CAREER: Effects of mitohormesis on reproduction and longevity

生物学的一个核心原则是，分配给繁殖和分配给延长寿命的过程是相互权衡的。生殖需要能量，能量的产生诱导线粒体内有害活性氧（ROS）的释放。活性氧是细胞呼吸的正常副产物，它会损害细胞，从而缩短寿命。然而，现在有几项研究表明，与不繁殖的动物相比，繁殖的动物体内ROS的损害通常不会改变，甚至会减少。此外，新的理论表明，在生殖过程中，低水平的ROS暴露不仅可以降低ROS的损伤，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繁殖过程中产生的ROS是否可以防止未来的ROS损伤，确定ROS损伤和线粒体性能如何随着繁殖经历和年龄而变化，并表征繁殖经历与寿命之间的关系。对线粒体功能、生殖和寿命之间相互作用的研究将被用作阿拉巴马州教育和提高科学素养的平台。与当地生物教师合作，将为七年级和九年级学生制定带有实验室的课程计划。这些课程将以线粒体和衰老的拟议研究为特色，并将提交给阿拉巴马州教育委员会，在阿拉巴马州的每个七年级和九年级的生物课堂上采用。此外，奥本的研究生将面临挑战，承诺定期参加研究生水平的研讨会“线粒体和能量学”。学生们将为奥本大学的“Get Under the Surface”项目准备并介绍一节课，该项目邀请五年级学生和他们的家长到校园参与一个互动实验室。这个CAREER项目的目标是：1)测试生殖是否可以防止未来的氧化损伤；2)确定连续繁殖的家鼠（小家鼠）的线粒体功能和细胞对诱导氧化应激源的反应是否会随着年龄的变化而变化。考虑到生殖对诱导衰老的过程具有潜在的保护作用，该项目的第三个目标是通过比较生育次数较少的雌性和生育次数较多的雌性的死亡年龄，来评估生殖与雌性小鼠寿命之间的相互作用。这项研究将采用几种尖端技术，包括测量线粒体产生的活性氧和在衰老过程中通常下降的器官的氧化损伤。此外，还将评估呼吸控制率、电子链复合物活性、线粒体生物发生、解偶联蛋白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影响的指标进行评估。这项研究将详细评估生殖在活性氧积累和对加速衰老的应激源的抵抗中所起的作用。与许多寻找繁殖和长寿之间权衡的机制基础的研究不同，这项研究将询问这种权衡是否真的存在。无论这项研究是否支持或反驳生殖过程中产生的活性氧导致衰老的观点，该项目都将改变生命史进化的研究，其结果将更好地理解衰老与生殖之间的机制关系。

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.