美国衰老研究在世界上既引领时代潮流，又宏大包罗万象。当今世界，没有哪个国家的衰老研究处于如此“高、大、全”的状态，其它英语母语国家均因国力人力不足，只能有所为而有所不为。美国老年学会是世界老年学界的大哥大，美国老年学会主席亦足以堪称老年学界的“美军司令”，或者称其为学术界的武林大师或一流高手应该不算夸大。美国老年学会主席Yu教授1992年（在我点破“羰氨交联共性”数月之后）提出合并自由基氧化和非酶糖基化衰老学说，然而此后两个衰老学说一直貌合神离。想当年我前往该实验室探个究竟，主席先生正在接电话，顺便在电话里把我一顿藐视：“正在作一个无意义的接见”。于是心中暗暗立志：一定要争一口气，改变这次接见的意义！

十多年之后，当我写成广义衰老学说，又征求当年的主席先生（此时已成为学术好友）的意见时，这位武林一流高手再也没有轻蔑其词，而是大袖一挥抽出科学宝剑 ……  下面请看“广义衰老学说是怎么炼成的” 之2——华山论剑（英文原文附后）：

 

美国老年学会主席Yu 教授的信:

我为这个迟到的答复道歉。 我一直在为我怎样能帮助你写这篇文章深思。我很欣赏你对发表一篇将对老年学专家和衰老研究产生重大影响的文章所作的努力。我对此不仅毫无疑义，实际上非常支持。如你来信的开头所述，你希望在《自然》或者《科学》那样的杂志发表它。坦白地说，我不能确信，因为那两本杂志对于一篇没有发现新的衰老基因或者一组延长寿命的基因的衰老机制的文章，甚至将没有兴趣进行审稿，因为我们知道，这些杂志的政策是向文章的时髦度倾斜，而不是向硬科学。为了如你所说对衰老的机理提出结论性的解释，你必须有一个统一的机制解释包括大部分(如果不是全部)关于衰老的现有的理论和假说。我的问题进而便是羰基应激衰老学说能否胜任如此重任？或者它仅仅是另一假说？我以为在其他人眼中，该学说并不比其他基于损害的衰老理论有何不同，为此已有太多有关衰老的文献和理论。因此，在开始撰写之前，我们必须达到一个共识，那就是你的学说将‘为何’并且‘如何’统一我们今天知道的全部衰老机制。我想，如果你能让我信服，然后我将相信这是一篇值得写的文章。 印博士，请别误会，我所作的一切，旨在试图助你一臂之力！

 保持联系！Byung Pal Yu

2483 Via Del Aguacate

Fallbrook, CA 92028

 

给Yu 教授的回信:

 

亲爱的Yu教授，我为迟到和实际上较有难度的回信抱歉。我反复阅读了您的非常诚恳的来信，并且深深地被您的直言不讳而感动。关于衰老研究领域当今的困惑和混乱，的确如您所述。这样的混乱的形势可能主要是因为衰老的问题博大精深和包罗万象进而需要哲学地综合地深思熟虑。眼下，我也许不能一下子就用我的衰老理论说服您，不过，我可以告诉您，我怎样说服了我自己而使我的思维到达了今天的状态。

由于我的受教育经历，我有幸提出了衰老的羰基毒化假说并且坚持至今。我的大学本科是在几乎纯（理科的）化学学科方面主修了5 年，然后致力于食品的加工储藏（类似‘食品老化’）的有关工作，进而在我的博士学习期间研究和揭示了老年色素形成的生物化学机制。这样知识背景，让我的思维产生了一个学术优势，即种种生物学现象在我的眼中很容易被显示成为了化学分子键和功能团（电子相互作用）的生动的图像过程。当我看见自由基生物化学反应和非酶糖基化生物化学反应时，我立即从化学键及功能团反应的角度看出了它们的异同。我在1992年的一篇文章里一针见血地指出了它们在自由基氧化和非酶糖基化衰老过程中的共性特征，就在同年，您和Kristal提出了合并这两个衰老学说。在分子水平，这两个衰老理论是与能量代谢相关的生化过程的最重要的衰老的理论。根据我的食品科学知识，我深知这两个过程也是‘食品老化’的最关键的生物化学起因，因为在食品贮存期间，尽管微生物作用和酶催化也是食物败坏变质的重要因素，但它们（后两者）不是自发产生的生物化学反应过程。

