生殖系的能量学和老化与雌性不育 Germline energetics, aging,and female infertility 《细胞代谢》 蒂力乔纳森 美国波士顿,马萨诸塞州综合医院,文森特生殖生物学中心, 美国波士顿,马萨诸塞州综合医院,妇产生殖科 森克莱尔大卫 美国波士顿,哈佛医学院,老化生物机理格伦实验室 美国波士顿,哈佛医学院,遗传学部 澳大利亚悉尼,新南威尔士大学医学部 通讯邮件: jtilly@partners.org (J.L.T.) 和 david_sinclair@hms.harvard.edu (D.A.S.) 尽管卵巢比其它大多数器官都更早的失能,可是与卵巢老化相关之代谢作用的工作还很少。近期的资料表明雌性哺乳动物在成年阶段可以通过生殖系干细胞的活化而定期的产生新的卵母细胞。有鉴于此,我们将生殖系统视为一个可以用来理解老化与代谢之联系的有力的临床相关的模型,在此我们探讨卵母细胞和它们的前体细胞应该如何在代谢上调整以维持和增进女性的卵巢功能和生殖力的最新理念。 前言 生命历史的早期,生物进化出了一种细胞可以在特定环境下最大化后代数量的复杂信号网络。这一至今仍存在于细胞中的古老网络,可在环境适宜时促进生长和生殖,并在环境苛刻时抑制生长生殖 (Kirkwood, 1987)。这一系统可在很大程度上解释为何很多物种可通过限食(DR)使健康受益,以及机体如何适应供给和能量需求的变化。随着我们对这一挣挫求活的网络更加了解,我们将逐渐可能用药物对其进行刺激。确实,一些模仿限食的分子药物正在研发中,以期解决那些与老化相关的病患,例如二型糖尿病、炎症和肌肉变性(muscledegeneration)(Blum et al., 2011; Chiba et al., 2010)。尽管这一领域飞速发展,但是与生殖潜能相关的这一方面却被忽视了。 卵巢作为研究老化的模型 哺乳动物卵巢的功能单元是被称为卵泡的多细胞结构(Gougeon, 1996)。每个卵泡是由阻滞在第一次减数分裂前期的女性生殖细胞卵母细胞,以及可以支持卵母细胞生长的围绕卵母细胞的单层或多层体细胞。起始于由卵母细胞和单层颗粒细胞组成的阻滞(原始)卵泡,每个卵泡皆试图完成后续的发育阶段,这需要颗粒细胞群体的大规模复制,以及被名为膜间质细胞(thecainterstitial cells)的第二类体细胞类型。通过复杂的细胞互作,卵母细胞获得了发育能力,因此可在排卵受精后启动胚胎发生(Matzuket al., 2002; Orisaka et al., 2009)。与此同时,卵泡体细胞变得对循环因子高度敏感,并分泌一系列激素,这些激素既可以作用于卵巢本部,也可以作用于许多其它组织,包括脑、骨、皮肤和心血管系统(Buckler,2005; Prior, 1998)。 以其对雌性性腺分泌功能和生殖力之维持的重要作用,卵巢的生命期由它具有的卵泡数量决定,这也被称为“卵巢储备”。自1950年代起,人们认为大多数雌性哺乳动物在大约出生时,其具有的卵巢储备无法更新(Zuckerman,1951)。随着对生长的激发,储备的每个卵泡,或者完成成熟,在排卵时释放其包含的卵母细胞,或者走向被称为闭锁(atresia)的退化过程。以往对小鼠、大鼠和人的卵巢研究表明,实际上绝大多数卵巢中的卵泡都走向了闭锁,最终导致卵巢储备在离个体死亡还很久的时候就消耗完了(Faddyet al., 1992; Gosden et al., 1983; Richardson et al., 1987)。更现代的研究工作表明,大规模卵母细胞丢失主要因为凋亡,它与其它器官系统的凋亡调控有很多相似之处,涉及一系列基因和信号通路(Tilly,2001)。卵泡的损失会被化疗、辐射和环境毒物等外部诱因急剧加速(Tilly, 2001),导致与自然月经相关的许多健康异况提早发生。 哺乳动物卵巢储备不可以耗竭的观点是基于出生后卵巢组织不具备可复制生殖细胞形成新的卵母细胞的假设的。这一假设与雌性非哺乳动物物种的观察结果完全相反,这些非哺乳动物包括苍蝇和鱼等,它们具有可以在成年时支持卵母细胞更新的生殖系干细胞(GSC)(Kirilly and Xie, 2007;Nakamura et al., 2010)。然而,在2004年发表的一份研究提供了数条证据,认为小鼠出生后的卵巢中存在雌性GSC(为了与雄性睾丸中存在的精原干细胞(spermatogonial stem cells)的命名法相匹配,更确切的名字应该是卵原干细胞(oogonialstem cells,OSC)),可以分化为卵母细胞并形成卵泡(Johnsonet al., 2004)。这些发现,因为有悖于通识,因此遭到很多科学家的质疑(Powell, 2007)。 尽管如此,卵巢储备是否可被补充成为许多实验室研究的焦点(Tilly et al., 2009)。经过这些努力,终于有三家实验室分别用不同的策略,从新生的和成年的小鼠卵巢中分离得到了卵原干细胞(Pacchiarotti et al., 2010; White et al., 2012; Zou et al., 2009),并从成人卵巢中分离得到一种与卵原干细胞类似的可转为卵母细胞的生殖祖细胞 (White et al., 2012)。