CAREER: Effects of mitohormesis on reproduction and longevity

职业：线粒体兴奋作用对生殖和寿命的影响

• 批准号: 1453784
• 负责人: Wendy Hood
• 金额: $ 103.25万
• 依托单位: Auburn University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1453784&HistoricalAwards=false
• 关键词: CAREER; Effects; mitohormesis; reproduction; longevity

A central tenet of biology is that allocation to reproduction trades off against allocation to processes that enhance longevity. Reproduction takes energy and energy production induces the release of damaging reactive oxygen species (ROS) within the mitochondria. ROS are normal byproducts of cellular respiration that can damage cells and as a result, reduce longevity. Yet, several studies have now shown that damage from ROS is typically unchanged or even reduced in animals that reproduce compared to those that don't. In addition, new theory suggests that low levels of exposure to ROS, as occurs during reproduction, not only lowers damage from ROS but may also protect cells from the cellular damage that contributes to aging. The goals of this project are to test if the ROS generated during reproduction protects against future ROS damage, determine how ROS damage and the performance of mitochondria change with reproductive experience and age, and characterize the relationship between reproductive experience and longevity in the house mouse. Research on the interaction between mitochondrial function, reproduction, and longevity will be used as a platform for education and the improvement of science literacy in the state of Alabama. In collaboration of with local biology teachers, lesson plans with labs will be developed for 7th and 9th graders. These lessons will feature the proposed research on mitochondria and aging and will be submitted to the Alabama State Board of Education for adoption in every 7th and 9th grade biology classroom in Alabama. In addition, Auburn graduate students will be challenged to commit to regular participation in outreach in a graduate-level seminar "mitochondria and energetics". Students will prepare and present a lesson for Auburn University's Get Under the Surface program that invites 5th grade students and their parents to campus to participate in an interactive laboratory. The goals of this CAREER project are to 1) test whether reproduction protects against future oxidative damage and 2) to determine if mitochondrial function and the cellular response to an induced oxidative stressor change with age in a continuously breeding species, the house mouse (Mus musculus). Given the potentially protective effects that reproduction has on processes that induce aging, a third goal of this project is 3) to evaluate the interaction between reproduction and longevity in female mice by comparing age at death in females that have bred few times verses those that have bred many times. Several cutting-edge techniques will be employed in this investigation including measurements of ROS production from mitochondria and oxidative damage in organs that commonly decline during senescence. In addition, respiratory control ratio, electron chain complex activity, mitochondrial biogenesis, abundance of uncoupling proteins and levels of endogenous antioxidants will be evaluated. The impact of treatment on insulin-like growth factor-1 and telomere length will also be evaluated as indicators of the impact of treatment on aging. This investigation will provide a detailed assessment of the role that reproduction plays in the accumulation of ROS and in resistance to stressors that hasten aging. Unlike many studies that have searched for a mechanistic basis for the tradeoff between reproduction and longevity, this study will ask whether such a tradeoff really exists. Whether this study supports or refutes the idea that ROS produced during reproduction contributes to age, the project will transform the study of life-history evolution, and the outcome will be a better understanding of the mechanistic relationship between aging and reproduction.

