[论文解读] Aging as a process of accumulation of Misrepairs

Jicun Wang-Michelitsch, Thomas M. Michelitsch|arXiv (Cornell University)|Mar 24, 2015

Genetics, Aging, and Longevity in Model Organisms参考文献 15被引用 7

一句话总结

本文提出了衰老的错误修复累积理论，认为衰老源于分子、细胞和组织层面错误修复（错误修复）的不可逆累积。与损伤累积不同，错误修复是生物体主动发起的修复过程，会扭曲结构完整性，导致组织、细胞和细胞外基质的逐步紊乱，最终表现为衰老。

ABSTRACT

We recently introduced Misrepair-accumulation theory as an interpretation on aging mechanism. For better understanding this theory, we discuss here in more details the new concept of Misrepair and the concept of accumulation of Misrepairs. I. Aging takes place uniquely on the systems that have a well-defined structure: an organization of its sub-structures. Aging of a non-living system is a result of accumulation of injuries (damage) of its structure. II. A generalized concept of Misrepair is important for reaching to a unified understanding of aging changes. In the situation of a severe injury, incorrect repair is a repair essential for maintaining structural integrity for increasing the surviving chance of an organism. With the same mechanism as that in "Misrepair of DNA" , the term of "Misrepair" can be used for describing all kinds of incorrect repairs on different types of living structures, including molecules, cells and tissues. A new concept of Misrepair is therefore proposed and defined as incorrect reconstruction of an injured living structure. Misrepair mechanism is beneficial for the survival of an organism, and it is essential for the survival of a species. III. Alteration of structure made by Misrepair is irreversible; therefore Misrepairs accumulate and disorganize gradually a structure, which appears as aging of it. Accumulation of Misrepairs takes place on molecular, cellular and tissue levels respectively: on tissue level, it appears as disorganization of cells and extracellular matrixes (ECMs); on cellular level, it appears as deformation of cytoskeleton and change of cell shape; and on DNA, it appears as accumulation of DNA mutations and alteration of DNA sequence. An essential change in aging of an organism is an irreversible change of the spatial relationship between cells/ECMs in a tissue. In conclusion, aging of an organism is a result of accumulation of Misrepairs on tissue level.

研究动机与目标

• 通过错误修复的视角而非单纯的损伤累积，建立一个统一的衰老理解框架。
• 定义并形式化‘错误修复’的概念，即在多个组织层次上对受损生物结构的错误重建。
• 解释为何错误修复虽最初有益于生存，但随时间不可逆地累积，最终导致衰老表型。
• 阐明衰老本质上是由累积错误修复引起的结构紊乱，而非单纯的机能衰退。
• 将组织水平的紊乱——尤其是细胞和细胞外基质的紊乱——定位为衰老的核心标志。

提出的方法

• 提出错误修复的广义定义：对受损生命结构的错误重建，适用于分子、细胞和组织层次。
• 将DNA错误修复与其它生物系统中的错误修复进行类比，将该概念扩展至遗传物质以外的领域。
• 分析衰老作为由错误修复的不可逆性驱动的过程，这些错误修复无法逆转，因此随时间累积。
• 从三个层次分析结构变化：分子层面（DNA突变）、细胞层面（细胞骨架变形、细胞形态改变）和组织层面（细胞与细胞外基质的组织紊乱）。
• 强调衰老的关键变化是细胞与细胞外基质之间空间关系的不可逆改变。
• 运用系统层面的推理，论证衰老是源于错误修复累积的结构紊乱的后果，而非随机损伤。

实验结果

研究问题

• RQ1 在衰老背景下，错误修复与单纯损伤累积有何区别？
• RQ2 如何将错误修复的概念泛化至从DNA到组织的各类生物结构？
• RQ3 为何错误修复会导致不可逆的结构紊乱，这种紊乱如何促成衰老？
• RQ4 结构完整性和空间组织在组织水平定义衰老中扮演何种角色？
• RQ5 错误修复累积机制如何解释衰老的渐进性和不可逆性？

主要发现

• 错误修复被定义为对受损生物结构的错误重建，其与单纯损伤不同，且具有生物起源。
• 错误修复机制在短期内有益于生存，但随时间不可逆地累积后转为有害。
• 错误修复的累积导致组织结构的逐步紊乱，尤其通过破坏细胞与细胞外基质之间的空间关系。
• 在细胞层面，错误修复表现为细胞骨架变形和细胞形态改变，导致功能衰退。
• 在分子层面，错误修复包括DNA突变和序列改变，这些因修复过程出错而累积。
• 衰老本质上是组织水平上不可逆的结构紊乱，其主要致病机制为错误修复的累积。