除此之外,小鼠的研究还实现了将获得的卵原干细胞重新送回成体卵巢,这些细胞可以分化而形成卵泡包裹的卵母细胞,并经成熟、排卵和受精而产生存活的胚胎和后代(White et al., 2012; Zou et al., 2009)。在低等生物中,这种生殖细胞的功能是与营养供应相连的(McLeodet al., 2010; Jasper and Jones, 2010),而且这种功能甚至可以控制机体老化的步伐(Hsinand Kenyon, 1999; Flatt et al., 2008)。正因如此,这些逆天的研究可以提供一个框架,将哺乳动物卵原干细胞的内容带到关于如何调控雌性生殖力和卵巢生命期的讨论中。 限食、长寿基因与雌性生殖力 坚持限食的小鼠和大鼠或者生殖力下降,或者完全不育 (Selesniemi et al., 2008;Visscher et al., 1952)。类似的,因为自我强制限食而体重降到理想体重之下的女性,其生殖力出现下降 (Bates, 1985),并且出现与卵巢缺陷女性类似的促性腺激素水平的显著变化。限食对生育力的负面影响已经被普遍认知,但是限食对生育力的正面作用却鲜为人知。大约一百年前,在大鼠上的研究发现,“绝经期被(限食)推迟,远远后于正常绝经的时间” (Osborne et al., 1917)。虽然啮齿类并不经历真绝经,这一研究,以及后续的许多啮齿类的研究,清楚的说明了适量的限食可以延长哺乳动物功能性卵巢的生命期。 乍一看,这一发现似乎同于“有限体细胞理论(dispoable soma theory)”,有限体细胞理论认为物种的寿命是其在进行生殖和维持体细胞之间如何分配其资源的直接结果 (Kirkwood and Holliday,1979)。但实际上,它与这一理论不同。通过对小鼠生存和生育的生理学和生态学数据的研究,以及对此所做的生命史建模,研究者认为小鼠限食所致的生育力短暂停止,是为了腾出精力维持生存力和生育力,以期在饥荒时刻过后得以恢复 (Shanley and Kirk- wood,2000)。 与这一观点一致的是,许多物种都可以在不牺牲生殖潜力的情况下延长寿命,包括 Podospora anserine (vanDiepeningen et al., 2010),酿酒酵母 (Jiang et al., 2000),秀丽隐杆线虫 (Wood et al., 2004),和果蝇 (Grandisonet al., 2009)。对于线虫,饥饿可以通过强力压制生殖干细胞来阻断生殖,并在重新饲喂是恢复配子发生以生育后代 (Angelo and Van Gilst,2009)。对于果蝇,改变特异氨基酸之均衡可以延长寿命且不影响生育力 (Grandison et al., 2009)。 可以模仿限食效果的SIRT1激活剂白藜芦醇( resveratrol),可以增进线粒体功能并可延长秀丽隐杆线虫和果蝇的寿命,使得每个个体产出的卵的数量增加 (Wood et al., 2004)。综合这些数据可知,在逆境中,许多生物在抑制生育力的同时也将保护生殖系细胞的防御系统升级。当环境改善时,生殖力就可以恢复。 哺乳动物可能也存在类似机制。如对性成熟小鼠逐步的减少四成卡洛里摄入量,虽然在限食过程中,这些小鼠的生殖能力受损,但与连续自由饮食(ad libitum fed,AL)的对照组相比,限食小鼠在恢复自由饮食后,其保持生殖力的时间要比自由饮食小鼠长很多 (Selesniemi et al., 2008) 。此外,在自由饮食小鼠每窝产仔数量接近于零的鼠龄时,经过数月限食而后恢复自由饮食的小鼠的胎仔数依然维持在很高的水平 (Selesniemi et al., 2008) 。这些啮齿类的研究说明,如果是适量的限食,或者中度限食后恢复正常饮食,生殖力不会受到负面影响,而且还可以被保持的更久。与这一观点相符的是,因限食而不育的女性在其恢复正常饮食后,其生殖力可快速恢复 (Bates, 1985) 。一个有益的尝试是,在正常食物中添加模仿限食的物质,以此激活生殖细胞防御网络,借之维持或保存卵母细胞的质量并延长生育期限。 以上发现强调,在研究雌性生殖力时,需要更好的确定机体响应限食或限食模仿物的分子机制,并对其进行验证。最初的关于限食是通过简单的降低代谢率或降低生成的活性氧(ROS)而被动发挥作用的设想现在大多被抛弃了。其实限食响应是一个本质上不同的模型,限食是通过主动激活一个机体在进化中得到的可在逆境中保证自身存活的响应而发挥作用的(Guarente,2008; Kirkwood, 2005)。限食响应的核心是所谓的“寿命调控通路(longevityregulatory pathway)”(图一)。 \0 \0 图一:促进健康和苟活的长寿通路。近来数据显示环境因子可通过调控代谢感知子,如SIRT1和AMPK等,来改变老化的进度。这些感知子与mTOR和胰岛素/IGF-1互作来控制细胞的生长和能量吸收。肥胖和老化降低了NAD+/NADH和 AMP/ATP的比例,而限食则相反。在其下游的诸多保护机制中,转录因子PGC-1α和FOXO的激活导致线粒体的功能和胁迫抵抗。综合起来,这个网络以线粒体为关键点调控细胞对胁迫、营养和代谢需求的响应。 