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今天,我们记录了OSKM的进展,并讨论了这种强大的治疗方法如何将细胞重新编程为年轻状态,至少部分地逆转了表观遗传改变的特征和其他特征。

细胞重新编程的诞生

2006,a study by Drs.Takahashi and Yamanaka showed that it was possible to reprogram cells using just four master genes named oct4,SOX2,klf4,and c-myc,或OSKM简称[1]。在此之前,假设卵细胞(卵母细胞)包含一系列复杂的因子,这些因子需要将体细胞重新编程为胚胎细胞。毕竟,将一个老化的卵细胞转化为新的动物并重新编程的壮举必须由卵细胞中存在的许多因素控制,or so they thought.

Takahashi和Yamanaka颠覆了这一想法,因为他们发现用OSKM将成年小鼠成纤维细胞(结缔组织细胞)重新编程为一种称为多能性的胚胎状态,只需要四个因素就可以实现这一转变。a state where the cell behaves like an embryonic stem cell and can become any other cell type in the body.

This discovery paved the way for research into how these programming factors might be used for cellular rejuvenation and a potential way to combat age-related diseases.

Cellular and animal rejuvenation

In 2011,一个法国研究小组,包括Jean-Marc Lemaitre,首次报道使用OSKM进行细胞再生[2]。During their life,cells express different patterns of genes,and those patterns are unique to each phase in a cell's life from young to old;this gene expression profile makes it easy to identify an old or young cell.当时,it was also known that aged cells such as fibroblasts have short telomeres and dysfunctional mitochondria,九个提出的衰老特征中的两个[3]。

Jean-MarcLemaitre和他的同事们测试了OSKM对正常老年人和100岁以上健康人的老年成纤维细胞的影响。他们在OSKM组合中添加了两个额外的多能性遗传因子,即Nanog和Lin28,并研究了这对基因表达的影响,telomeres,以及这些老年人的线粒体。

They discovered that together,这六个因子能够迅速地将这些细胞从老的供体重新编程为多功能状态;these were to be known as induced pluripotent stem cells (iPSCs).研究人员注意到,这些细胞的生长速度比他们重新编程的老年细胞要快;they also had longer telomeres as well as mitochondria that behaved in a youthful manner and were no longer dysfunctional.

研究人员的最后一步是利用其他重编程因子引导ipscs再次成为成纤维细胞。These fibroblasts no longer expressed the gene patterns typically associated with aged cells of this kind but instead had a gene expression profile indistinguishable from those of young fibroblasts.In addition to this,他们还发现端粒长度,线粒体功能,氧化应激水平已全部恢复到年轻成纤维细胞的典型水平。

This was the first evidence that aged cells,even from very old individuals,可以恢复活力,and this was followed by a flood of independent studies confirming these findings in the same and other types of cells.

Could this be done in living animals??

虽然已经证明在实验室的培养皿中可以使老化的细胞恢复活力,许多研究人员认为将其转化为活的动物是不可能的,由于Oskm的连续表达被认为会在动物体内诱发癌症[4]。这将在2016年12月发生变化。

教授胡安·卡洛斯·伊兹皮苏亚·贝尔蒙特and his team of researchers at the Salk Institute reported the conclusion of their study,which showed for the first time that the cells and organs of a living animal could be rejuvenated [5].研究人员制作了这段短片来解释衰老研究的巨大突破。

For the study,研究人员使用了一种专门设计用于比正常小鼠更快衰老的前体小鼠,以及一种设计用于正常衰老的小鼠菌株。两种类型的小鼠在接触抗生素强力霉素时都被设计成表达OSKM。是通过饮用水给他们的。他们让OSKM基因在水中包含强力霉素两天,然后将其去除,使OSKM基因再次沉默。然后,老鼠休息五天,然后再接触强力霉素两天;在研究期间重复这个循环。

经过六周的治疗,which steadily reprogrammed the cells of the mice,the researchers noticed improvements in their appearance,包括减少与年龄相关的脊柱弯曲。Some of the mice from both experiment and control groups were also euthanized at this point so that their skin,kidneys,胃and spleens could be examined.对照组小鼠与治疗组相比出现了一系列与年龄相关的变化,which had a number of aging signs halted or even reversed,包括一些表观遗传改变。与未经处理的前体对照小鼠相比,经处理的小鼠的平均存活时间也增加了50%。应该注意的是,并非所有老化迹象都受到部分重新编程的影响,and if treatment was halted,衰老的迹象又出现了。

