细胞生物学210-15-1第十四章： 细胞衰老、死亡与癌变

1,Chapter 14,Cell Aging, Death, and Cancer,2,关于老龄化问题,3,14.1 Cell aging,衰老的概念 现代人类面临着3种衰老： 生理性衰老 病理性衰老 心理性衰老 衰老(aging, senescing)是机体在退化时期生理功能下降和紊乱的综合表现,是不可逆的生命过程。人的衰老与细胞的衰老相关联。,4,衰老基因,5,Hayflick界限,The possibility that the process of cell aging and death is under genetic control was first suggested in 1961 when Leonard Hayflick reported that normal human fibroblasts have a built-in limit to the number of times they can proliferate. His experiments revealed that fibroblasts taken from an embryo and grown in culture divide about 50 times before they deteriorate and die In contrast, fibroblasts taken from adults multiply only 15-30 times before dying. Fibroblasts isolated from young children suffering from Werner's syndrome, a rare disease that causes youngsters to age prematurely, divide only 2-10 times in culture.,6,Microscopic appearance of young and old human fibroblasts Maintained in Tissue Culture (Left) Young fibroblasts that have divided a relatively small number of times in culture exhibit a thin, elongated shape. (Right) After dividing about 50 times in culture, the cells undergo a variety of degenerative changes and eventually die. Note the striking difference in morphology between old and young cells.,7,Further evidence for a relationship between aging and a cells proliferative capacity came with the discovery that the number of times a cell can divide in culture is related to the life span(寿限)of the organism. Thus cells of the Galapagos tortoise, whose maximum life span is about 175 years, divide more than a 100 times in culture before dying, whereas cells obtained from mice, whose life expectancy is only a few years, divide fewer than 30 times,8,Correlation between an Organism's Maximum Life Span and the Number of Times Its Cells Divide in Culture before Dying,9,14.1.3 细胞衰老的特征,细胞内水分减少 色素生成和色素颗粒沉积 细胞质膜的变化 线粒体的变化 细胞核的变化 细胞骨架的变化 蛋白质合成的变化,10,14.1.4 细胞衰老的理论,基因程序理论 损伤积累理论 端粒假说 线粒体损伤论 自由基理论,11,自由基攻击细胞的证据,12,青 春 常 在,13,14.2 Cell death and its regulation,Cell death keeps our hands from being webbed, our embryonic tails from persisting, our immune system from responding to our own proteins,and our brain from being filled with useless electrical connections. Cellular interactions regulate cell death in two fundamentally different ways.,14,First, most cells, if not all, in multicellular organisms require signals to stay alive. In the absence of such survival signals, frequently referred to as trophic factors(营养因子), cells activate a “suicide” (自杀)program. Second, in some developmental contexts, including the immune system, specific signals induce a “murder”(谋杀) program that kills cells. Whether cells commit suicide for lack of survival signals or are murdered by killing signals from other cells, recent studies suggest that death is mediated by a common molecular pathway.,15,14.2.1 细胞死亡的意义,细胞数量控制 细胞质量控制 形态发生,16,Apoptosis during the metamorphosis of a tadpole into a frog,17,Sculpting the digits in the developing mouse paw by apoptosis,18,14.2. 2 细胞的生存,The earliest studies demonstrating the importance of trophic factors(营养因子） in cellular development came from analyses of the developing nervous system. When neurons grow to make connections to other neurons or to muscles, sometimes over considerable distances, more cells grow than will eventually survive. Those that make connections prevail and survive；those that fail to connect die.,19,The function of cell death in matching the number of developing nerve cells to the number of target cells they contact,20,Extracellular survival factors suppress apoptosis,Survival factors, just like mitogens and growth factors, usually bind to cell-surface receptors. Binding activates signaling pathways that keep the death program suppressed, often by regulating members of the Bcl-2 family of proteins. Some factors, for example, stimulate the increased production of apoptosis-suppressing members of this family.,21,Two ways in which survival factors suppress apoptosis,?,22,14.2.3 Programmed Cell Death(PCD),程序性细胞死亡, 又称细胞凋亡(apoptosis) Apoptosis的概念源自于希腊语，原意是指树叶或花的自然凋落； 细胞发生程序性死亡时，就像树叶或花的自然凋落一样，凋亡的细胞散在于正常组织细胞中，无炎症反应，不遗留疤痕。 死亡的细胞碎片很快被巨噬细胞或邻近细胞清除，不影响其他细胞的正常功能。,23,Cell death,24,Apoptotic cells break apart without spewing forth cell constituents that might harm neighboring cells,25,Comparison of cell neorosis and apoptosis,26,Major steps in apoptosis,27,程序性死亡细胞的DNA降解,28,14.2.3 程序性细胞死亡的机理,2002年的诺贝尔生理学和医学奖授予了在器官发育和程序性细胞死亡研究领域中做出奠基性贡献的3位科学家: 英国的Brenner、Sulston和美国的Horvitz 他们创造性地用线虫作为实验模型,实现了对器官发育过程中细胞分裂、分化的原位观察,完成了细胞图谱的绘制, 在此基础上发现并研究了调控器官发育程序性细胞死亡的关键基因及其功能并进一步在高等哺乳动物中发现了相关功能基因。,29,30,雌雄同体的秀丽新小杆线虫,31,The complete cell lineage of C. elegans is known,About 10 rounds of cell division, or fewer, create the adult worm, which is about 1 mm long and 70 m in diameter. The adult worm has 959 somatic cell nuclei (hermaphrodite form) or 1031 (male). 发育过程中有131个细胞进行了程序性细胞死亡 有6对染色体，约3000个基因,32,秀丽新小杆线虫中参与 程序性细胞死亡控制的基因,15个相关基因，分成4类： 2个决定死亡基因，即ces-1(ces表示CE