虽然在数十个物种中已发现数以百计的长寿基因,但是特异调控限食响应的关键调控子只涉及四个信号通路。它们就是胰岛素/类胰岛素生长因子传信、哺乳动物雷帕霉素靶点(mTOR)通路、腺苷酸活化蛋白激酶(AMPK)和司徒林(Sirtuin)。除了司徒林最初是以基因沉默调控子的角色被发现的(Klar et al., 1979) ,其它通路在被怀疑与衰老相关之前数十年都被认为参与感知营养水平。近年来发现这四个通路联合起来形成一个复杂的调控网络,这一网络可以响应细胞内外环境的变化,并通过保存或利用能量来实现细胞对组织损伤、坏死和疾病的抵御,这就将代谢和衰老两个领域整合了起来(Canto and Auwerx, 2009; Katewa and Kapahi, 2011) 。 但我们可以预想,至少这些通路的某几个可能对雌性生殖细胞是有用的,但对于雌性生殖细胞,关于通路的研究主要集中在卵母细胞生长的激活而不是卵的质量 (Reddy et al., 2008; Li et al., 2010)。一些例外包括:mTOR与PI3K/PTEN通路的整合,PI3K与mTOR整合调控卵母细胞的减数分裂进程,而PTEN与mTOR整合调控受精卵的胚胎基因组激活 (Lee et al., 2012; Zheng etal., 2010) 。此外,小鼠卵母细胞表达了许多司徒林家族成员。其中值得关注的是,鼠卵中司徒林三(sirtuin-3)的功能缺失使线粒体活性氧产量增加,并妨害了受精后植入前胚胎发育 (Kawamura et al., 2010) 。 饮食对卵母细胞质量的影响 虽然早期的报道认为减少食物摄入可以延缓大鼠和小鼠卵泡的消耗 (Lintern- Moore and Everitt, 1978; Nelson et al.,1985),但是限食后自由饮食的大龄雌性,和连续自由饮食的同龄雌性类似,它们的卵巢储备,相对于年轻成年雌性而言,都出现了显著降低(Selesniemiet al., 2008)。因此,限食对雌性生育繁殖和子代存活的益处应该不是通过维持卵巢储备量实现的。虽然,限食带来的益处可能部分的是由于,它改善了高龄雌性的子宫能力来建立并支持妊娠,但人类的卵母细胞捐献研究表明,高龄相关的不育,可以通过借用年轻成年捐助者的卵母细胞来有效的克服(Kleinand Sauer, 2002; Sauer et al., 1992)。事实上,既然女性在六十余岁时还可以作为代孕者完成妊娠和生产(Paulsonet al., 2002; Sauer et al., 1995),那么决定女性成功妊娠率的那个最重要的因子,就是卵母细胞质量而不是子宫缺陷(Navotet al., 1991)。 具有发育能力的卵子的产生,需要减数分裂的十足完成,能够在精子钻入后将染色体的数目减半。受精时雌雄原核的融合使新形成的胚胎恢复了正常的染色体数目。不幸的是,随着年龄增长,减数分裂的细胞周期有很大的错误倾向,导致非整倍型卵母细胞的形成 (Hassold and Chiu, 1985; Hassold and Hunt, 2009;Hunt, 1998)。虽然女性在盛龄初期排卵依然在持续,但是随着女性年龄的增大,卵母细胞质量开出出现问题,受精和胚胎发育失败、流产和出生缺陷的风险加大。最广为人知的雌性老化影响是在怀孕子代中21三体(唐氏综合征)的风险急剧增大,其发生在妙龄女性中占临床妊娠的比例大约2%,而在盛龄女性则占临床妊娠的30%甚至更多(Hassold and Chiu, 1985)。 由于越来越多的女性在其生育期的后半段怀孕,因此克服这种由年龄增长引起的卵母细胞质量的降低成为临床上更加迫切的事情(Matthews and Hamilton, 2009; Ventura, 1989) 。与这一问题纠缠在一起的是女性生育力中存在的固有问题,即便使用了诸如体外受精等辅助生殖技术。因为造成卵母细胞质量随年龄下降的因素有很多,人类生殖领域里很多人认为任何单一或简单药物介入都难以解决这一问题。然而,近期小鼠上的研究表明,这些基础概念,例如出生时卵巢储备是固定的,可能并非确然如此。比如,近期小鼠上的工作揭示,持续限食7个月后自由饮食1个月的雌鼠,相比于持续自由饮食的雌鼠,并不存在任何显著的卵母细胞质量下降的特征(Selesniemiet al., 2011) 。值得注意的是,在持续限食的老化雌鼠卵母细胞中存在的非整倍型、减数分裂纺锤体异常、染色体排列紊乱、线粒体聚合和ATP水平下降等的发生率增加,在经历持续限食的老化雌鼠卵母细胞中却并不存在。虽然这些有利影响背后的机理依然需要更多的研究去追寻,但是卵子中存在的老化相关非整倍型和纺锤体缺陷至少不再是医疗操作可望不可及的目标了。 能量、老化与线粒体的作用 无论你研究的是代谢还是老化,都难以忽视线粒体,它是处于细胞能量生产和利用之中心的结构。为满足基础代谢需求,每个人每天需要大约65千克ATP,而线粒体对人体内大多数的ATP的产生是至关重要的(Törnroth-Horsefield and Neutze, 2008) 。线粒体的其它关键功能还包括钙离子缓冲、氧化还原(redox)平衡、程序化细胞死亡(凋亡)。