世界生命科学前沿动态周报（三十四）

（11.29 -- 12.05 / 2010）
美宝国际集团:陶国新 

　　本周动态包括以下内容：老鼠实验表明修复端粒可以逆转衰老；发现新的抗癌免疫细胞；Lkb1促进造血干细胞生存；成熟血细胞与其亲代干细胞的信息反馈；分子“开关”影响衰老和代谢疾病；共生菌影响果蝇的交配倾向。

1. 老鼠实验表明修复端粒可以逆转衰老
【摘要】
　　据香港《文汇报》11月30日报道，哈佛科学家最近破天荒地令年老的老鼠器官获得新生，成功逆转衰老过程，这项突破成果或有望防治脑退化症(老人痴呆症)、糖尿病和心脏病等疾病，甚至有望打开永恒青春的奥秘，进一步迈向研制“长生不老药”。科学杂志《自然》网站28日刊登美国哈佛医学院的科研报告，研究员饲养了一些经基因改造的老鼠，令它们因缺乏“端粒酶”(telomerase)而未老先衰，出现嗅觉衰退、脑部缩小、不育、肠部和脾脏受损等疾病，使它们皮肤、大脑、内脏和其它器官老化。
所谓“端粒”，是指染色体末端的DNA重复序列，作用是保持染色体的完整性。“端粒”的长度反映着细胞复制史及复制潜能，被称作细胞寿命的“有丝分裂钟”。报道称，科研人员将这些老鼠分为两组，把一种名为“4-羟基他莫昔芬”的定时释放药物，植入其中一组老鼠的皮下，重启它们体内休眠的“端粒酶”基因。结果在短短1个月内，注射药物的老鼠体内长出许多新的细胞，主要器官运作功能改善，身体差不多完全“返老还童”，雄性老鼠更恢复生育功能。注射药物的实验鼠最终活到正常鼠的寿命，但并不比普通鼠寿命长。
进行研究的德皮尼奥博士表示，实验鼠对人类而言，就像一个40岁的人，身体未老先衰像80多岁的老人，而这项实验逆转衰老过程，把他变回50岁一般。德皮尼奥说：“这些是严重衰老的动物，但经过一个月治疗后，它们已有具体康复迹象，包括脑部长出新的细胞。”他指出，这是首次有老鼠实验成功把衰老过程逆转，意味着一些老化的器官也有“重生”的可能。
不过，要把这一科技应用于人体身上将会较为困难，老鼠一生中都能制造端粒酶，但是人类到成年后便会自动“关掉”这种基因，从而阻止细胞增长失控，以免转化成癌症。因此，提升人体的“端粒酶”水平虽然或有助减缓衰老速度，但同时增加患癌的风险。德皮尼奥认为，“TERT”疗法如果是分阶段进行，和只用于身体没有癌细胞及较为年青的人身上，疗法或对人体安全。牛津大学生物化学家考克斯认为，这项研究“非常重要”，证明原则上短期恢复成人体内的“端粒”，能令年老的组织重生和恢复生理功能。（来源：中国新闻网 发布时间：2010-11-30 11:05:34）

【点评】
　　该基因改造老鼠试验第一次在动物身上实现了通过修复端粒而“返老还童”，虽然在正常衰老的老鼠身上还未有研究以及应用在人体上还遥遥无期，但是它证明了复原端粒可以逆转衰老。这在动物实验方面为人体再生复原科学再添有利证据，证明衰老组织是可以复原到年轻态的。

【原文摘录】Nature advance online publication doi:10.1038/nature09603
Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice
Mariela Jaskelioff, Florian L. Muller, Ji-Hye Paik, et al.
An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo1. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, Dcx+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.

2. 发现新的抗癌免疫细胞

【摘要】
　　丹麦科研人员不久前发现一种新的免疫细胞能协助抵抗癌症。他们正据此研制一种新型癌症疫苗，目前正在进行临床试验。人体免疫抑制细胞和癌细胞可以产生一种特殊的双加氧酶，来抑制免疫细胞的攻击性，使其缺乏足够攻击力抵抗癌细胞侵袭，甚至还会被癌细胞吞噬。双加氧酶的存在使现有癌症疫苗的有效性大打折扣。丹麦海莱乌医院癌症免疫治疗中心的研究者在最新一期美国学术刊物《血液》上报告说，他们发现人体免疫系统中存在一种此前未知的细胞，这种细胞可以杀死那些产生双加氧酶的细胞。新发现的细胞在消灭免疫抑制细胞的同时，还能直接攻击癌细胞。
领导这项研究的马斯·哈尔·安德森说，研究小组正在研制一种新型癌症疫苗，通过增加上述抗癌细胞的数量，提高机体免疫系统的攻击力，从而抵抗癌症。海莱乌医院正用新疫苗对一些肺癌患者开展临床试验，目前的治疗效果明显好于常规疗法。研究小组认为，从原理上说，这种可有效抑制双加氧酶产生的癌症疫苗有望与其他疗法协同治疗多种癌症。（来源：新华网 2010-12-2 10:33:22）

