论坛题目

SA6 044 衰老不再是生物学的不解之谜

SA6 044 AGEING IS NO LONGER AN UNSOLVED BIOLOGICAL PROBLEM

SA6 044-1 衰老的生物学起因揭秘

L. HAYFLICK - University of California, San Francisco (The Sea Ranch, CA, United States of America)

生命终结可包括四大要素：衰老、寿命决定、老年病以及死亡。生物分子的修复更新系统在生物体的生殖成熟之前占上风。然后，生命天平由于熵增向分子去功能化方向倾斜，从而导致种种衰老表象。组成生命维持的修复和更新系统的生物分子也会同样遭到损伤，恰是这个生命维持系统决定了寿命的长短。调控生物分子合成的基因组间接地决定寿命的长短，这与随机代谢损伤造成的衰老有着根本的区别。衰老性改变直接增加了老年性疾病的易感性。

【译者注:大师中的大师 HAYFLICK 首先提出细胞衰老的概念，但现在最反对用细胞分裂衰老来看整体衰老。本文生命终结四大要素果然为澄清玉宇之举（当然花了美国人民不少美金），但大师关于“熵增”如何造成“分子去功能化”的化学考试似乎并不及格。后面 KIRKWOOD 提出的四大问题可不是随便就可蒙混过关的哟，建议大师还是实事求是，把笔者4年前的文章扛出来当挡箭牌】

（英文原文） 

SA6 044-1 THE CAUSES OF BIOLOGICAL AGEING ARE KNOWN

L. HAYFLICK - University of California, San Francisco (The Sea Ranch, CA, United States of America)

The finitude of life is divided into aging, longevity determination, age associated diseases and death. The efficacy of repair and turnover systems is favored over molecular dysfunction until reproductive maturation when the balance slowly shifts in favor of accumulating dysfunctional molecules caused by increasing entropy (dispersal of energy) and resulting in the aging phenotype. The molecules that compose repair and turnover systems also suffer the same fate as do their substrate molecules. It is these maintenance systems that are the determinants of longevity. The genome indirectly governs the anabolic determinants of longevity. This is fundamentally different from the stochastic, catabolic processes of aging. Age changes simply increase vulnerability to age-associated diseases.

SA6 044-2 理解生物衰老的原因

R. HOLLIDAY - The Australian Academy of Science (Canberra, Australia)

声势浩大的生物学探索使得解读为什么衰老成为可能，我们终于理解了为什么哺乳动物有着不同的最大寿限，也越来越清楚动物存活最好的策略是发育成熟并繁殖但不投入大量资源去无限制地维持机体的存在。这是一个在繁殖和机体维持两者之间的资源投资博弈。如此一来，不同生物种系之间的不同衰老速率的问题就迎刃而解：因为这样，发育和繁殖快者命舜，而发育繁殖慢者寿昌。这个差别源自用于维持机体的资源投入的差别。大量研究表明，机体维持效率与最大寿限有关，因此衰老可被定义为机体维护的最终失败。另外，生物界存在着多种维持生命的机制，这由多种基因和代谢资源的应用方式所决定。宏而论之，与衰老过程相关的不同的退行性改变，有着花样繁多的起因。

【译者注: 澳大利亚衰老研究大师，HOLLIDAY，以动物种系寿差研究，以及基因和发育衰老研究见长，今天终于找到了不同生物种系之间的不同衰老速率的答案。所谓“发育成熟后才有衰老的故事”！中国科学院今天仍在发育和衰老研究上大把烧钱，又被老外给玩了一把】

（英文原文） 

SA6 044-2 UNDERSTANDING THE BIOLOGICAL REASONS FOR AGEING

R. HOLLIDAY - The Australian Academy of Science (Canberra, Australia)

A broad biological approach makes it possible to understand why ageing exists and also why different mammalian species have very different maximum lifespans. It has become apparent that the best strategy for animals’ survival is to develop to an adult and reproduce, but not to invest resources in maintaining the soma indefinitely. There is a trade-off between the investment of resources in reproduction, and the survival time of the soma. At a stroke, this solves the problem of different rates of ageing in different species, because those that develop and reproduce fast have short lifepans, and those that develop and reproduce slowly have long lifespans. This difference is due to the resources invested in the maintenance of the adult soma. There is much evidence that the efficiency of maintenance correlates with maximum longevity. Thus, ageing can be defined as the eventual failure of maintenance. It has also become evident that there are many maintenance mechanisms, and these depend on very many genes, and the investment of considerable metabolic resources. A broad interpretation of the different degenerative changes during ageing should be adopted, with the general conclusion that ageing is multi-causal.

SA6 044-3 衰老问题不再，但更多问题涌现——展望前方的挑战

T. KIRKWOOD - Institute for Ageing and Health, Campus for Ageing and Vitality, University of Newcastle

     一段时期以来，严谨的科学研究甚至因为衰老过程太复杂而欲放弃对其的探索。而今天，我们终于有了一个对于为什么衰老的极好的诠释。衰老是潜移默化的，与身同在的，维持和修复受限造成的损伤积累。这个维持和修复能力，当然受制于大自然的选择（所谓躯体可弃）。然而，衰老之谜告破并不意味着对于其中细节的解读很快就可以被用到生活实际中来。有关衰老机理的内在的复杂性提示需要引入系统生物学等诸多方法去分析：1）细胞维护系统如何以及为什么易受伤害；2）该系统如何被调控；3）损伤如何变成退行性疾病的病理；4）在哪些靶位可以成功地反制损伤。这些挑战性的问题将唤起对延续至今的衰老研究的革命性地改变。

【译者注: 英国衰老研究大师，KIRKWOOD 执语言优势，长期蛰伏，窥探天下，一有机会，下山摘桃，收获渔翁利。但终究是纸上得来，食而不化，曾常常因感叹衰老过程太复杂而提出放弃衰老研究，今天当仁不让，出来分一块奶酪。惨不忍读的是，居然提出四项早已是科学‘大后方’的‘展望前方的挑战’】

（英文原文）

SA6 044-3 AGEING IS SOLVED BUT ITS SOLUTION ALSO HIGHLIGHTS ITS COMPLEXITY - GEARING UP FOR THE CHALLENGES AHEAD

T. KIRKWOOD - Institute for Ageing and Health, Campus for Ageing and Vitality, University of Newcastle (Newcastle upon Tyne, United Kingdom)

After a long period when ageing was dismissed as just too complicated for serious scientific study, we now have a very good idea about the underlying reasons for why ageing occurs and how it is caused. Ageing occurs through the gradual, lifelong accumulation of damage that results from the limited capacity for maintenance and repair, which in turn has been strongly shaped through natural selection (the “disposable soma”). Nevertheless, the fact that the enigma of ageing is now ‘solved’ does not mean that the detailed understanding that will be needed to make practical use of its solution is near at hand. The intrinsic complexity of the mechanisms indicated by the solution requires the adoption of systems-biology approaches to the analysis of: (i) how the networks of cellular maintenance are vulnerable to damage, (ii) how these networks are regulated, (iii) how damage plays into the pathogenesis of degenerative diseases, and (iv) where interventions might most successfully be targeted. These challenges will require radical changes in the ways that ageing has been investigated to date.

Reference: Kirkwood TBL. A systematic look at an old problem. Nature 2008; 45:644-647.