线粒体在整个细胞中不断地运动着,进行着融合、分裂和降解,以此来消除和替换损坏的细胞器,并满足浮动的细胞能量需求(Palmeret al., 2011) 。 果蝇、大鼠、小鼠、猕猴和人的数据都显示,随着组织的老化,线粒体的数量和活性都出现下降,代之以其尺寸的增大(Cho et al., 2011; Ferguson et al., 2005; Short etal., 2005; Wallace, 2001) 。线粒体缺陷与常见的老化相关疾病,诸如动脉粥样硬化(atherosclerosis)、肥胖诱发的二型糖尿病、肌肉减少症(sarcopenia)和神经退行性失调,或者相关或者发挥一定作用(DiLisa et al., 2009; Lin and Beal, 2006; Wallace, 2001) 。其中的过程包括线粒体膜电势和ATP产出的下降、线粒体通透转移孔(mitochondrial permeability transition pore,mPTP)活化的增多、线粒体膜的去极化、以及线粒体基质内溶物向细胞质的泄露(DiLisa et al., 2001; Hafner et al., 2010; Liu et al., 2011; Wallace, 2001) 。 除了老化与老化相关疾病,一些证据还支持线粒体是啮齿类和人类通过限食获益的调控子(Cerqueira et al., 2011; Civitarese et al., 2007;Lo pez-Lluch et al., 2006, 2008)。在一系列物种中(Guarente,2008; Johannsen and Ravussin, 2009),限食都可以增加线粒体之数量、并增益其功能。但在大鼠的最近一份研究中,却未发现这一变化(Hancocket al., 2011)。被认为是限食生理的调节子的sirtuin-1(SIRT1)-AMPK网络,可以使线粒体的数量和活性都有所增加(Gerhart-Hineset al., 2007),同样,诸如白藜芦醇(Baur et al., 2006; Feige etal., 2008; Funk et al., 2010; Lagouge et al., 2006)、SRT1720(Minoret al., 2011)、二甲双胍(Canto et al., 2009; Suwa et al.,2006)等限食模仿物可以刺激SIRT1和AMPK活性的,也是如此。在果蝇和线虫里,已经知道线粒体代谢的调整是限食延长寿命所需要的 (Bahador- ani etal., 2010; Bishop and Guarente, 2007; Zid et al., 2009),并且是充分的(Bahadoraniet al., 2010; Durieux et al., 2011; Rera et al., 2011) 。 线粒体与卵母细胞能力 在各种可能的卵母细胞从限食中获得益处的机理中,最有可能的原因之一是阻止在老化雌性的卵母细胞中发生的异常线粒体聚合与ATP水平之下降(Selesniemi et al.,2011)。许多研究都认为卵子中可用ATP的不足,与染色体分离异常之间存在联系,其中染色体分离异常又可能是减数分裂纺锤体异常的结果(Eichenlaub-Ritteret al., 2004; Schon et al., 2000; Zheng et al., 2007)。纺锤体异常将造成卵母细胞成功受精的能力下降,并且造成由这些能力不足的卵子生成的合子难以发育到囊胚(Bentov et al., 2010)。与这一理念一致的是,小鼠卵母细胞线粒体氧化还原的缺陷会使减数分裂成熟和受精的潜能下降,同样,植入前胚胎发育的潜能也有所下降(Van Blerkom et al., 1995)。 小鼠上的其它研究说明,卵母细胞在精子传入后如不能充分调整ATP的含量,将破坏细胞内的钙振荡(Igarashiet al., 1997, 2005),而钙振荡对于调节受精后的那些保证胚胎发育潜能的事件是至关重要的(Dumollardet al., 2004; Vitullo and Ozil, 1992)。在人卵中,ATP水平与胚胎发育和植入的潜能是正相关的(Van Blerkom et al., 1995)。这些发现,以及在盛龄女性经常出现的卵母细胞线粒体肿胀和生殖嵴异常(Mü ller-Ho ̈ cker et al., 1996),共同支持以下观点:大龄女性卵子和胚胎质量下降的一个主要原因是卵母细胞的生物产能能力的受损。 当评估线粒体在卵母细胞发育、减数分裂成熟、受精和植入前胚胎能力中的中心作用时,还必须考虑线粒体生理的其它方面。明显的是,ATP生产相关的氧化还原步骤里形成的ROS,与线粒体的生物能是密切相关的。反过来,在小鼠上报道的老化雌鼠卵母细胞质量可以被成年期持续的抗氧化剂处理来维持 (Tarı n et al., 2002a) 也就不足为奇了。不幸的是,这一方法会给生殖道的其它细胞和组织带来损害,造成胎儿损失和胎仔数下降(Tarı netal.,2002b)。因此,长期系统性使用抗氧化剂,对改善人类的雌性不育,几乎没有任何临床价值。 