“广义胡焕庸线”的 National Geographic 图示 一、广义胡焕庸线 （胡焕庸线的一般化推广） 2014-12-24 真傻提出： “类似胡焕庸线，非洲、南美洲、美国、欧洲等处也有类似的植物生长的边界线，即广义的胡焕庸线。在农牧业为主的社会，植物生长的情况，与人口密度的分布有一定的关系：人必须一定量的水、粮食和蔬菜。 ” http://blog.sciencenet.cn/blog-107667-853546.html 在 2015-11-23 19:42 进一步说明： “人口分布，直接受到水资源等客观条件的制约。因此，植物的繁茂状态，是人类存在的先决条件，但不一定有人（如太冷）。在天气较暖的地区，这两种分布应该有较强的相关性。” 二、美国“国家地理National Geographic”的直观证据 地球上哪里没有人（This map shows where on Earth humans aren’t），这幅照片明显地给出了“广义胡焕庸线”： https://www.nationalgeographic.com/science/2020/06/where-people-arent/ 这是裁剪出的我国“胡焕庸线”： 对照： 美卫星的植物碳汇图 https://www.sciencemag.org/news/2014/12/satellite-captures-glowing-plants-space 参考资料： 胡焕庸线_百度百科 https://baike.baidu.com/item/%E8%83%A1%E7%84%95%E5%BA%B8%E7%BA%BF 中国气象数据网，2019-04-23，这条线为何被称为“最牛分界线”？ https://www.sohu.com/a/309859242_99963284 北京山东同乡沙龙，2017-06-18，原来每个国家都有一条“胡焕庸”线 https://www.sohu.com/a/149896721_163277 National Geographic，2020-06-05，This map shows where on Earth humans aren’t A new map shows where people have the lowest impact—but are those the best places to protect? https://www.nationalgeographic.com/science/2020/06/where-people-arent/ https://migrate.readersupportednews.org/news-section2/318-66/63361-this-map-shows-where-on-earth-humans-arent Eric Hand，SCIENCE，2014-12-18，Satellite captures glowing plants from space https://www.sciencemag.org/news/2014/12/satellite-captures-glowing-plants-space 相关链接： 2017-08-26，“广义胡焕庸线”的存在被证实！ http://blog.sciencenet.cn/blog-107667-1072822.html 2014-12-22，胡焕庸线：清晰可见（美卫星的植物碳汇图） http://blog.sciencenet.cn/blog-107667-853546.html 2015-10-01，胡焕庸线：尚未突破 http://blog.sciencenet.cn/blog-107667-924668.html 感谢您的指教！ 感谢您指正以上任何错误！ 感谢您提供更多的相关资料！
汉语是联合国官方正式使用的 6种同等有效语言之一。请不要歧视汉语！ Chinese is one of the six equally effective official languages of the United Nations. Not to discriminate against Chinese, please! “任何人类历史的第一个前提无疑是有生命的个人的存在 ［注：手稿中删去了以下这一段话：“这些个人使自己和动物区别开来的第一个历史行动并不是在于他们有思想，而是在于他们开始生产自己所必需的生活资料。”——编者注］ 。 因 此第一个需要确定的具体事实就是这些个人的肉体组织，以及受肉体组织制约的他们与自然界的关系。当然，我们在这里既不能深入研究人们自身的生理特性，也不能深入研究各种自然条件——地质条件、地理条件、气候条件以及人们所遇到的其他条件 ［注：手稿中删去了以下这一段话：“但是，这些条件不仅制约着人们最初的、自然产生的肉体组织，特别是他们之间的种族差别，而且直到如今还制约着肉体组织的整个进一步发达或不发达。”——编者注］ 。 任 何历史记载都应当从这些自然基础以及它们在历史进程中由于人们的活动而发生的变更 出发。 ” 马克思 和 恩格斯 ：《费尔巴哈》（1845—1846 年）。《马克思恩格斯选集》第 1 卷第 24 页。 https://www.marxists.org/chinese/marx-engels/03/003.htm “广义胡焕庸线”的存在被证实！ 2014-12-24 真傻提出： “类似胡焕庸线，非洲、南美洲、美国、欧洲等处也有类似的植物生长的边界线，即广义的胡焕庸线。在农牧业为主的社会，植物生长的情况，与人口密度的分布有一定的关系：人必须一定量的水、粮食和蔬菜。 ” http://blog.sciencenet.cn/blog-107667-853546.html 发 表于 2015-11-23 19:42 人口分布，直接受到水资源等客观条件的制约。因此，植物的繁茂状态，是人类存在的先决条件，但不一定有人（如太冷）。在天气较暖的地区，这两种分布应该有较强的相关性。 http://bbs.sciencenet.cn/thread-2379584-1-1.html http://www.tech110.net/home.php?mod=spaceuid=11851do=blogid=74006 目前看上去被证实存在： 搜狐，2017-06-17，原来每个国家都有一条“胡焕庸”线 http://www.sohu.com/a/149799395_534679 这几天， 一条 82岁 高龄的地理分割线又火了。这就是中国人口分布的分界线，也称作“胡焕庸线”。 （1）美国U型 线也和“胡焕庸线”类似，与美国的地形 、降雨量分割线基本吻合。 （2）加拿大由于北方太冷，其超过90%的加拿大人口居住在距离美国边境250公里以 内的南部地区，因此加国的“胡焕庸线”也大致位于此线附近。 （3）俄罗斯 的“胡焕庸线”是一条近似 斜线，基本分割了俄罗斯的欧、亚地区和南部地区。俄罗斯欧洲部分人口，就占了全国的75%。 （4）澳洲地广 人稀，其“胡焕庸线”可以大致用一条分割东西部的直线来表示。澳洲大部分人口位于直线以东，主 要集中在东南部沿海的悉尼、墨尔本、布里斯班等城市。线的西部只有零星的城市。 （5）日本 的“胡焕庸线”，则是一个倾 斜的矩形。矩形内的关东平原（东京）、浓尾平原（名古屋）、近畿平原（大阪、京都、神户）、濑户内海沿岸和九州岛的福冈，是日本人口最密集的区域。 （6）法国是典型的一城独大（首都）型，类似的还有西班牙。大巴黎都会区（下图圈内）的人口就占全法国人口的20%，GDP占全法国近40%。 （7）最后看全球的人口分布。 世界的“胡焕庸线”可以较简单粗暴的概括为“ 深V地 带”，该地带内的西欧、印度、中国是世界人口最稠密的地方。当然，还有美国、埃及北部、西非、巴西东南岸、东南亚爪哇等人口聚集地。 