现代生物科学关于老年色素研究的第一本国际权威著作由美籍印度学者主编，该学者从此在该领域，声名鹊起，独霸一方。关于老年色素研究的系列国际会议连续开了六届。作为该领域另一位权威教授，瑞典国家医学会副主席乌尔夫-波龙克的学生，有幸出席了最后几届该系列会议，踏及世界诸国，交会各路豪杰，将老年色素的生化形成机理写成了我的博士论文，也写成了一些集大成综述（综述发表后该系列国际会议从此没有再开）。我们的工作为老年色素研究竖立了一个近乎结论的里程碑，然而也无意中夺取了别人头顶耀眼的光环。从此在该领域，中国人不再无足轻重，中国人成为竞争对手，“中国崛起”与“中国威胁论”一起被提上了议事日程。在当年“集大成综述”被审稿的过程中，我隐约感到了科学竞争的残酷，一句该领域的常识用语“老年色素是生物体衰老的重要指标”被指责为盗用了xxx的原创思想……

十多年后，当我们的“广义衰老学说”又落在了xxx国际权威学术大师的手中，其命运可想而之。

如果说审稿大师“超一流”的“夺命否定”并没有直截了当的“刀起头落”，然而在“故意歪解”和“近乎无赖”（也许是‘无知’）的审稿评论的字里行间随处都可以感觉到 “泰山压顶”式的“刀光剑影”。

无奈，只有一件事可做——据理力争！

或者在烈火中凤凰涅槃，或者在烈火中化为灰烬……

  

（先给英文原文, 中文译文在后）

《Experimental Gerontology》杂志编辑部来信：

Dear Dr. Yin,

We have now received the comments to your article mentioned above from the referees. Could you please comment on them and let us have your reply as soon as possible?  

        Reviewer 1:

The review authored by Dazhong Yin and Keji Chen entitled "The Essential Mechanisms of Aging: Irreparable Damage Accumulation of Biochemical Side-Reactions" argues for a mechanism of aging. As stated by the authors: "In summary, direct DNA damage and mutation in comparison with protein impairments are either less important or disease-related, which may not be the crucial issue of physiological aging of higher animals. Whereas biological systems of anti-stresses, protein turnover, metabolisms and homeostasis regulated by genetic network are the key elements of aging mechanisms, various irreparable accumulations of protein alterations induced by spontaneous biological side-reactions turn out to be the center of aging biochemistry."

The authors state that there are numerous hypotheses of aging. They conclude that protein cross-linking brought about by free radical derived mechanisms is the most important determinant of normal aging.

Unfortunately, this conclusion is neither novel nor is it supported by literature precedence. While cross-linked forms of protein do appear to accumulate during aging the functional consequence of this accumulation is largely unknown. The authors simply assume that this in turn results in deranged function. In addition, the authors do not make a convincing argument for why other theories can be excluded other than referencing these claims with articles that do not support their contention. In short, this review does little more than repackage a hypothesis that has been stated before and does little to convince the reader of its validity.

 Reviewer 2: 

This is a clearly written review of the many factors that are associated with the aging process and merits publication. The only issue that might give a wrong impression is the statement (top 3 lines on page 11) that protein degradation is a result rather than a cause of aging. It is well established that oxidation of proteins renders them susceptible to proteolytic degradation. Accordingly, a decline with age in the levels of proteases that degrade oxidized proteins may lead to the accumulation of oxidatively modified proteins, which the author points out is an important function in aging.

An error on page 23, line 9: "A basic notion..." not "An basic notion...".

 

我们给编辑部的回复：

Dear Dr. Beatrix,

Thank you very much for facilitating the publication of our review paper “The essential mechanisms of aging: irreparable damage accumulation of biochemical side-reactions" (Ms.#7078) and sending us the reviewers’ comments on March 22, 2005. We are delighted to read that the reviewers have confirmed positively our scientific and literature descriptions on current status of aging studies (as this topic covered an enormous huge realm, it’s very hard to command all relevant fields) just as the 1^st Reviewer concluded in his comments “this review does little more than repackage a hypothesis that has been stated before …”.

Referring to reviewers’ comments we wish to present our discussions as follows:

1)          The reviewer 1 stated: “They conclude that protein cross-linking brought about by free radical derived mechanisms is the most important determinant of normal aging.” We regret to say this is a misunderstanding of our proposed theory. The free radical mechanisms, in our opinion, is narrow-minded (as we have already clarified in our Ms.) in explaining aging mechanisms. Our key issue about the causes of aging (not yet the aging mechanisms) are “biological side-reactions”, particularly those side-reactions related to biological energy metabolisms. For instance, the diabetes accelerated glycation and related carbonyl stress may also be very critical for physiological aging alterations.

2)          The reviewer 1 continued: “Unfortunately, this conclusion is neither novel nor is it supported by literature precedence.” The free radical mechanisms of aging is surely not novel (and even is scientifically problematic), but the “biological side-reactions”, the “entropy biochemistry of aging”, the “focusing on process beyond causes”, the “direct DNA damages and mutations are mainly disease-related”, and the “carbonyl stress may be one of the most crucial culprits of aging” are all our original contributions in the review as well as in the scientific field related.