在一个更基础的层面上,线粒体生理学中引人注目的另一方面是,卵母细胞线粒体的数量,从未成熟卵母细胞中的5-10千,扩增到成熟MII卵母细胞的1-5十万生殖更多(Jansen and Burton,2004; Piko and Matsu- moto, 1976)。目前还不清楚为什么在卵母细胞成熟过程中线粒体需要如此大量的扩增。一个观点认为这是卵母细胞在为成功受精和胚胎卵裂所增加的能量需求做一个主动的筹备。这一观点看起来是合理的,特别是考虑到线粒体复制机器在卵母细胞发育到MII期即被关闭,它直到胚胎发育到囊胚,植入到子宫壁的时候才重新启动(Larsson et al., 1998)。对应的,可以想见,胚胎从一细胞的合子发育到100个或更多细胞的囊胚的过程中,线粒体的数量将出现急剧的下降,对植入前胚胎的线粒体DNA(mtDNA)的检测(Spikings et al., 2007; Waiet al., 2008),以及囊胚每个细胞线粒体数目的检测(Van Blerkom, 2008)也支持这一推测。 值得一提的是,线粒体的mtDNA含量,而不是线粒体的数目(每个线粒体含有1-10个mtDNA拷贝),可能是卵母细胞能力的更可靠的指标。以前的研究表明卵母细胞和早期胚胎的mtDNA拷贝数分别与受精和发育潜能成正相关(Santos et al., 2006; Spikings et al., 2006)。实际上,胚胎发生之成功与受精时卵子所含mtDNA的阈值相关,所含mtDNA低于此阈值的卵母细胞,其成熟失败、受精率下降和胚胎发育阻滞的趋势会上升(El Shourbagy et al.,2006; Piko and Taylor, 1987; Reynier et al., 2001; Santos et al., 2006; Waiet al., 2010)。此外,猪卵的研究揭示,在体外成熟阶段抑制mtDNA的复制,导致受精能力的下降和胚胎发育的阻滞,并且这些表征的严重程度与mtDNA拷贝数的最低阈值密切相关(Spikingset al., 2007)。 卵母细胞的另一个值得注意的特征是线粒体变得非常小(直径≤1微米),并且具有电子致密基质和较少的嵴。尽管有这些特征,卵母细胞的线粒体是高度活化的,并产生卵母细胞和早期胚胎所需的大部分能量(Dumollardet al., 2007; Motta et al., 2000; Van Blerkom et al., 1995)。受精之后,发育胚胎的线粒体进行了急剧的超微结构变化。到囊胚形成时,线粒体变长,并具有复杂的嵴和低电子密度的机制,这种形态更像体细胞(Sathananthan and Trounson, 2000; Van Blerkom, 1989a, 1989b, 1993; Van Blerkomand Motta, 1979; Van Blerkom et al., 1973)。这种线粒体形态的变化的意义何在尚不清楚,但是体外发育阻滞的人类胚胎经常含有向正常形态转变失败的线粒体,这种转变可能是为了弥合发育胚胎的能量需求而做出的(Van Blerkom, 1989a)。 最后一点,卵母细胞之线粒体可能生殖过程中起到另外一种关键作用:它们是线粒体基因组从一代到下一代的单亲遗传的资源。现在已经明确知道父源(精子的)线粒体在新形成的胚胎的前几个卵裂时就被降解了,只有母源线粒体留下来最为这些细胞器复制的根源,传递给胚胎和后代(Cummins, 1998; Giles et al., 1980; Hutchison etal., 1974; Kaneda et al., 1995; Sutovsky et al., 2000)。性别特异性的选择抑制父源mtDNA传递的机理目前还不完全清楚。但在许多物种中,这种选择似乎是因为精子来源的线粒体的泛素化使它们得以被清除出胚胎(Sutovskyet al., 2004)。同样不明白的是,为什么父源mtDNA被主动的选择来抵制。一个观点认为,它是为了将精子发生过程中因为精子暴露于ROS所致的mtDNA突变的遗传最小化(Aitken, 1995)。与这一观点一致的是,精子的线粒体mtDNA常常携带突变和缺失(Reynieret al., 1998),而这又与精子动力不足和雄性不育相关(Kao et al., 1995;Ruiz-Pesini et al., 2000; St John et al., 2001)。 不管驱动mtDNA单亲遗传的机理是啥,也不管它到底能带来什么益处,这一过程都需要严格的保证雌性生殖系的mtDNA的完整性。否则,因为卵母细胞的线粒体是后代胚胎线粒体的根源,如果雌性生殖系mtDNA完整性不得保持,就会发生积累突变的浩劫(Jansenand de Boer, 1998)。为保证线粒体基因组稳定性的无性的维持,细胞形成了一个多步骤的过程,这包括初期的对可被接受mtDNA基因型的数量限制,以及随后的一段海量扩增期。之后,在后代增进适应能力的需求压力下,发生了大规模的竞争性筛选(Jansen,2000)。数量限制事件发生于胚胎发育之时,因为从受精卵到囊胚的发育过程中,胚胎的mTDNA含量以及每个细胞的线粒体数量都从峰值水平指数的急剧降低。