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饥饿的魔力:改善健康、辅助化疗、逆转糖尿病

2017-04-05 咖喱鸡 科研圈

每个月节食五天,会对健康产生什么影响?这不是减肥达人的经验分享,而是科学家的正经研究:节食与正常饮食的循环交替,可以使体内多种干细胞更加活跃,带来意想不到的好处。

开篇提醒

本文中介绍的研究工作处于基础研究或初期临床阶段。控制体重有益健康,但请不要在阅读本文后擅自绝食。

在成年动物的多种组织和器官中,都存在能够分化形成特定种类体细胞的组织特异性干细胞。小肠上皮的持续更新、破损皮肤的愈合,都是干细胞的功劳。

然而,随着年龄的增长或是某些疾病的到来,组织干细胞的自我更新和分化能力可能受到损害。

癌症患者接受化疗后,经常会产生造血干细胞活性降低、新生血细胞(尤其是淋巴细胞)减少的副作用,由于造血干细胞主要位于骨髓中,这种副作用的学名叫做“骨髓抑制”。

I型和II型糖尿病患者的胰岛组织中,胰岛干细胞分化为b细胞的能力常常下降,发生于b细胞的脱分化和转分化水平同时升高,导致胰岛中能够正常分泌胰岛素的胰岛b细胞数量下降,糖尿病发生。

如果有一种手段,能够重新激活这些病例中的造血干细胞和胰岛干细胞,就可能逆转淋巴细胞或胰岛b细胞不足的症状。美国南加州大学老年医学和生物学教授、长寿研究所所长瓦尔特?朗哥(Valter Longo)多年来的一系列研究工作认为:饥饿,具体来说是模拟饥饿饮食与正常饮食的交替,可能是重新激活干细胞的有效手段。

当人或动物停止进食进入饥饿状态,身体会发生一系列的变化,来应对能量和营养物质的缺乏,尤其是经历长时间饥饿(饥饿状态持续超过24小时)后,身体将进入一种与正常状态差异较大的代谢模式。在这种状态下,动物体内的多种器官会经历质量和体积的减小,组织内干细胞分化形成体细胞的活动也会减弱,然而与此同时,干细胞的自我更新式分裂活动则会加强,当饮食恢复正常,这些活跃的组织干细胞会迅速进行增殖和分化,产生更多的干细胞和体细胞,来逆转饥饿过程中器官的容量衰退。

节食可以减轻化疗副作用的猜想由来已久。饥饿状态下,包括干细胞在内的正常细胞会进入应激状态,这种状态能够帮助它们应对化疗带来的生存压力,并在化疗结束后迅速恢复,使化疗造成的正常细胞损伤尽量减小;但是癌细胞常常丧失了在饥饿状态下产生应激反应的能力,也就比正常细胞更容易被化学疗法彻底清除[1]。

2009年,朗哥教授研究组在 Aging 杂志上发表了一项小型临床研究的结果[2],在这项与医学博士谭雅?多尔夫(Tanya Dorff)合作进行的临床试验中,10位患有不同癌症的志愿者自愿接受化疗前48-140小时、化疗后5-56小时的节食,并对有节食或没有节食情况下进行化疗的副作用进行自我评价。从结果来看,除了饥饿和虚弱之外,节食本身没有给志愿者带来严重的副作用,但可以使部分患者在放疗后的疲劳、衰弱、脱发等副作用略有减轻。然而也必须注意到,在接受统计的14项副作用中,只有疲劳和衰弱两项的减轻程度达到了统计上的显着性差异。

在另一项涉及10名患者的临床试验中,朗哥教授研究组计数了患者在两轮化疗期间的血液中淋巴细胞和髓细胞(髓细胞指非淋巴细胞的血细胞)数量,发现在化疗前进行72小时的节食,可以有效抑制化疗后淋巴细胞数量和淋巴细胞与髓细胞比例的下降,而如果化疗前的节食只有24小时,上述保护效果则不会呈现。