自由基氧化和非酶糖基化衰老过程是至今我们发现的两个，并且是最关键的两个，能够自发进行的毒性（分子水平的）衰老生化过程。这个过程其实隐含于(大多数衰老理论植根其中的)各个生物学水平，包括细胞水平，器官/系统水平和整体动物水平。有趣的是，我偶然意识到这两个衰老的理论有一个共同的毒化过程，即羰基毒化过程！这个过程现在一般被公认为‘二级衰老起因’。

在开始时，我没敢说羰基毒化是衰老的机制的关键，因为在过去二十年期间，分子遗传学专家不断地报告发现衰老相关基因。我需要首先理解他们所报道的衰老基因的精确含意。当越来越多的这种基因在低等动物体内发现后，我们清楚地知道了它们在生命过程的病理和生理状态中的功能。例如sir2，SIRT1，就是与能量代谢相关的基因，这样的基因和基因群对动物体机能的调控实际上影响了能量代谢或其它诸多系统，象应激保护系统，修理恢复系统和自动平衡系统等等。因此我们现在可以十分自信地说，动物体内的数以万计的遗传因子是以一种合作的方式通过基因组成的网系统调节着各种动物的寿命。

基于上述讨论，环境伤害对先天遗传形成的机体地挑战则无疑成为导致衰老的关键的因素。至此，我仍不敢断言羰基毒化是衰老过程的核心，因为氧自由基对机体的损伤如此强大，并且无所不在，几乎与绝大多数疾病密切相关。其实我们都明白‘疾病加速衰老’这个道理。这就是为什么我在最近的一篇文章中指出‘生化副反应’是广义的衰老起因。但是我们现在面临的一个难题是如何关联‘生化副反应损伤’与‘衰老的速率’，或最大寿命(MLS)，我们从未找到它们之间正相关的有力证据。我们含糊地知道环境伤害和衰老变化（或MLS）之间隔了一堵‘高墙’，一堵机体赖以生存的具有防护维修功能的‘万里长城’。绝大多数衰老/抗衰老的研究只在‘墙’的一边瞎扑腾，却期望找出‘墙’的另一边发生的真正衰老过程！ 

损伤 — 修复（之墙） = 衰老

（译者根据以前的文章通讯补充）

到底‘墙’的另一边发生了什么？ 所谓‘真正衰老’过程？衰老相关的改变到底主要有哪些？

实际上，我们早已不是这个领域的外行，我们已经拥有了大量的资料和信息。我们已经从老年退行性疾病和在尸体解剖研究中获得了许多知识，无论在器官水平还是在细胞水平，特别是在分子水平的衰老研究中，例如皮肤起皱，血管硬化，老年斑形成，种种病理生理相关的器官纤维化，以及我所熟悉的白内障和脂褐素的增龄性累积等等。这里，就在这里，我们看见了所谓真正衰老，诸多衰老相关的蛋白质的改变 (令人吃惊，与基因很少有关)，竟然，不饱和羰基化合物造成的交联在其间起着关键的作用，并且恰到好处地给熵增衰老理论提供了具体的生化诠释。