事实上,原始生殖细胞的每个细胞只有10个或更少的线粒体,这与每个卵子所含的成百上千的线粒体形成鲜明对比 (Jansen and Burton, 2004;Piko and Matsumoto, 1976)。后面一点展示了mtDNA选择过程中的第二步的重要性,它意味着一段时间的低选择性海量扩增可能允许线粒体DNA的某种程度的基因漂移(Brown et al., 2001)。第三步,也是最后一步,即大规模的竞争性选择,是在真实机制方面最不确定的。 有一个理论认为由闭锁导致的包含卵母细胞的卵泡的持续死亡,是为了确保卵泡在排卵时可以释放一个具有最高水平mtDNA完整性的卵子(Jansen andBurton, 2004; Jansen and de Boer, 1998)。虽然这一说法很诱人,但是目前还缺乏直接的证据。然而,在临床上女人的缺失突变的mtDNA通常不会被传递到子代,这一观察说明确保母源mtDNA完整性的被严密控制的监控系统是存在的。此外,常见的△mtDNA4977缺失突变在不能受精的人卵中,比早期卵裂的胚胎中要多(Brenner et al., 1998; Perez et al.,2000),并且三分之二的退化或阻滞卵母细胞携带着这种△mtDNA4977缺失突变(Duranet al., 2011)。 能量学、老化和雌性不育:将之联系起来 线粒体功能受损、生物能的能力的欠佳和在老化雌性中卵母细胞发育能力的下降之间的直接因果关系还没有被明确的建立。尽管如此,这些相关性的证据正逐渐固化,比如长寿通路与不育之间的联系。仓鼠和小鼠上的研究报道了母源老化与卵母细胞ATP含量和线粒体数目的急剧下降相关。此外,施加于成体的限食不仅给老化鼠卵子质量的多个指标带来益处,也延长了其自然生殖期限,这一事实深刻说明介导体细胞对限食做出相应的同一信号通路也可作用于雌性生殖系细胞。最近的一些研究结果,诸如在大鼠和小鼠卵母细胞观察到司徒林的表达(Kawamuraet al., 2010; Luo et al., 2012),限食增加了大鼠卵巢中司徒林的表达(Luo etal., 2012),以及从缺乏线粒体相关司徒林三的卵母细胞长成的胚胎的发育严重受损,这些发现都支持上面的结论(Kawamuraet al., 2010)。 虽然已经有一些进展将能量、老化和不育联系起来,但我们离理解或操控那些影响雌性不育的生物产能和长寿通路还有很长的路要走。因此,目前已有的实验和临床数据可以被视为一个冒险故事的开篇,可能某一天我能可能得到在人类辅助生殖中用于对卵子质量、受精和植入前胚胎发育的临床操作的前所未有的机遇。展望未来,我们将总结两个整合了这里讨论的概念的,可能在未来出现的两个实例。 自体生殖系线粒体能量移植与卵子质量 在1990年代中后期,因为胚胎质量和植入失败原因而数次妊娠失败的27位女性参加了一项名为卵母细胞细胞质移植的生育技术测验(Barritt et al., 2001; Brenner etal., 2000; Cohen et al., 1997, 1998; Harvey et al., 2007)。假设这些女性不孕的原因是老化相关的卵母细胞质量受损,她们在进行下一轮IVF时,把取自年轻捐献者的卵母细胞(也就是别的女性的卵)细胞质转移到她们的卵母细胞中。首次所做的三十例卵胞质移植的女性,有13个诞育了婴孩(共17个婴孩,包括11个单胎,1个双胞胎和1个四胞胎),还有一个孕早期流产(45,XO核型)。怀孕的双胞胎中,一个女性的核型正常,另有一个染色体异常(45,XO)。在这些婴孩里,染色体异常率(1/17,5.9%)是在美国当时同龄女性IVF结果的正常范围内的(Harveyet al., 2007)。这些早期IVF连续失败的小部分女性能够达到如此高的受孕率,使人们认识到,人类辅助生殖终将找到新方法以应对卵子和胚胎质量导致的不育。 虽然有其它临床工作迅速的跟进了(Lanzendorf et al., 1999);但是期盼能被广泛应用于临床的卵胞质移植技术只存在了很短时间,部分原因是考虑到线粒体的异质性(Barrittet al., 2001; Brenner et al., 2000)。虽然这一技术涉及的是将供体卵的胞质,而不是纯化的线粒体移植入受体卵,但人们普遍认为此技术给受体卵带来的益处是源自于从供体移植来的有活性的线粒体(Bentov et al., 2011; Van Blerkom et al., 1998)。这一结论在动物实验上被证实(ElShourbagy et al., 2006; Yi et al., 2007),并在某种程度上,对卵胞质移植的携带生母和卵供体方线粒体的儿童的研究,也证实了这一点(Brenneret al., 2000; Barritt et al., 2001)。到目前为止,线粒体异质性对这些儿童健康的负面影响还不明确,但是动物模型暗示,因为某些原因,它至少需要被关注。例如,小鼠的研究揭示线粒体异质性会引发成年时出现的代谢综合征(Actonet al., 2007)。其它研究揭示线粒体异质性也可能对认知能力产生负面影响(Sharpley etal., 2012)。 除此之外,卵母细胞线粒体所含的遗传物质与生父生母贡献的核内基因有本质的不同。