相关链接： 2014-12-22，胡焕庸线：清晰可见（美卫星的植物碳汇图） http://blog.sciencenet.cn/blog-107667-853546.html 2015-3-30， Zenas（真傻，Zheng-Ling YANG）个人创新观点汇总（第一批） http://bbs.sciencenet.cn/thread-2379584-1-1.html 2015-10-01，胡焕庸线：尚未突破 http://blog.sciencenet.cn/blog-107667-924668.html Population density (people per km2) map of the world in 1994. Red and pink areas denote regions of highest population density. https://en.wikipedia.org/wiki/World_population#/media/File:World_population_density_1994.png World population, From Wikipedia, the free encyclopedia The distribution of human world population in 1994 https://upload.wikimedia.org/wikipedia/commons/b/bc/Population_density.png Population, From Wikipedia, the free encyclopedia 感谢您的指教！ 感谢您指正以上任何错误 ！ 感谢您提供更多的相关资料！ http://www.sohu.com/a/149799395_534679 美国的人口密度分割线是一个不规则的U型线。 算上阿拉斯加、夏威夷及其它的一些海外领地，U型线内外的面积大约为50%对50%，人口比例为14%：86%，GDP比例约为11%：89%。虽然比例没有中国的悬殊，但仍然有地域分布不均的情况。 美国U型 线也和“胡焕庸线”类似， 与美国的地形、降雨量分割线基本吻合。美国人口主要分布在东、西海岸、五大湖沿岸、密西西比平原和南部德州、佛州，避开了中西部地势较高的落基山脉和科迪勒拉山脉。
前面博文所述广义衰老学说是怎么炼成 之（ 3 ）夺命审稿经过生死抗争，终于过关斩将，凤凰涅槃，被美国《实验老年学》杂志作为标新立异之作刊登在 2005 年第六期的首页（ Exp. Gerontol. 2005, 40(6); 455-465 . ）。于是就有了后来笔者在衰老，千古之谜的终结文章里叙述的世界衰老研究领域的突然认知大转变。至此，衰老不再是生物学的不解之谜 在笔者的科学生涯中，曾喜欢把一句话经常放在嘴边：这一辈子争取为科学做成一件事 前面的半件 解读为什么衰老 。现在这前半件事既然玩成得差不多了，那么后面半件事如何抗衰老也许可以拿出来弄弄玩玩了。于是就有了与剑桥大学 千岁教授 Aubrey de Grey 之间的太极推手 笔者与 Aubrey 之间的交往应该是始于世纪之交的一个偶然机遇（准确年代最好得问 Aubrey ）。因有事回瑞典林雪平大学医学院去找曾把我引入科学世界的博士导师 Ulf Brunk ，在走廊上遇到了一个大胡子，就是 Aubrey 。闲聊中知道他是来探讨衰老机理和体内随增龄蓄积的生物垃圾（老年色素形成）等问题（这个问题后来成为他抗衰老 7 大战役中 2 个大战役的内容）。因为笔者的导师 Brunk 教授是老年色素研究的欧洲大牌，所以他特地前来咨询。谈笑中他终于知道， Brunk 教授实验室真正在玩老年色素形成机制的化学白痴却是来自东土大唐的取经人 Great China ，大中 是耶。 1995 年那篇 Yin 与 Brunk 一道署名的羰基毒化衰老学说以及老年色素生化形成机理等综述其实是中国创造，只是 Made in Sweden 。（又：自从 Great China 回东土大唐当特聘教授以后， Brunk 实验室的哪些玩不转化学的师弟们只能膜拜顶礼所谓的垃圾堆积衰老学说了，参见后面的对话 de Grey ）。 然而，令人哭笑不得的是当 Great China 回到东土大唐后因为大唐的评价标准等等原因，又只好试图请西洋菩萨保佑，共同发表衰老和抗衰老的 SCN 文章，于是有了下面的与千岁教授之间关于衰老和抗衰老的风云对话 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 ，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 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 8:33PM 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, Id 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,August5,20063:52PM 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,August10,20069:35AM 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 Ulfs 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 its 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 its only one of the damage-related consequences in my subject). Cancer is one of the most dangerous aging-related diseases however, its 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 Id 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 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, Id expect that human beings may make better SENS in the future. Best Regards! Dazhong 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,August10,20067:35PM 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
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, its 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
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 couldhelp 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 Id 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 dont 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, Id 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 Id 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
标签: 广义
