[论文解读] Development of aging changes: self-accelerating and inhomogeneous

Jicun Wang-Michelitsch, Thomas M. Michelitsch|arXiv (Cornell University)|Mar 26, 2015

Genetics, Aging, and Longevity in Model Organisms参考文献 3被引用 5

一句话总结

本文提出，老年斑和动脉粥样硬化斑块等衰老变化通过一种由错误修复累积驱动的自加速、非均匀过程发展。根据错误修复累积理论，每次错误修复都会增加邻近亚结构的损伤敏感性并降低其修复效率，从而形成反馈回路，使病变集中化并加速生长，解释了为何老年斑生长更快且在空间上聚集。

ABSTRACT

Aging changes including age spots and atherosclerotic plaques develop in an inhomogeneous and accelerated manner. For understanding this phenomenon, some aging changes are analyzed by Misrepair mechanism, a mechanism proposed in Misrepair-accumulation theory. I. Misrepair is a strategy of repair for survival of an organism in situations of severe injuries; however a Misrepair alters the structure of a tissue, a cell or a molecule, which are the sub-structures of an organism. II. Misrepair of a sub-structure also alters the spatial relationship of this sub-structure with its neighbor sub-structures. Thus a Misrepair leads to increased damage-sensitivity and reduced repair-efficiency of these sub-structures. As a result, Misrepairs have a tendency to occur to the sub-structure and its neighbor sub-structures where an old Misrepair has taken place. In return, new Misrepairs will increase again the damage-sensitivity of these sub-structures and the surrounding sub-structures. By such a vicious circle, the frequency of Misrepairs to these sub-structures is increased and the range of affected sub-structures is enlarged after each time of Misrepair. Thus, accumulation of Misrepairs is focalized and self-accelerating. III. Focalized accumulation of Misrepairs leads to formation and growing of a "spot" or "plaque" in a tissue. Growing of a spot is self-accelerating, and old spots grow faster than new ones. New spots tend to develop close to old ones, resulting in an inhomogeneous distribution of spots. In conclusion, the inhomogeneous development of aging changes is a result of self-accelerated and focalized accumulation of Misrepairs; and the process of aging is self-accelerating.

研究动机与目标

• 解释老年斑和动脉粥样硬化斑块等衰老变化的非均匀性和自加速发展机制。
• 研究生物亚结构（分子、细胞、组织水平）的错误修复如何导致邻近结构损伤敏感性增加。
• 建立反馈机制模型，说明先前的错误修复如何放大未来错误修复的频率和空间扩散。
• 证明该机制如何导致病灶集中、加速的病变生长以及衰老病理的非均匀分布。
• 支持错误修复累积理论作为理解衰老病理非线性进展的统一框架。

提出的方法

• 通过错误修复累积理论的视角分析衰老变化，重点关注修复错误的结构和空间后果。
• 将错误修复建模为改变生物亚结构的结构完整性和空间关系的过程。
• 引入一种反馈机制，即每次错误修复都会增加邻近亚结构的损伤敏感性并降低其修复效率。
• 利用该反馈回路模拟组织水平亚结构中错误修复累积的自加速特性。
• 证明该过程导致病灶集中形成，并随时间推移呈现增长速率加快的特征。
• 将该模型应用于解释组织中老年斑和斑块的聚集现象及加速生长。

实验结果

研究问题

• RQ1 错误修复的累积如何导致自加速的衰老变化？
• RQ2 为何老年斑和斑块等衰老病变以非均匀、非均匀分布的方式发展？
• RQ3 亚结构之间的空间关系在错误修复后如何放大损伤敏感性？
• RQ4 先前的错误修复如何增加邻近亚结构未来发生错误修复的可能性？
• RQ5 哪些机制可以解释老年病变比新形成的病变生长更快的观察结果？

主要发现

• 亚结构的错误修复会增加其损伤敏感性并降低修复效率，从而形成反馈回路，放大未来错误修复事件。
• 位于错误修复部位附近的邻近亚结构也因空间关系改变而经历损伤敏感性增加和修复效率降低。
• 错误修复的累积效应导致病变的自加速和集中性累积，解释了为何老年斑比新病变生长更快。
• 由于现有错误修复部位周围损伤敏感性空间传播，病变倾向于成簇形成和生长。
• 该过程导致衰老病理的非均匀分布，与临床观察到的老年斑和动脉粥样硬化斑块一致。
• 错误修复累积的自加速特性为衰老相关组织退化的非线性进展提供了机制性解释。