与此对应,此种方法诞育的儿童具有的遗传物质,来源于三个不同来源而不是两个:生母的,生父的,和捐卵者的。除了异源卵胞质移植带来的一系列潜在的伦理问题和法律问题,美国食品药品管理局(FDA)也将此技术视为以生成胚胎为目的的人类生殖细胞的遗传操作。因此,在2001年FDA立法,规定异源卵胞质移植不可再应用于人类的辅助生殖,除非将此此技术提交审查并通过新药调查(InvestigationalNew Drug (IND))指南的检验(Zoon, 2001)。虽然应用女性体细胞的自体线粒体可以避免线粒体异质性,但是体细胞线粒体也具有老化相关mtDNA损伤的倾向并导致可遗传的突变。将这些线粒体在受精时导入卵母细胞,会导致突变线粒体在新胚胎和其后代中扩散,这种风险对开发临床技术而言风险过大。 然而,卵原干细胞在成年小鼠和生殖期女性卵巢里的发现(Johnson et al., 2004; White et al., 2012; Zou etal., 2009),使修正版卵胞质移植成为可能的事。此种新技术被称为奥哥闷特(AUGMENT,也就是自体生殖系线粒体能量移植,Woods et al., 2013),此法从自体生殖系中获得细胞质提取物或纯化的线粒体,以使因老化而受精和胚胎发生能力受损的卵子生物产能重新恢复活力(图二)。 \0 \0 图二:奥哥门特(自体生殖系线粒体能量移植)改善IVF表现的可行方法。线粒体活力和产能能力的降低造成了老化相关雌性生育的受损,即便患者使用了诸如IVF等辅助生殖技术。在卵胞质精子注射过程中将患者自体自然卵子前体细胞(卵原干细胞)的线粒体注入到同一患者的卵子内,可增加此卵子的线粒体阈值水平,为其提供足够的能量,来支撑受精和胚胎发生的完成。 不仅因为这些供能的细胞器是来自患者自身的,用卵原干细胞的线粒体来提高卵和胚胎质量的方法的优点还有很多。首先,既然卵原干细胞是生成卵母细胞的自然前体细胞(White et al., 2012; Zou et al., 2009),如果生殖系的线粒体控制确实有别于体细胞,那么使用卵原干细胞来源的线粒体使卵子年轻化,这与世代之间母源线粒体传递的生存和选择过程是共通的。其次,源自缓慢分裂的干细胞/祖细胞的卵原干细胞线粒体,与同一患者体细胞的线粒体相比,它们的基因组可能免于损伤的积累。人类卵原干细胞的初步观察结果是支持这一观点的(Woods and Tilly, 2013)。与此可能同等重要的观察是,通过检测各个时段ATP的合成量,源自人类卵原干细胞的线粒体的生物产能潜力,远远超过源自其它很多细胞系的同等数量的线粒体,这些细胞系包括胚胎干细胞和成体干细胞(Woodsand Tilly, 2013)。最后一点是,使用卵原干细胞,与非生殖系细胞相比,可以避免线粒体中含有细胞系特异的关键核编码蛋白。综合上述所有考虑,以及上述的以前在临床前和临床中获得的概念验证型数据,以及奥哥门特在安全的改善人类辅助生殖时没有临床的、法律的和异源性卵胞质移植的各种生物学问题,可见奥哥门特前景光明,值得考虑。 线粒体激活子增益卵子质量 克服卵子能量缺陷的另一种可行办法是研制新的可提高卵母细胞线粒体数量或线粒体ATP生成能力的生物或化学物质。开发这种可以复制限食给老化雌性卵子质量所带来的益处(Selesniemiet al., 2011)的化合物将成为人类辅助生殖领域的一个重大成果。主要的难点在于用于大规模线粒体筛选分析的卵母细胞数量严重不足,以及利用小鼠做老化分析的成本和复杂度。然而,小鼠和人的卵原干细胞的出现可能使之成为可能,因为这些干细胞可以在体外扩增并产生无限的细胞用来筛选(Whiteet al., 2012)(图三)。因为这些细胞是自然的卵母细胞祖细胞,可以想见在如果一个化合物可以使卵原干细胞线粒体壮大的话,那它对于卵母细胞应该有类似的功效。除此之外,卵原干细胞可以用作筛选平台来为某一个化合物或某一家族化合物壮大雌性生殖细胞线粒体数量和活力的分子事件的分析。如果以前述长寿调节通路之关键组分(图一)的理想操作来致成卵原干细胞的话,则益处更大。建立这些雌性生殖系细胞有助于鉴定那些协调卵母细胞生物产能的潜在控制节点。反过来,它又可能引出更直接的方法来确定用于检测是否可以改善老化雌性小鼠的卵母细胞质量。 \0 \0 图三:雌性生殖细胞线粒体激活子的鉴定和应用。人类卵原干细胞是卵母细胞的前体细胞,它们的培养可以用于筛选可以增进包括mtDNA含量、线粒体膜电势和ATP生成能力等线粒体各方面动态的生物物质或药物。筛选所得物质,可进一步用于体内体外是否可将老化对卵子质量、胚胎发育能力和生育的损害最小化的检验。 有充分的理由相信,与直接用线粒体移植来改善卵子能量状况类似,卵母细胞或胚胎线粒体能量受损的患者的IVF表现会因线粒体激活子而获益(Bentov etal., 2010; Van Blerkom, 2011)。而且,线粒体激活子还可能作为一种体内用的试剂,来确保卵巢刺激后,从卵巢排出的或从IVF患者取得的卵母细胞在生物产能层面对于后续成熟和完整发育是完全齐备的。这些线粒体激活剂的一个潜在可用的例子是可以改善因年龄增长而增加的卵母细胞非整倍性的增加,这种现象,至少在小鼠上已经被证实是与排出卵子的线粒体缺陷和能量不足相关的(Selesniemiet al., 2011)。 