将抗衰老工程策略介绍来中国

——印大中给“千岁教授”奥布里·德格雷的信：

星期五  2006年 8月4日

亲爱的奥布里，感谢您授权让我们将你的抗衰老工程策略（SENS）介绍来中国。然而为了能真正成功地做SENS，我们首先需要对于衰老机理的正确地理解和解释。我个人认为，衰老过程的生物化学本质已经在我(我们)早期的文章里得到了深刻地阐述。随函附上我的一篇对衰老过程的生化本质的文章，请查阅。 希望能听到你的专家意见和评论。 如果你在阅读之后觉得有共识，我将乐意邀请你一同写文章向《自然》或者《科学》杂志投稿，标题可为"衰老，千古之谜的终结“。

问好！

大中

Aubrey的答复：将抗衰老工程策略介绍来中国

星期六  2006年 8月5日

你好，大中，非常感谢发来的文章，昨晚读过。总的说来，我同意你的很多观点。的确，Brunk教授及他的思想在我早期认识衰老机制的过程里起了非常重要的作用。通过与他交谈(以及过后与亚历克斯·特曼的交谈)，我开始构想抗衰老蓝图，尽管并非完全集中在对付线粒体的衰老改变。

我认为你我之间在衰老问题上的主要差别是，我认为尚无足够的证据表明突变在衰老过程中没有很大关系，因此我以为我们应该既防止基因突变又阻止蛋白质聚集和交联的增加。另外，我们也不能忘记细胞数目的增龄性变化 – 有些细胞逐渐走向死亡而不被替换， 例如在心脏或者黑质体中；有些细胞累积，例如不活泼免疫细胞等，尽管他们死去最好。 这些事件可能在衰老过程中也很重要 —— 或许不象大多数组织中的蛋白质聚集物和交联结构那样 —— 但是即使一两个身体组织中有那些成分，仍然将坏得足以杀死我们，因此我们不可忽视他们。

你我的之间的一个相对较次要的认识差别是，我认为区分衰老和疾病是一个孬想法。我喜欢认为老年退行性疾病是衰老过程中的一个晚期阶段。这意思也就是说，如果我们推迟身体各个组织的衰老也将推迟老年性疾病的发生，这也就是说衰老性疾病告诉了我们衰老包括了哪些方面的内涵。例如，如果我们说癌症是一种衰老相关的疾病而并非衰老的一部分，并因此决定我们能忽视在衰老过程中的染色体突变 ——但是那将是一个错误 ——，因为我们若忽视了染色体的突变，我们将不能推迟癌症的发生，进而我们将全部死于癌症，那将很不令人满意！

请读我的一些概述文章并且告诉我你的想法。

http://www.sens.org/manu12.pdf

http://www.sens.org/manu16.pdf

http://www.sens.org/FHT-PP.pdf

祝祺！

奥布里

印大中给奥布里·德格雷的信: 抗衰老与理解衰老本质

星期四，2006年8月10日

亲爱的奥布里， 感谢你的评论意见和坦率的讨论。我高兴地感到这是真正科学家之间的难得的高水平讨论。我从你的文章受益良多，并非常欣赏你在抗衰老研究领域极为宽广的知识面和睿智的抗衰老策略。

有关我曾经工作学习过的瑞典Linkoping 大学，你可能已经注意到，虽然我出自（博士毕业于）Brunk教授的研究室，我的观点与乌尔夫·布伦克和（师弟）亚历克斯·特曼的观点颇为不同。乌尔夫在亚细胞水平，以线粒体溶酶体为轴心研究衰老现象。亚历克斯则在近年提出了一个生物垃圾积累衰老理论，这甚至可以是一个500 年前就被人推出的衰老学说 (开个玩笑)。 我的衰老学术”语言”主要是化学语言，聚焦于生物化学的分子功能团的作用这个层面。这不是象基因组学和蛋白质组学这些当前时髦的概念，相反”在亚分子水平看衰老机制”。从这个角度看错综复杂的衰老过程，衰老的本质则变得显而易见，一目了然。