3)          The reviewer 1 also stated: “While cross-linked forms of protein do appear to accumulate during aging the functional consequence of this accumulation is largely unknown.” It is true that the functional consequence of intra-cellular accumulates, such as lipofuscin, is largely unknown. However, a variety of other crosslinkage-related functional retardations are well studied and some examples are listed below:

a)  opacity of lens and further cataract formation due to cross-linked crystallins

b)  crosslinkage of elastic tissues (e.g. collagen in blood vessels) during aging

c)  increase of AGEs (GOLD, MOLD, CML, pentosidine et al.) and ALEs

d)  cellular membrane and cytoskeleton rigidity and in-solubility

e)  increased thickness of glomerular basement membrane

f)  multiple fibrosis during aging (speeded by inflammation)

g)  stiffening of joints, decline of lung elasticity, et al.

h)  and probably atherosclerosis and amyloid formation due to deficient clearance

Moreover, organ-specific and disease-accelerated protein alterations may largely be viewed as speeded aging-related changes (when repairing is disturbed or inhibited). The author would also refer to a recent review by Grune and Davies (2004) IJBCB, 36: 2519-2530 for obtaining more information about protein aggregation during aging.

4)            Finally, the reviewer 1 wrote: “In addition, the authors do not make a convincing argument for why other theories can be excluded…. this review does little more than repackage a hypothesis that has been stated before and does little to convince the reader of its validity.” We wonder why reviewer 1 suggested us to exclude the other theories and tended to overlook the validity of our hypothesis as well. Our theory has evolved from those principal aging hypotheses and many of them are our solid foundation. We are standing on a stage supported by numerous scientific achievements in the related fields, so they are not going to be excluded arbitrary rather being interpreted properly. A specific progress we made is that we went down to a sub-molecular level and extracted the essential (general) biochemistry behind the aging process. This is obviously much more than a “simple repackage” (also see point 2), rather approaching (or revealing?) a resolution of the ever confusing mechanism of aging.

5)            The reviewer 2 thinks “that might give a wrong impression is the statement that protein degradation is a result rather than a cause of aging. It is well established that oxidation of proteins renders them susceptible to proteolytic degradation. We believe that protein degradation is neither a result nor a cause of aging. Protein degradation (for an adult), in our opinion, is mainly for routing restorative turnover or repairing of damages due to biological side-reactions. We fully agree with further statement by reviewer 2: “A decline with age in the levels of proteases that degrade oxidized proteins may lead to the accumulation of oxidatively modified proteins”. We wish to acknowledge our sincere thanks for his kind suggestion on an error correction on page 23.

 We hope these discussion answered the reviewers questions clearly and correctly.

Best Regards！

Dazhong Yin

Professor, Chairman of the Aging Biochem Lab

Hunan Normal University

  

实验老年学杂志编辑部来信（译文）:

 亲爱的印博士， 我们现在已经得到了审稿人对你们的综述文章的意见。 请对他们的意见作出评论，并且尽快给我们回复。

 

审稿专家1： 印大中和陈可冀的综述"衰老机制本质：生物化学副反应损伤的失修性累积"提出了一个衰老机制。 如作者所说“总之，尽管直接的DNA损伤和突变与种种老年性疾病息息相关，但与衰老过程中生理性的无所不在的蛋白质损变的积累相比，DNA损伤的影响则为次重要或主要呈现病理特征。尽管由遗传所调控的抗应激、蛋白质更新、新陈代谢和机体稳态等基因网络系统扮演着高等动物衰老的先天性制约因子的角色，而自发进行的生化副反应导致的机体失修性改变则为环境相关因素导致衰老的主要表现形式”。

作者罗列了众多衰老假说。 他们认为自由基导致的蛋白质交联是正常老化最重要的决定因素。

令人遗憾，这个结论既不新鲜也没有文献的支持。蛋白质的交联确实似乎在衰老过程中积累，但这个积累的后果基本上未知。作者仅仅是假设该积累造成了机体功能的紊乱。另外，作者没有提出可信的论点来说明为什么其他衰老理论可以被排除。简而言之，这篇综述仅仅是在简单重新包装以前已经被阐明的诸多衰老假说，很难能使读者信服它的价值。

 

审稿专家2： 该综述写作清楚，给出了与衰老过程相关的诸多因素，值得发表。唯一可能产生错误印象的地方是说蛋白质降解是衰老的一个结果而不是衰老的起因 (在第11 页上的前3条线)。 然而确定的事实是蛋白质的氧化使得它们更易受到降解。因此，蛋白酶水平增龄性下降可能导致蛋白质的氧化性损伤累积，正如作者指出那是衰老的一个重要的表象。 另外，在第23页第9行："A basic notion..." 不是 "An basic notion...".