在酵母和小鼠体内,朗哥教授和同事们对上述“节食降低化疗后骨髓抑制”现象的机制进行了研究[3]。结果发现,饥饿可以抑制小鼠体内的 GH/IGF-1 信号通路,从而提高细胞抵抗压力的能力。在造血干细胞中,饥饿则会使造血干细胞的自我更新式分裂(产生新的造血干细胞)和分化式分裂(产生新的血细胞)能力都有所提高,同时使分化比例更加均衡,克服化疗后淋巴细胞与髓细胞比例下降的副作用。也就是说,节食对于化疗后骨髓抑制副作用的降低,正是得益于饥饿对于造血干细胞的激活。

对于身体已经十分虚弱的癌症患者来说,要在化疗前后忍受72小时的节食,可能是一件很不人道也可能带来健康隐患的事情。考虑到这一点,朗哥教授研究组开发了一种“模拟饥饿饮食”,这种为期五天基本为素食的饮食能在降低能量摄入、有效模拟节食所产生的细胞内信号通路改变的同时,为身体补充维生素和矿物质,降低节食给身体带来的负担。

人“模拟饥饿饮食”能量及营养物质含量,小鼠模型中配方有相应改变(表格汉化自参考文献[5])

在美国国立卫生研究院的官方网站上,可以看到限制饮食与乳腺癌、前列腺癌化疗副作用关系的二期临床试验正在进行,项目计划招募120名受试者。

在小鼠模型中,朗哥教授和同事们最近发现,模拟饥饿饮食(4天)和正常饮食(10天)的交替喂养还能产生另外一种效果:刺激胰岛细胞的重编程。这项研究发表于2017年2月23日的 Cell 杂志。在模拟饥饿饮食的喂养之下,小鼠的胰岛中有更多细胞进入活跃状态,并在恢复正常饮食之后分化产生更多能够分泌胰岛素的胰岛b细胞。更令人兴奋的是,在糖尿病小鼠模型中,模拟饥饿饮食与正常饮食的交替喂养可以显着提高小鼠合成胰岛素的能力,控制小鼠血糖。在体外培养的人类胰腺细胞中,朗哥教授也观察到了类似的现象,说明此种饮食模式也可能增强人类糖尿病患者自身合成胰岛素的能力[4]。

针对糖尿病患者的干细胞疗法正在发展,这种疗法希望向患者的胰腺中移植胰岛干细胞,以达到恢复胰岛b细胞含量和胰岛素分泌能力的目的。然而如何激活移植后的干细胞,使它们分化为胰岛b细胞一直是个难题。朗哥教授希望他们的特殊饮食方法可以帮助解决这一问题。

模拟饥饿饮食与正常饮食交替喂养对小鼠胰岛细胞构成的影响(图片汉化自参考文献[4])

对于模拟饥饿饮食和正常饮食的交替,朗哥教授研究组还进行了更加丰富的小鼠模型实验和人类临床试验。人类临床试验中,38名健康受试者被随机分为两组,三个月的模拟饥饿饮食降低了受试者的体重,也同时降低了受试者体内与衰老、癌症、糖尿病、血管疾病相关生物标记分子的水平。小鼠模型中,从小鼠中年时期(16个月)开始进行模拟饥饿饮食和正常饮食的交替喂养,虽然没有提高小鼠的年龄极限(约34.5个月),但有效提高了小鼠的平均寿命。小鼠免疫系统和神经系统的健康程度都在这种饮食的影响下得到了提高,癌症发病率则有所下降[5]。当然,我们也必须注意到这种特殊的饮食方式有效降低了小鼠的体重,而控制体重本身就对健康有着多方位的促进作用。

模拟饥饿饮食与正常饮食交替喂养降低小鼠体重,延长小鼠寿命(图片汉化自参考文献[5])

作为南加州大学长寿研究所所长,瓦尔特?朗哥教授一直是限制饮食与疾病关系这一研究领域中的代表性科学家。此时此刻,相关的动物实验和人类临床试验依旧在向前推进。朗哥教授和他的同事们究竟会创造出怎样更加科学的模拟饥饿饮食食谱,这样的饮食又会在多大的程度上为哪些患者带来福音?我们拭目以待。

原始出处 :