我很理解你我在衰老相关问题上的认知差别，这些差别合情合理，因为你的主攻目标是做SENS （抗衰老），而我的首要目标是诠释衰老的真正机制，我称之为衰老过程的生理生化本质。毫无疑义，很多疾病与衰老相关，疾病(象炎症和糖尿病等等)可能加速人体衰老，反过来衰老也可能潜移默化导致疾病(尤其是老年退行性疾病)的产生。在我看来，在一个人能活到他的最大的寿命之前，全部衰老相关的疾病应该首当其冲地被有效地治疗。 (这可能使治疗癌症在你主题中变得极为重要，然而（癌变）在我的研究主题内只是诸多损伤的后果之一)。

癌症是与衰老相关的最危险的疾病之一；不过，衰老过程中的其它老年退行性疾病，象动脉粥样硬化，老年痴呆症，糖尿病等与癌症一样有害。即使现代医学能够成功地限制癌症的发生，我们身体仍将面对与增龄相伴而来，并且无所不在的器官纤维化和蛋白质交联聚集 (例如皮肤，肺脏，血管，肝脏，肾脏，膀胱等器官和细胞的弹性纤维组织的硬化改变)。 这就是我乐意称之为”真正衰老”或”生理性衰老”的身体变化。

我当然同意细胞数目随龄减少可能是寿命长短的一个制约因子。然而我的主要兴趣在细胞”为什么死”和”什么”使它们死。通过研究大量的生化副反应，我认识到我们已经查明了导致生物体损伤的主要上游起因，包括第一原因，第二原因等。第一伤害原因主要是外因 (像氧自由基) 这类伤害一般为可修理性伤害 (或疾病性伤害，身体组织往往无法忍受这类伤害)；第二伤害原因，正如我10 年以前便已明确提出的，主要指羰基应激类交联性损伤积累，而今已经被认识到是最关键的衰老性生化大分子改变[1]，因为这是一大类不能被修复的永久性熵增改变。

回到抗衰老（SENS），我相信当我们真正认清衰老过程的本质之日，便是能制定正确的抗衰老策略之时。如果你认为我们的讨论确有意思，我将期望人类的抗衰老实践会更有些意思了。 

致最好的问候！

大中

 [1] TJ Lyons, Glycation, Carbonyl Stress, EAGLEs, and the Vascular Complications of Diabetes. Seminals in Vascular Medicine Vol 2 (2). 2002, 175-189. “The glycation hypothesis has developed over the past 30 years, evolving gradually into a carbonyl stress hypothesis (经过30年的发展，非酶糖基化假说逐渐衍进为羰基应激假说)”

奥布里·德格雷的回信：抗衰老与理解衰老本质

星期四，2006，8月10日

你好，大中， 感谢你精致的解答。是的，你说的很对，细胞走向死亡，一定是有某些因素使它们发生了病变，而当他们本该死亡又奋力抵抗也一定是有某些因子使然。

因此，如果我们真的能如你所说在亚分子水平处理细胞内部的种种麻烦，我们将能(虽然间接地，但是有效地！) 应对细胞死亡和细胞拒绝死亡的诸多问题。或许全面思考这些问题的最科学理性的策略是时时注意，让细胞生存或死亡均与抗衰老息息相关，只是有时这一个策略简便易行，有时却是另一个。

祝祺！

奥布里

（信件英文原文）

To make SENS in China

Friday, August 4, 2006 8:33 PM

Dear Aubrey,

Thanks for your courtesy to let us introduce your SENS to China. To go straight forward to make SENS, we need to have a right explanation on the aging mechanisms. Personally, I believe the biochemical process (essence) of aging has been already highlighted in my (our) early works.  

Attached please find one of my recent papers relevant to the key biochemistry of aging. Your expertise and comments are greatly appreciated. If you have a common sense after your reading, I’d like to invite you to together write a paper with a title such as “Aging, time to draw resolution” to the journal like Nature or Science.

Regards!

Dazhong

Re: To make SENS in China

Saturday, August 5, 2006 3:52 PM

Hi Dazhong,

Many thanks for sending this paper. I read it last night.

In general I agree very much with what you say. Indeed, Ulf played a very important part in my early thinking about aging: it was through talking to him (and later to Alex Terman) that I began to formulate a model of how to address aging that did not centre wholly on mitochondrial mutations.

I think the main difference between your position and mine is that I think there is still not enough evidence to be sure that mutations don't matter much in aging, so I think we should attack those as well as attacking the buildup of aggregates and crosslinks. We must also not forget that there are changes in cell number <[--]> cells dying and not being replaced, such as in the heart or the substantia nigra, and cells accumulating when it would be better if they died, such as inactive immune cells. These things may also matter in aging <[--]> maybe not so much as aggregates and crosslinks in most tissues, but even if there are only one or two tissues where these things matter more than aggregates or crosslinks, that would still be bad enough to kill us, so we must not ignore them.