生物学的一个核心宗旨是，分配复制的分配与分配给提高寿命的过程的分配。繁殖吸收能量和能源产生可诱导线粒体内有害活性氧（ROS）的释放。 ROS是细胞呼吸的正常副产品，可能会损害细胞，从而降低寿命。然而，一些研究表明，与没有的动物相比，繁殖的动物中，ROS的损害通常不变，甚至减少。 此外，新理论表明，在繁殖过程中发生的低水平的ROS暴露水平不仅降低了ROS的损害，而且还可以保护细胞免受导致衰老的细胞损伤。该项目的目标是测试生殖过程中产生的ROS是否可以防止未来的ROS损害，确定ROS损伤和通过生殖体验和年龄变化的损害和性能如何变化，并表征House Mouse中生殖体验与寿命之间的关系。 关于线粒体功能，繁殖和寿命之间相互作用的研究将被用作教育平台，并改善阿拉巴马州的科学素养。与当地生物学教师合作，将为7年级和9年级的实验室制定课程计划。这些课程将以有关线粒体和衰老的拟议研究为特色，并将在阿拉巴马州的每7年级和9年级生物学课堂中提交阿拉巴马州教育委员会进行收养。此外，奥本研究生将受到挑战，要求他们定期参加研究生级研讨会“线粒体和能量学”。学生将为奥本大学的《表面课程》准备并介绍一堂课，该课程邀请5年级的学生及其父母到校园参加互动实验室。该职业项目的目标是1）测试生殖是否可以防止未来的氧化损害，以及2）确定线粒体功能以及对诱导的氧化应激源的细胞反应是否随着持续繁殖物种的年龄而变化，House Muse（Mus Musculus）。鉴于繁殖对诱导衰老的过程产生的潜在保护作用，该项目的第三个目标是3），通过比较雌性在繁殖几次繁殖的雌性中的死亡年龄来评估雌性小鼠的繁殖与寿命之间的相互作用。这项研究将采用几种尖端技术，包括测量线粒体的ROS产生以及在衰老过程中通常下降的器官中的氧化损伤。此外，将评估呼吸控制比，电子链复合活性，线粒体生物发生，未偶联蛋白的丰度和内源性抗氧化剂水平。治疗对胰岛素样生长因子1和端粒长度的影响也将作为治疗对衰老的影响的指标。这项调查将详细评估繁殖在ROS积累和抵抗加速衰老的压力源方面发挥的作用。与许多研究在繁殖和寿命之间进行权衡的机械基础的研究不同，这项研究将询问这种权衡是否真的存在。这项研究是否支持或反驳繁殖过程中ROS产生的想法有助于年龄，该项目将改变对生活历史的进化研究，结果将更好地理解衰老与繁殖之间的机械关系。

项目成果

A mitohormetic response to pro-oxidant exposure in the house mouse

家鼠对促氧化剂暴露的线粒体激素反应

• DOI: 10.1152/ajpregu.00176.2017
• 发表时间: 2018
• 期刊: Integrative and Comparative Physiology
• 作者: Zhang, Yufeng;Humes, Frances;Almond, Gregory;Kavazis, Andreas N.;Hood, Wendy R.
• 通讯作者: Hood, Wendy R.

High activity before breeding improves reproductive performance by enhancing mitochondrial function and biogenesis

繁殖前的高活性通过增强线粒体功能和生物发生来提高繁殖性能

• DOI: 10.1242/jeb.177469
• 发表时间: 2018
• 期刊: The Journal of Experimental Biology
• 作者: Zhang, Yufeng;Brasher, Adam L.;Park, Noel R.;Taylor, Halie A.;Kavazis, Andreas N.;Hood, Wendy R.
• 通讯作者: Hood, Wendy R.

Changes in Metabolism, Mitochondrial Function, and Oxidative Stress Between Female Rats Under Nonreproductive and 3 Reproductive Conditions

• DOI: 10.1177/1933719118766264
• 发表时间: 2019-01-01
• 期刊: REPRODUCTIVE SCIENCES
• 影响因子: 2.9
• 作者: Hyatt, Hayden W.;Zhang, Yufeng;Kavazis, Andreas N.
• 通讯作者: Kavazis, Andreas N.

Current versus future reproduction and longevity: a re-evaluation of predictions and mechanisms

当前与未来的繁殖和寿命：对预测和机制的重新评估

• DOI: 10.1242/jeb.132183
• 发表时间: 2016
• 期刊: Journal of Experimental Biology
• 影响因子: 2.8
• 作者: Zhang, Yufeng;Hood, Wendy R.
• 通讯作者: Hood, Wendy R.

Life History Trade-offs within the Context of Mitochondrial Hormesis

• DOI: 10.1093/icb/icy073
• 发表时间: 2018-09-01
• 期刊: INTEGRATIVE AND COMPARATIVE BIOLOGY
• 影响因子: 2.6
• 作者: Hood, W. R.;Zhang, Y.;Kavazis, A. N.
• 通讯作者: Kavazis, A. N.