[1]Alessandro Laviano, and Filippo Rossi Fanelli. Toxicity in Chemotherapy — When Less Is More, the New England Journal of Medicine, 14June 2012,N Engl J Med 2012 doi: 10.1056/NEJMcibr1202395

[2]Fernando M. Safdie ,Tanya Dorff ,David Quinn et.al. Fasting and Cancer Treatment in Humans: A Case series report, Aging, 1 December 2012 doi: 10.18632/aging.100114

[3]Chia-Wei Cheng, Gregor B. Adams, Laura Perin et.al.  Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regenerationand Reverse Immunosuppression, Cell Stem Cell, 5 June 2014, doi: 10.1016/j.stem.2014.04.014

[4]Chia-Wei Cheng, Valentina Villani, Roberta Buono et.al.Fasting-Mimicking Diet Promotes Ngn3-Driven b-Cell Regeneration to Reverse Diabetes, Cell, 23 February 2017,doi: 10.1016/j.cell.2017.01.040

[5]Sebastian Brandhorst, In Young Choi, Min Wei et.al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan, Cell Metabolism, 7 July 2015, doi: 10.1016/j.cmet.2015.05.012

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    2017-06-07 Tulipzyz

    节食阶段如何避免低血糖发生?

    0

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    2017-04-10 哈夫

    我认为只有细胞重生才是解决方法

    0

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    2017-04-10 大爰

    学习了增加知识了分享了谢谢!

    0

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    2017-04-09 绛珠草小姐

    学习了,谢谢

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=207853, encodeId=2dff20e8531c, content=节食阶段如何避免低血糖发生?, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ef621732290, createdName=Tulipzyz, createdTime=Wed Jun 07 21:34:08 CST 2017, time=2017-06-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=186457, encodeId=94c818645e5b, content=我认为只有细胞重生才是解决方法, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2017/08/03/49a8b8e59b1110232178c436948997ae.jpg, createdBy=90151681386, createdName=哈夫, createdTime=Mon Apr 10 18:09:52 CST 2017, time=2017-04-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=186345, encodeId=3c3c1863450e, content=学习了增加知识了分享了谢谢!, beContent=null, objectType=article, channel=null, level=null, likeNumber=141, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20200816/e4675a86ea694f12b82202b320dc2654/12f6b900498349e994ce8f516a584d6a.jpg, createdBy=09431951290, createdName=大爰, createdTime=Mon Apr 10 07:35:41 CST 2017, time=2017-04-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=186240, encodeId=710f1862406c, content=学习了,谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=101, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://q.qlogo.cn/qqapp/101296147/1A51842815047D40BFDAA8D69AA8E519/100, createdBy=fd7f2029163, createdName=绛珠草小姐, createdTime=Sun Apr 09 18:28:47 CST 2017, time=2017-04-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=185677, encodeId=f0681856e70f, content=好文章学习了!!, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20200816/e4675a86ea694f12b82202b320dc2654/12f6b900498349e994ce8f516a584d6a.jpg, createdBy=09431951290, createdName=大爰, createdTime=Fri Apr 07 07:16:27 CST 2017, time=2017-04-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1454737, encodeId=45911454e37b8, content=<a href='/topic/show?id=d370101185d7' target=_blank style='color:#2F92EE;'>#饥饿#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=101185, encryptionId=d370101185d7, topicName=饥饿)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=5c9a5593064, createdName=guojianrong, createdTime=Thu Apr 06 15:13:00 CST 2017, time=2017-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=185537, encodeId=e76318553efc, content=学习了谢谢了。, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3zSn0GqHrsfLPeNmuNF9ibgMfMOAs7Iic5MpiaU8RLmRH67xCKuk5wzfhb7G4ib7ia6z9lrnsTicj1nAUfEOMecZDtvvu/0, createdBy=d7f91939785, createdName=186****0580(小山羊), createdTime=Thu Apr 06 10:41:45 CST 2017, time=2017-04-06, status=1, ipAttribution=)]
    2017-04-07 大爰

    好文章学习了!!

    0

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    2017-04-06 186****0580(小山羊)

    学习了谢谢了。

    0

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