由于许多衰老起因（如氧化应激，虽然作为衰老性改变的间接因子，或为外因）在加速衰老（生物体本身的分子改变）的过程中均扮演了很重要的角色，我原本并没打算以羰基毒化理论的优点批判(或者取代)其他重要的理论，直到最近我才被迫思考这件事。现在我愿更清楚地说明，羰基毒化衰老理论的最大突破旨在从亚分子水平观察和思考衰老过程的变化。换句话说，从分子功能团的视角思考和诠释衰老之谜！在具代表性的主要几类生物大分子结构中，例如脂类，碳水化合物，蛋白质和核酸，仅存在有限的几种亚分子功能基团（例如-COH，-CHO，-COOH，-NH，-SH，等等），它们的生物化学反应特性均在现代科学的理解和掌握之中。从亚分子水平思考衰老原理，似可认为是羰基毒化理论给我们彰显的一个崭新地思维方式。我相信从这观察视角/水平，我们能够最终统一绝大部分(如果不是全部的)现有的衰老的理论。

最后，考虑到限制饮食延寿（或者肥胖短寿）的机理，一个简单的解释可能就是由于对我们的消化系统的解毒能力有限（能力饱和）。我们的消化体系对食品中的羰基化合物的解毒至关重要，例如仅谷胱甘肽转移酶（GSHT，且不说P-450的解毒功效）已经占了肝脏可溶性蛋白质总量的3-5% （Yu 教授为国际限食抗衰老研究的权威教授，译者注）。

我希望上述关于羰基毒化衰老机理的思维发展过程，可以帮助您理解我的手稿之外的一些情况。

我希望这些信息可能有用，并且没有浪费您宝贵的时间，顺致圣诞和新年的最好祝愿！

大中

 

(英文原文)

Dear Dr. Yin:

I apologize for this belated reply. I have been thinking hard for how I could help you out with MS writing. I appreciate that you are eager to publish a paper that will have a great impact on the minds of gerontologists and the aging literature. And I have no problem with the intent, and in fact I’d support the idea.

As you stated at the beginning, you like to have it published in something like the Nature or Science. Frankly, I am not sure that short of discovery of aging mechanism, or a aging gene or a group of genes that are involved in life extension, those two journals would not be interested in even reviewing the type of the MS you are writing because as we know their policy is slanted toward to popularism among the reader rather than hard science.  

In order to create a impact on the aging literature and/or draw a resolution as you said, you have to have a unified mechanism that encompasses most, if not all, existing hypotheses and theories of aging. So my question is then that can the carbonyl toxification of aging be capable of doing that, or is it just another hypothesis? I am afraid that to others’ eyes, it is no different than other damage-based hypotheses, for which too many are already in the aging literature.

    So, before starting to writing, we have to come to some resolution and understanding on the fundamentals of your proposal as to why and how it can  unifying  all aging  mechanisms as we know today. I think that If you could convenience me, then I believe such a paper worth writing.  

Dr. Yin, please don’t misunderstand me, I am just trying to help you more objectively.

Keep in touch.

Byung Pal Yu

 

Dear Professor Yu,

 

I am sorry for the slow and actually quite difficult correspondence. I read over your very honest letter again and deeply moved by your sincerity. Your descriptions about the current confusions of aging are true in scientific society in the field. Such chaotic situation may be mainly because of that the aging problem is too extensive and comprehensive and need collective philosophical pondering. At this time I may not be able to convince you with my aging hypothesis, however, I’d like to tell you how I convinced myself and reached current state.

  I happened to propose and stick to the carbonyl stress hypothesis of aging partly due to my educational background. I was majored almost in the subject of pure (theoretical) chemistry for 5 years, and then worked through food reservation (a sort of ‘food aging’), and came up with the study of biochemical mechanisms of age pigment formation (during my Ph.D. study). Such education built an advantage that what so ever biological phenomena appear to me may easily turn to be pictures of chemical (molecular) bonding process. When I see free radical biochemistry and glycation biochemistry I see immediately their similarities and differences as I pinpointed in a paper in 1992, the same year you and Kristal combined the two aging theories. At the molecular level these two aging theories are the most important aging theories relating with the energy consumption process. With my food reservation knowledge, I understood that these two processes are also the most critical biochemistry of “food aging”, besides microbial and enzymatic deteriorations during food storage, which (the latter two) are not spontaneous chemical processes.