也许最重要的是,当以这种周期性方式进行的部分重编程重置了一些表观遗传老化迹象时,它没有重置细胞分化,这会使细胞恢复到胚胎状态,并忘记它以前是什么样的细胞;你可以想象,这对活生生的动物来说是件坏事。

最后,not only did OSKM expression at least partially rejuvenate cells and organs in progeric mice,but it also appeared to improve tissue regeneration in the engineered 12-month-old normally aging mouse group.研究人员观察到,部分重编程提高了这些小鼠在胰腺组织再生的能力,导致β细胞增殖增加;此外,骨骼肌中的卫星细胞增多。这两种类型的细胞在老化过程中都会下降。

未来的潜力和挑战

By far,将部分细胞重新编程转化为人类的最大障碍是需要找到一种方法来激活细胞中的OSKM因子,而无需让我们的身体对强力霉素等药物作出反应。这样做可能需要我们开发能够激活OSKM的药物,编辑我们身体中的每个细胞以对一种特殊的化合物(如强力霉素)作出反应,这将是非常具有挑战性的,尽管可能,或者甚至编辑种系,使我们的孩子出生时对所选择的化合物有这样的反应,这是一个道德梦魇,更不用说成功做到这一点的技术挑战了。Whatever the solution is,它需要实用。

另一个主要障碍是要找到一种适合长期使用的方法,不需要不断的维护,lest the aging signs return rapidly,就像在治疗中断的老鼠身上一样。尽管有理由相信,考虑到老鼠和人类的新陈代谢以及我们卓越的修复系统之间的差异,人类的这些症状不会恢复得那么快,它很可能会在适当的时候返回。So,找到一种经济有效的方法来保持循环处理的进行是至关重要的;这可能通过药物或短暂的基因治疗来实现。

结论

Assuming that these barriers can be overcome,生物技术的迅速发展提供了一个理由,让我们相信他们会,因此,部分细胞重编程可以有效地预防甚至治愈衰老疾病。

我们可以预见到早期,first-pass use of this approach in a preventative way: older people at risk of age-related diseases could be given partial reprogramming in order to halt or at the least significantly slow down this aspect of aging and thus reduce their risk of developing age-related diseases.

More refined stages may see it being used in a more focused manner to repair a certain organ or tissue damaged by injury or disease.In another,更先进的,脚本,为了彻底预防老年病,保持老年人的健康,可以尝试逐步实现老年人的全身康复。积极主动,能够继续享受生活。

The rapid progress of medical technology could potentially mean that such cellular reprogramming therapies may become available in the not too distant future.我们当然希望如此。

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〔1〕Takahashi,K.山本,S.(2006).Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.细胞,126(4),663-676.

[2] Lapasset,L.,MilhavetO.PrieurA.Besnarde.Babled,A.Aït-Hamou,N.… & Lehmann,S.(2011).通过多能状态重新编程,使衰老和百岁人类细胞恢复活力。基因与发育,25(21),2248~2253。

[3]L_Pez OT_n,C.,布拉斯科MA.Partridge,L.,塞拉诺M.& Kroemer,G.(2013)。衰老的特征细胞,153(6),1194-1217。

〔4〕阿巴德,M.MosteiroL.,PantojaC.,CanameroM.人造丝,T.,Ors一、…和曼萨那勒斯,M(2013)。体内重编程产生具有全能性特征的畸胎瘤和iPS细胞。Nature,502(7471),340。

〔5〕Ocampo A,Reddy P,Martinez-Redondo P,Platero-Luengo A,Hatanaka F,Hishida T,Li M兰德Kurita M贝雷特E阿劳卡T瓦兹奎兹·费雷尔E,多诺索德,罗马JLXJ,罗德里格斯·埃斯特班C,NuNeez G,Nu_ez Delicado E,Campistol JM,吉伦一世Guillen P伊兹皮苏阿-贝尔蒙特JC。通过部分重编程在体内改善与年龄相关的特征。细胞。2016;167:1719—33。

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史蒂夫·希尔

As a scientific writer and a devoted advocate of healthy longevity and the technologies to promote them,Steve为社区提供了数百篇教育文章,interviews,播客,helping the general public to better understand aging and the means to modify its dynamics.他的资料可以在H+杂志上找到,长寿记者,Psychology Today and Singularity Weblog.他是这本书的合著者。预防所有人老化”—大众探索循证方法延长健康生活的指南(出版)。
  1. 1月17日,二千零一十九

    好文章!有什么关于OSKM适合(或不适合)的想法吗?)使用SENS ESQ损伤修复方法来治疗老化??

    It seems like getting OSKM to really work could potentially skip some of the required SENS steps??

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