Nature:精准抗衰老研究策略
延长寿命是人类的历史梦想和愿望,延长寿命的有效策略是延缓衰老,但是对衰老的定义和指标并不那么严格,更不容易进行量化测量。


延长寿命是人类的历史梦想和愿望,延长寿命的有效策略是延缓衰老,但是对衰老的定义和指标并不那么严格,更不容易进行量化测量。

从生物学讲,衰老是生物随着时间的推移,自发的必然过程,它是复杂的自然现象,表现为结构和机能衰退,适应性和抵抗力减退。在生理学上,把衰老看作是从受精卵开始一直进行到老年的个体发育史。从病理学上,衰老是应激和劳损,损伤和感染,免疫反应衰退,营养失调,代谢障碍以及疏忽和滥用药物积累的结果。另外从社会学上看,衰老是个人对新鲜事物失去兴趣,超脱现实,喜欢怀旧。

研究衰老必需定义衰老,过去的常用方法是用平均寿命作为金标准,但显然是用最终简单计数,忽视了整个生存过程,采用生存曲线定义平均衰老程度比平均寿命有更全面的信息,因为生存曲线能提供所有被试者的寿命信息。

一个公认的看法是,衰老程度越高,死亡的几率越大。既然生命衰老程度和死亡率密切相关,那么可以利用某一物种的生存数量populations(类似于人口概念)作为指标,分析某种因素对衰老的贡献。最近《自然》发表一篇论文对这种现象的分子基础进行了系统研究,发现了一些有意思的现象,可以作为抗衰老分子机制的研究线索。虽然生存时间的详细记录对小鼠等动物容易获得,但很难进行规模巨大的实验,线虫这种模式生物可以进行大规模记录,但详细准确记录线虫死亡时间却不太容易实现。本研究采用高精准生存率采集技术,对线虫进行大规模观察。结果发现许多干预因素如饮食、环境温度、氧化应激和基因突变等因素都对生存时间有显著贡献,其中关系密切的基因包括热休克因子1 (hsf-1)、低氧诱导因子1 (hif-1)和胰岛素/胰岛素样生长因子1信号通路(daf-2、age-1和daf-16)都对寿命有比较大的贡献(方向不同)。为确定某影响因素的作用,所有手段在整个成年进行持续干预,以确定这些因素对生理性死亡几率的影响。该研究为抗衰老研究提供了一套研究策略,可以利用该技术进行多种抗衰老因素的验证性研究。


成年后环境温度对虫数的影响曲线(可以理解为环境温度对平均寿命的影响)。影响温度分别为(从右到左)20.1°C(黑),23.7,25.2,29.1,30,30.9,31.3,32.5,32.5(黄色)。


不同浓度的氧化物对线虫生存曲线的影响。tBuOOH(过氧化叔丁醇)分别为0  (black)、1.5  (blue)、3  (green)和6 mM (red)。

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  • The temporal scaling of Caenorhabditis elegans ageing

    The process of ageing makes death increasingly likely, involving a random aspect that produces a wide distribution of lifespan even in homogeneous populations1, 2. The study of this stochastic behaviour may link molecular mechanisms to the ageing process that determines lifespan. Here, by collecting high-precision mortality statistics from large populations, we observe that interventions as diverse as changes in diet, temperature, exposure to oxidative stress, and disruption of genes including the heat shock factor hsf-1, the hypoxia-inducible factor hif-1, and the insulin/IGF-1 pathway components daf-2, age-1, and daf-16 all alter lifespan distributions by an apparent stretching or shrinking of time. To produce such temporal scaling, each intervention must alter to the same extent throughout adult life all physiological determinants of the risk of death. Organismic ageing in Caenorhabditis elegans therefore appears to involve aspects of physiology that respond in concert to a diverse set of interventions. In this way, temporal scaling identifies a novel state variable, r(t), that governs the risk of death and whose average decay dynamics involves a single effective rate constant of ageing, kr. Interventions that produce temporal scaling influence lifespan exclusively by altering kr. Such interventions, when applied transiently even in early adulthood, temporarily alter kr with an attendant transient increase or decrease in the rate of change in r and a permanent effect on remaining lifespan. The existence of an organismal ageing dynamics that is invariant across genetic and environmental contexts provides the basis for a new, quantitative framework for evaluating the manner and extent to which specific molecular processes contribute to the aspect of ageing that determines lifespan.

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