[论文解读] Tissue fibrosis: a principal proof for the central role of Misrepair in aging

Jicun Wang-Michelitsch, Thomas M. Michelitsch|arXiv (Cornell University)|May 6, 2015

Spaceflight effects on biology参考文献 6被引用 4

一句话总结

本文主张，组织纤维化是衰老过程中'错误修复'起核心作用的首要生物学证据，提出由于固有缺陷的胶原蛋白修复机制不断累积——这些修复本意是修复组织损伤，但本质上存在缺陷——最终导致纤维化、器官硬化和功能衰退。作者证明，纤维化体现了错误修复的不可避免性与自我加速特性，为错误修复累积衰老理论提供了有力证据。

ABSTRACT

Tissue fibrosis is the phenomenon that a tissue has progressive deposition of collagen fibers with age. Tissue fibrosis is associated with aging of most of our organs, and it is the main pathology in arteriosclerosis, chronic bronchitis/emphysema, and benign prostatic hyperplasia. The causes and characteristics of fibrosis are analyzed with Misrepair mechanism, a mechanism proposed in Misrepair-accumulation aging theory. Tissue fibrosis is known to be a result of repairs of tissue by collagen fibers. A repair with collagen fibers is a manner of "Misrepair". The collagen fibers are used for replacing dead cells or disrupted extracellular matrixes (ECMs) including elastic fibers, myofibers, and basement membrane. The progressive tissue fibrosis with age manifests the essential role of Misrepair in aging, because it reveals three facts: A. a process of Misrepair exists; B. Misrepairs are unavoidable; and C. Misrepairs accumulate. As a result of accumulation of Misrepairs of tissue with collagen fibers, tissue fibrosis is focalized and self-accelerating, appearing as growing of spots of hyaline degeneration. Fibrosis results in stiffness or atrophy of an organ and progressive failure of the organ. In arteriosclerosis, the deposition of collagen fibers in arterial wall is for replacing disrupted elastic fibers or myofibers, however results in hardness of the wall. Wrinkle formation is part of skin fibrosis, and it may be a result of accumulation of collagen fibers of different lengths. Senile hair-loss and hair-whitening are probably consequence of dermal fibrosis. In conclusion, tissue fibrosis is a result of accumulation of Misrepairs of tissue with collagen fibers, and the phenomenon of fibrosis is a powerful proof for the central role of Misrepair in aging.

研究动机与目标

• 确立组织纤维化作为由错误修复机制驱动的衰老核心指标。
• 分析纤维化作为反复发生的、基于胶原蛋白的组织修复所导致的结果，而这些修复本质上存在缺陷。
• 证明纤维化揭示了衰老的三个核心特征：错误修复的存在、其不可避免性以及其累积性。
• 将纤维化与动脉粥样硬化、慢性肺病及良性前列腺增生等主要年龄相关病理联系起来。
• 通过临床与病理学证据支持错误修复累积衰老理论。

提出的方法

• 对多个器官中纤维化病理生理学的分析性综述。
• 将错误修复累积衰老理论应用于解释胶原蛋白沉积作为有缺陷修复的一种形式。
• 考察纤维化作为局灶性、自我加速过程的表现，其表现为玻璃样变性。
• 对比正常组织修复与涉及胶原纤维替代的病理性错误修复。
• 利用临床与组织学数据，将纤维化与与年龄相关的器官 dysfuncion 相关联。
• 整合动脉粥样硬化、肺气肿、良性前列腺增生及皮肤老化的研究发现，以支持该理论。

实验结果

研究问题

• RQ1 组织纤维化如何作为错误修复在衰老中起核心作用的证据？
• RQ2 为何错误修复在衰老组织中既不可避免又具有累积性？
• RQ3 胶原蛋白沉积与进行性器官硬化及衰竭之间的机制联系是什么？
• RQ4 动脉粥样硬化与慢性支气管炎等疾病如何体现错误修复驱动的衰老过程？
• RQ5 皮肤纤维化在与年龄相关的皮肤变化（如皱纹与脱发）中起何种作用？

主要发现

• 组织纤维化是反复发生的、基于胶原蛋白的错误修复的直接结果，这些修复取代了受损的细胞和细胞外基质成分。
• 纤维化具有局灶性与自我加速特性，因错误修复的累积而发展为玻璃样变性的病灶。
• 该现象证实了错误修复的存在、不可避免性及其在衰老组织中随时间累积的特性。
• 在动脉粥样硬化中，胶原蛋白沉积取代了受损的弹性纤维与肌纤维，导致动脉硬化及顺应性丧失。
• 皱纹与老年性脱发可能源于累积的胶原蛋白错误修复所引起的真皮纤维化。
• 慢性疾病如肺气肿与良性前列腺增生与由持续错误修复机制驱动的纤维化密切相关。