【点评】
新的免疫细胞既能消灭免疫抑制细胞，还能直接攻击癌细胞，对于对抗癌细胞是好消息。但是另一方面，新的免疫细胞的数量和活力需要小心控制，是否会导致自体免疫问题也需要进一步澄清。

【原文摘录】Blood, Nov 2010; doi:10.1182/blood-2010-06-288498
Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators
Rikke Bæk Sørensen, Sine Reker Hadrup, Inge Marie Svane, et al.
Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathological settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in cancer patients but also in healthy individuals. We show that the presence of such IDO-specific CD8+ T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO+ suppressive cells. This had profound effects on the balance between IL-17-producing CD4+ T cells and regulatory T cells. Furthermore, this caused an increase in the production of the pro-inflammatory cytokines IL-6 and TNF- while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (i.e. the TLR9 ligand CpG, soluble CTLA4 or IFN-) induced IDO-specific T cells among PBMC from cancer patients as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies where IDO play a significant regulatory role. The present describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells "supporter T cells".

3. Lkb1促进造血干细胞生存

【摘要】
　　造血干细胞对高能和氧化压力非常敏感，对它们的静止与增殖之间的平衡进行调控是响应代谢压力、同时保持其长期再生能力所需要的。新的研究表明，Lkb1肿瘤抑制因子和代谢传感器在维持造血细胞的能量平衡中起关键作用，被发现是细胞周期调控及能量平衡所必需的，造血干细胞细胞周期调节和生存对Lkb1的依赖性要强于其他造血细胞。

【点评】
　　对造血干细胞的生命属性和代谢机制又多了些了解。

【原文摘录】Nature doi:10.1038/nature09571
Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells
Daisuke Nakada, Thomas L. Saunders & Sean J. Morrison
Little is known about metabolic regulation in stem cells and how this modulates tissue regeneration or tumour suppression. We studied the Lkb1 tumour suppressor and its substrate AMP-activated protein kinase (AMPK), kinases that coordinate metabolism with cell growth. Deletion of the Lkb1 (also called Stk11) gene in mice caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion and pancytopenia. HSCs depended more acutely on Lkb1 for cell-cycle regulation and survival than many other haematopoietic cells. HSC depletion did not depend on mTOR activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP levels. HSCs deficient for two catalytic α-subunits of AMPK (AMPK-deficient HSCs) showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell-cycle regulation between HSCs and some other haematopoietic progenitors.

4. 成熟血细胞与其亲代干细胞的信息反馈

【摘要】
　　澳大利亚墨尔本Walter and Eliza Hall Institute的一项最新研究表明成熟血细胞能够与亲代干细胞“沟通”，并影响其行为。机体内血细胞反馈环的发现为研究干细胞机能紊乱引起的疾病及开发新的治疗方法开辟了新道路。研究结果发表在11月29日的PNAS上，揭示了从前未知的血细胞间的相互关系。
来自分子医学系的Carolyn de Graaf博士和Doug Hilton教授以及来自癌症和血液病学系的Warren Alexander领导了该项研究。“我们知道血液干细胞可生成所有类型的成熟血细胞。科学家们一直猜想是外部的因素调控了血细胞生成，并且两个群体相互孤立存在，”Hilton教授说：“然而新研究表明成熟细胞事实上可反作用于干细胞，改变其基因表达以及影响它们的行为。”研究人员发现血细胞异常可引起反馈环失调，进而对血液干细胞产生影响。研究人员在动物模型中研究了一种抑制血小板生成的转录因子Myb，在检测Myb缺失对细胞的影响时发现了这一现象。de Graaf博士说Myb基因缺失可导致动物血液中产生高水平的血小板，从而引起维持干细胞的信号途径发生改变。“当信号途径发生改变时，这些干细胞不再维持在一种‘静止状态’，而是在不断地循环，生成成熟干细胞，”de Graaf博士说：“最终干细胞会耗尽，由于缺乏足够的干细胞生成新的红细胞和白细胞，从而导致机体血液疾病发生。”此外，研究人员还利用新一代的基因组技术鉴定了缺陷信号所致的血液干细胞中的基因标记。这些基因标记有可能在将来用于诊断和辅助疾病治疗。“如果我们能够了解这些基因在干细胞维持和血细胞生成中的重要作用，我们就能够找到一些新途径提高移植技术和血液疾病的治疗，”de Graaf博士说。Hilton教授认为新发现将使那些干细胞衰竭的患者受益。“我们所要做的事情就是确定这些干细胞的衰竭是否是由于成熟血细胞和干细胞之间的错误沟通所致，这些发现将有可能促使我们找到新的途径治疗这些疾病，”Hilton教授说。（Science Daily 2010-12-1 10:23:13 ）