A more minor difference between your position and mine is that I think it is a bad idea to distinguish aging from disease. I prefer to think of age-related diseases as some of the later stages of aging. That means, if we postpone all aspects of aging we will also postpone the diseases of aging, but it also means that the diseases of aging can tell us what aspects of aging we should include. For example, if we say that cancer is an age-related disease and not part of aging, we may decide that we can ignore chromosomal mutations in aging <[--]> but that would be wrong, because if we ignore those mutations we will not delay cancer and we'll all die of cancer, which would be ... unsatisfactory!

Please read some of my overview papers and tell me what you think.

http://www.sens.org/manu12.pdf

http://www.sens.org/manu16.pdf

http://www.sens.org/FHT-PP.pdf

Cheers,

Aubrey

To make SENS vs to understand essence

Thursday, August 10, 2006 9:35 AM

Dear Aubrey，

Thanks for your comments and frank discussion. I feel this is a rear communication between real scientists and I enjoy the high level of discussion. I learned a lot from your papers and admire very much your broad scientific knowledge and intelligent strategies towards anti-aging.

Referring to Linkoping you may already notice, although I come from Ulf’s lab, my perspective is quite different from those of Ulf Brunk and Alex Terman. Ulf is looking the aging problem at the sub-cellular lever, the mitochondria-lysosome axis. Alex is talking an aging theory of biological garbage accumulation which could be a theory of 500 years ago (a joke). My ‘language’ is mostly chemical language, focusing on functional groups of biochemical molecules. This is not the currently popular concept, like genomics or proteomics instead it’s looking at the aging mechanisms at a sub-molecular level. From this angle the complicated aging process then becomes simplified and obvious (transparent).

I understand very well the differences between yours and mine and it is very reasonable. Because your intension is to make SENS, whereas mine is to explain the real aging, the physiological aging process, which I call the ESSENCE of aging. It is true that many diseases are aging dependent, namely diseases can accelerate aging process (like inflammation, diabetes etc), aging may in turn underlie diseases (particularly chronic diseases). In my opinion, all aging-related diseases should be effectively treated, for the first hand, before a person can live to his Maximum Life-span. (This may make treating cancer become so important in your subject, although it’s only one of the damage-related consequences in my subject).

Cancer is one of the most dangerous aging-related diseases however, it’s just as harmful as atherosclerosis, Alzheimer disease, diabetes mellitus and other chronic diseases during aging. Even modern medicine can successfully restrict cancer our body may still face overwhelming fibrosis and/or protein aggregation developing in almost every organ (e.g. skin, lung, blood vessel, liver, kidney, bladder…) in our body. This is what I’d like to call the ‘real aging’, the physiological aging.

I certainly agree that cell number is decline during aging which could be the limit of a life. But my interest is mainly on ‘Why’ the cells die and ‘What’ make them die. Through studying biochemical side-reactions, I understood we have already found out the main causes, the primary and the secondary upstream causes. The primary causes or damages are basically extrinsic (like free radicals) and mainly repairable (intolerable) the secondary, the carbonyl stress, as I pinpointed ten years ago, has become the most critical today ^[1] mainly because it is irreparable.

Come back to SENS, I believe we can make right strategies when we understand the ESSENCE. If you think my discussion do make sense to you, I’d expect that human beings may make better SENS in the future.

Best Regards!

Dazhong

[1] TJ Lyons, Glycation, Carbonyl Stress, EAGLEs, and the Vascular Complications of Diabetes. Seminals in Vascular Medicine Vol 2 (2). 2002, 175-189.

Re: To make SENS vs to understand essence

Thursday, August 10, 2006 7:35 PM

Hi Dazhong,

Thanks for this elaboration. Yes, you are right that when cells die there must be something that makes them sick, and conversely when cell refuse to die when they should there must also be something that makes them do that.

Therefore, if we can really address internal cellular problems, which are mostly sub-molecular as you say, we can (indirectly, but effectively!) fix the cell death and cell death-resistance problems. Maybe the best way to look at the overall problem is to keep in mind always that both of these approaches can work, and sometimes one will be easier, sometimes the other.

Cheers,

Aubrey