  The oxidative and glycative stresses are two, and the only two, crucial spontaneous deleterious biochemical aging causes (at molecular level) that we can find up to date, and they are implied at all the other biological levels, including cellular level, organ/system level and the whole animal level (in which most other aging theories rooting out). Interestingly, I realized by chance that these two aging theories have a common toxification process, namely, the carbonyl stress process! These process is now generally agreed as a ‘secondary aging cause’.

  At beginning, I did not dare to say the carbonyl stress is the very key of aging mechanisms because genetic scientists keep on reporting aging-associated genes during the past two decades. I need to understand what they are talking about and the exact meaning behind their findings. When more and more such kind of genes have been discovered in lower animals, we see clear their functions which are scattered in different physiological and pathological systems, such as sir2, SIRT1, which are energy metabolism related. Manipulation of such genes are actually playing with energy metabolism, and/or similarly the other systems, like stress defending system, repairing system and homeostasis etc. Thus we are quite confident to say, genetic system regulates life-span by a net system of genes in a co-operative pattern to settle a relatively species-specific longevity.

   When environmental challenges turn out to be the critical factors of aging following above discussion, I did not dare to conclude that carbonyl stress is the center of the story because free radical damages are so overwhelmingly related with most diseases, and we all understand ‘diseases accelerate aging’. That is why I stated ‘biochemical side-reactions’ for a broad definition of aging causes in a recent paper. But now the most difficult problem we are facing is when trying to correlate damages with aging speed or the maximum life span (MLS), we never make the end meet. We vaguely know that the damages and MLS are separated by a ‘wall’, the ‘Great Wall’ of our repairing system. Most aging studies are kicking at one side of the wall and expected to draw the pictures of aging process which is progressing at the other side!

   What is happening at the other side of the wall, the ‘real’ aging process? The aging related alterations?!

Actually, we are not laymen in this field, we do have a plenty of information. We have collected a large body of knowledge from chronic diseases and autopsies at organ level, cellular levels etc. particularly at the molecular level, as wrinkled skin, stiffened blood vessels, the senile plaques, versatile disease-related fibrosis, the cataract and lipofuscin that I am familiar with. Here, it is here, we see the aging, the aging-related alterations (surprisingly, have very little to do with genes), where unsaturated carbonyl-related crosslinkings play a crucial role as even to give explanation to the entropy theory of aging.

   Since many aging causes (like oxidative stress) are important (although in an indirect manner and as an external factor) to underlie aging alterations (which are internal molecular alterations), I have not intended to specify the unique significance of the carbonyl stress theory to criticize (or replace) other great theories, until I was pushed to do something like that recently. Now I’d indicate more clearly that the carbonyl stress aging is tackling the aging alterations (process) at a sub-molecular level. In other words, at the level of the molecular functional groups! In typical bio-macromolecules, such as lipids, carbohydrates, proteins and nuclear acids, there are only a few functional groups (e.g. -COH, -CHO, COOH, -NH, -SH, etc.) all with clearly understood biochemical reactivity. The concern at sub-molecular level may, therefore, be the key progress that the carbonyl stress theory has highlighted/developed in aging study, and I believe we can, from this base/level, unify most (if not all) existing aging theories.

  Finally, referring to the advantages of dietary restriction (or the disadvantage of over-diet), an simple explanation may be due to the limitation (saturation) of the detoxification capability of our digestion system. Since the detoxification of food is so important that even the decarbonylation enzyme GSHT (need not to mention P-450) already consists of 3-5% of the total soluble proteins in liver.

  I hope the story of my thinking may help you understand more the development of my ideas in addition to the descriptions written in my manuscript.

  I hope these information may be useful and bring a nice time to you, together with my best wishes for the Merry Christmas and the New Year season.

  Yours,

  Dazhong

 

 

 

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