【点评】
　　干细胞的活动规律受到机体的系统调控，成熟细胞会反馈信息到调控体系来调节干细胞的活动。说明一个体系里的上下游部分不是相互独立的，一个整体里的各个体是相互关联的，一个个体的异常影响的不仅仅是自身。   
【原文摘录】PNAS  doi: 10.1073/pnas.1016166108
Regulation of hematopoietic stem cells by their mature progeny
Carolyn A. de Graafa,b, Maria Kauppic, et al.
Thrombopoietin (TPO), acting through its receptor Mpl, has two major physiological roles: ensuring production of sufficient platelets via stimulation of megakaryocyte production and maintaining hematopoietic stem cell (HSC) quiescence. Mpl also controls circulating TPO concentration via receptor-mediated internalization and degradation. Here, we demonstrate that the megakaryocytosis and increased platelet mass in mice with mutations in the Myb or p300 genes causes reduced circulating TPO concentration and TPO starvation of the stem-cell compartment, which is exacerbated because these cells additionally exhibit impaired responsiveness to TPO. HSCs from MybPlt4/Plt4 mice show altered expression of TPO-responsive genes and, like HSCs from Tpo and Mpl mutant mice, exhibit increased cycling and a decline in the number of HSCs with age. These studies suggest that disorders of platelet number can have profound effects on the HSC compartment via effects on the feedback regulation of circulating TPO concentration.

5. 分子“开关”影响衰老和代谢疾病

【摘要】
　　来自Harvard School of Public Health的科学家发现一种分子“开关”能够关闭某些细胞进程来抵抗衰老和代谢疾病。尽管还需要更多的研究，这一发现很可能有助于开发新的途径来终止或减慢诸如2型糖尿病和心脏病等代谢疾病的进展。用基因改造的老鼠模型，研究衰老过程中转录辅抑制物SMRT (silencing mediator of retinoid and thyroid hormone receptors)蛋白的作用，发现衰老细胞积累了更多的SMRT蛋白。在大多数代谢组织中SMRT的表达和结合到PPAR受体随年龄增加。SMRT通过RID1和RID2两个结构域调节核受体信号途径。通过基因工程选择性失活RID1，使SMRT结合转移到RID2相关核受体，增强了细胞对氧化损伤的敏感性，引起早衰和相关代谢疾病伴有线粒体功能降低和抗氧化基因表达。

【点评】
　　该研究丰富了对于衰老的理解和抗老化途径的探索。

【原文摘录】Cell Metabolism, 2010; DOI: 10.1016/j.cmet.2010.11.007
Nuclear Receptor Corepressor SMRT Regulates Mitochondrial Oxidative Metabolism and Mediates Aging-Related Metabolic Deterioration.
Shannon M. Reilly, Prerna Bhargava, Sihao Liu, et al.
The transcriptional corepressor SMRT utilizes two major receptor-interacting domains (RID1 and RID2) to mediate nuclear receptor (NR) signaling through epigenetic modification. The physiological significance of such interaction remains unclear. We find SMRT expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Genetic manipulations to selectively disable RID1 (SMRTmRID1) demonstrate that shifting SMRT repression to RID2-associated NRs, notably PPARs, causes premature aging and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. SMRTmRID1 cells exhibit increased susceptibility to oxidative damage, which could be rescued by PPAR activation or antioxidant treatment. In concert, several human Smrt gene polymorphisms are found to nominally associate with type 2 diabetes and adiponectin levels. These data uncover a role for SMRT in mitochondrial oxidative metabolism and the aging process, which may serve as a drug target to improve health span.

6. 共生菌影响果蝇的交配倾向

【摘要】
　　通常认为交配倾向是在物种形成早期就确立的事情。该研究通过果蝇实验发现体内共生菌也会影响果蝇交配倾向。通过用不同食物喂养由同一群果蝇分成的两组，而后混合两组果蝇，发现果蝇倾向于和同组的果蝇交配，该倾向从第一代可持续至少37代。而喂食中加入抗生素能消除这种倾向性，表明是果蝇菌群的缘故。进一步研究表明这些共生菌会改变果蝇表皮的性信息素水平从而影响其交配倾向。

【点评】
越来越多的研究表明共生菌群对动物有着重要影响。

【原文摘录】PNAS  DOI: 10.1073/pnas.1009906107
Commensal bacteria play a role in mating preference of Drosophila melanogaster
G. Sharon, D. Segal, J. M. Ringo, et al.
Development of mating preference is considered to be an early event in speciation. In this study, mating preference was achieved by dividing a population of Drosophila melanogaster and rearing one part on a molasses medium and the other on a starch medium. When the isolated populations were mixed, “molasses flies” preferred to mate with other molasses flies and “starch flies” preferred to mate with other starch flies. The mating preference appeared after only one generation and was maintained for at least 37 generations. Antibiotic treatment abolished mating preference, suggesting that the fly microbiota was responsible for the phenomenon. This was confirmed by infection experiments with microbiota obtained from the fly media (before antibiotic treatment) as well as with a mixed culture of Lactobacillus species and a pure culture of Lactobacillus plantarum isolated from starch flies. Analytical data suggest that symbiotic bacteria can influence mating preference by changing the levels of cuticular hydrocarbon sex pheromones. The results are discussed within the framework of the hologenome theory of evolution.