  

我们的回复（译文）:

 非常感谢协助我们的综述文章“衰老机制本质：生物化学副反应损伤的失修性累积(#7078)”的发表进程和寄给我们审稿专家（2005年3月22日）的意见。我们很高兴注意到审稿专家对我们关于衰老研究的科学描述和文献知识的认可 (衰老问题涉及到非常巨大的研究领域，贯通掌握相关的学科领域本身就已非常难能可贵)。正象第1审稿专家在他的意见里断定："这篇综述将过往的种种理论重新装配成了一个新假说…". 参照审稿专家的意见，我们提出讨论如下：

 1) 审稿专家1 说："作者断定自由基伤害造成的蛋白质交联是最重要的正常衰老的决定因素"。我们遗憾地说这是对我们提出的衰老理论的一个误读。我们认为，以自由基损伤解释衰老机制是狭隘的(我们已经在综述里阐明)。我们关于衰老起因(且不谈衰老的机制) 的关键词是"生化副反应"，特别是那些与生物能量代谢有关的生化副反应。例如，糖尿病加速的非酶糖基化过程以及与之相关的羰基应激，也可以是生理性衰老改变的重要原因。

 

2) 审稿专家1 继续说道： "令人遗憾，这个结论（自由基损伤蛋白质造成交联衰老）既不新鲜也没有文献的支持"。我们同意：衰老的自由基机制肯定不是新理念(并且在科学上很成问题)。 不过"生化副反应"， "衰老的熵增生物化学"，"在衰老原因之外关注衰老过程"， "直接的DNA 损害和突变主要与老年病有关"， 以及“羰基应激可能是生物体老化最主要的罪犯"等理念都是我们在本文中的原创，同样也是对于相关科学领域的原创性贡献。

 

3) 审稿专家1又说：“蛋白质的交联确实似乎在衰老过程中积累，但这个积累的后果基本上未知”。可以认为这些交联蓄积的后果在细胞内部还基本不明，例如脂褐素对细胞功能的影响基本未知。然而，大量其它与蛋白质交联相关的机体功能退变已被研究得非常深入，现举例如下：

a) 由于眼球晶体蛋白交联造成的眼球晶体混浊和白内障的形成

b) 伴随衰老出现的弹性蛋白及组织的交联硬化(例如在血管里的胶原)

c) 与龄俱增的AGEs (GOLD, MOLD, CML, pentosidine) and ALEs等

d) 随增龄而出现的细胞膜和细胞骨架的刚性增加和溶解度下降

e) 伴随衰老进程出现的肾小球基底膜增厚

f) 在老化期间越来越普遍的器官纤维化 (被炎症加速)

g) 伴随衰老出现的关节变硬和肺组织的弹性下降等等

h) 以及也许由于代谢产物清理缺陷而形成的动脉粥样硬化和淀粉样蛋白形成

另外，有器官特异性的和被疾病加速的蛋白质结构改变也基本上可被认为是被加速了的衰老表象 (一旦机体的修复机能被扰乱或者被抑制)。

在此，作者也提请大家注意参考Grune 和Davies最新发表的综述 (2004) IJBCB，36；2519-2530以获得更多的关于衰老过程中蛋白质聚集变性的资料。

 4) 最后，审稿专家1 写到："另外，作者没有提出可信的论点来说明为什么其他衰老理论可以被排除。简而言之，这篇综述仅仅是在简单重新包装以前已经被阐明的诸多衰老假说，很难能使读者信服它的价值"。我们觉得奇怪为什么审稿专家1建议我们否定其它衰老理论的价值并且倾向于也忽略我们的学说的价值。我们的理论从那些当今最主要的衰老学说中逐步衍生发展而成，它们中的许多理论是我们衰老学说的坚实基础。我们站在一个有着很多科学成就支持的平台上，因此那些学说不会被粗暴地排除而只会被正确地解读。我们的衰老学说取得的独特的进步是我们走入了一个新水平——亚分子水平，并且抽象出了潜藏在衰老过程背后的基本的(广义的)生物化学本质。这远远超过(也可参见本回答中的第2 点) 审稿专家1所说的“简单重新包装”；相反，接近(或揭示)了一个至今仍无比混乱的衰老机制的极佳答案。

 5) 审稿专家2说：该文“唯一可能产生错误印象的地方是说蛋白质降解是衰老的一个结果而不是衰老的起因，然而确定的事实是蛋白质的氧化使得它们更易受到降解。”我们认为，蛋白质被降解既不是衰老的结果也不是衰老的原因。在我们看来，蛋白质降解(对于成年人来说)主要是机体对于日常生化副反应损害的修复和更新。我们完全赞成审稿专家2的观点："蛋白酶水平增龄性下降可能导致蛋白质的氧化性损伤累积。"，我们诚挚感谢审稿专家2关于改正在第23 页上的一项错误的友好建议。

 我们希望这些讨论清楚而正确回答了审稿专家的问题。

最好的祝福！

 

印大中

湖南师范大学 教授， 衰老生化研究室 主任

  

转载本文请联系原作者获取授权，同时请注明本文来自印大中科学网博客。
链接地址：https://blog.sciencenet.cn/blog-38405-323716.html

上一篇：广义衰老学说是怎么炼成的（2）——华山论剑
下一篇：广义衰老学说是怎么炼成的（4）—— 千年狂想