c) the ability to withstand toxins. A common feature of these stresses is mitochondrial dysfunction. Mitochondrial dysfunction has long been associated with the aging process and the onset of numerous diseases. Mitochondrial function decreases with age as the biogenesis of mitochondria declines over the lifespan of the organism. We propose to investigate the effects of a) hypoxia, b) oxidative stress and c) potentially harmful compounds identified in Canada's Chemical Management Plan on mitochondrial biogenesis and the cellular aging process. Protein factors protecting the cell from these stresses (SIRT1, HIF, NFE2L, PGC-1) will be assessed for their expression, function, changes in post-translational modifications, and effects on mitochondrial biogenesis over time in a cell senescence model. The influences of overexpression, knock down, and ablation of modification of such factors on mitochondrial biogenesis and cellular aging will be assessed. Overall, the proposed research into factors which affect cellular aging will significantly advance our understanding of this basic biological phenomenon and assist in the development and discovery of therapeutic agents that minimize the detrimental effects of aging.

加拿大人口正在老龄化。老年人是增长最快的年龄组，2010年，估计有480万加拿大人年龄在65岁或以上（占人口的14.1%），预计这一数字在未来25年将翻一番，达到1040万（占人口的23.5%）。了解影响衰老的分子基础的环境因素将在不久的将来对加拿大人的健康老龄化至关重要。我的NSERC计划研究衰老的生化方面，研究衰老的分子机制以及环境因素如何促进或抑制细胞的衰老过程。衰老本身与缺血性疾病（心脏骤停、中风）的高发病率相关，并且老年人失去科普与这些疾病相关的因素的能力，这些因素包括a）氧气不足（缺氧），B）氧化应激（活性氧（ROS）的产生）和c）耐受毒素的能力。这些压力的一个共同特征是线粒体功能障碍。线粒体功能障碍长期以来与衰老过程和许多疾病的发生有关。线粒体功能随着年龄的增长而降低，因为线粒体的生物发生在生物体的寿命中下降。我们建议调查的影响a）缺氧，B）氧化应激和c）在加拿大的化学品管理计划对线粒体生物合成和细胞衰老过程中确定的潜在有害化合物。将评估保护细胞免受这些应激的蛋白质因子（SIRT 1、HIF、NFE 2L、PGC-1）的表达、功能、翻译后修饰的变化以及在细胞衰老模型中随时间对线粒体生物合成的影响。将评估这些因子的过表达、敲低和修饰的消除对线粒体生物发生和细胞衰老的影响。总的来说，对影响细胞衰老的因素的拟议研究将大大促进我们对这一基本生物学现象的理解，并有助于开发和发现最大限度地减少衰老有害影响的治疗药物。