从原理上讲,减数分裂纺锤体的形成和维持是能量驱动的,在很大程度上这两个事件会在老化雌性卵母细胞中失败(图四)。其所致之染色体排列紊乱或分配不均所引发的卵子染色体过多或过少的遗传缺陷会在受精后传递到对应的胚胎中(Gaulden, 1992)。在临床上,母源老化引发的卵子或胚胎非整倍性会直接导致三体受孕、植入失败和流产的增加(Benadivaet al., 1996; Hassold and Chiu, 1985; Munne and Cohen, 1998; Munne et al.,1995)。研发可以在排卵前或IVF取卵前增进卵子产能能力的口服药物使得,可以从生殖期晚期女性中获得更多的遗传正确、受精后胚胎发育无碍的卵母细胞。反过来,此策略也将缓解老化相关的流产和生产缺陷以及唐氏综合征的风险。 \0 \0 图四:母源老化对卵子质量和雌性生殖力的负面影响。图中展示母源老化所致的卵母细胞的生物产能潜力的相关缺陷对卵母细胞获得受精能力的损害。老化雌性卵母细胞的能量不足导致减数分裂纺锤体的形成和维持的受损、受精时减数分裂中遗传物质的分配不均、以及非整倍性受孕,这些又导致植入前胚胎发育阻滞、植入失败、流产和生产缺陷。 致谢 蒂力实验室之工作受源自国家老化研究所的即时促进新方法拓展研究(MERIT)奖励(NIH R37-AG012279)、格伦医学研究基金会和柔森堡亨利和薇薇安慈善基金的资助。森克莱尔的工作受NIH项目R01-AG028730、奥利森医学基金会、格伦医学研究基金会、青少年糖尿病基金会、线粒体疾病联合基金和熟思该大卫的慈善捐助。作者感谢伍兹参与的讨论以及对帝力初步工作的引用。帝力全称具有美国专利某某和相关工作的知识产权。帝力和森克莱尔是(马萨诸塞州剑桥)奥瓦科学公司的创办人。森克莱尔是(华盛顿特区)苦河八公司和(马萨诸塞州剑桥)的葛兰素史克公司的思锤思公司的创始人和顾问。 参考文献 Acton, B.M., Lai, I.,Shang, X., Jurisicova, A., and Casper, R.F. 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刚在 王庆林那里 看到了《人民日报》网站的一个链接:“ 美刊:中国因三点赶不上美国 ”,这个“摘译”漏掉了中国未来最为关键的因素——人口因素,即计划生育造成的中国人口结构危机使得中国没有什么美好的前景。 原文段落是 : And things are only likely to get worse for China. Because of the one-child policy, China will soon suffer the most severe aging process in human history. The ratio of Chinese workers per retiree will plummet from 8:1 today to 2:1 by 2040. The fiscal cost of this swing in dependency ratios alone may exceed 100 percent of China’s GDP. The American working-age population, by contrast, will expand by 17 percent over the next 40 years. America’s fiscal future may not be bright, but it is brighter than China’s. 【翻译:——对中国而言还有雪上加霜的一条。由于一胎化政策,中国很快就要承受人类历史上最严重的老龄化过程。中国劳动人员和退休人员的比例将从现在的8比1暴跌到2040年的2比1。仅仅这种抚养比的变化,就可能使得财政成本超过中国100%的GDP。相比之下,美国未来40年的劳动人口会增加17%(译注:美国的比例到2040年是2.68比1,见 美国国会报告CRS-15页 )。美国财政的未来可能并不光明,但是比中国的光明。】 不知道中国媒体漏译这一段有什么意义,“吾谁欺,欺天乎?”
前一篇文章讲的是发在国外的地震文章否定了中国至今仍未放弃的地震预报事业,算是“中国地震学”内外有别。这一篇讲“中国人口学”的内外有别(本人早说过,人口控制论、中医、地震预报是当代三大官办伪科学,所以表现相似也不奇怪)。 《科学》这一期是人口学专辑。《科学》(Science)是美国科学促进会(AAAS)主办的杂志,AAAS有极强的自由左派 (liberal leftist) 意识形态( http://rogerpielkejr.blogspot.com/2011/04/analysis-of-nisbet-report-part-ii.html ),一些文章倾向于环保左派观点,比如倾向于反坝(曾在2008年刊登过紫坪铺水库引发汶川地震的报导、2009年刊登过韩国反坝行动的报导)、渲染全球变暖(比如气候门丑闻之后刊登美国250多名院士支持气候变暖结论的文章——并且配了一幅伪造的北极熊照片)、渲染人口过剩和资源危机。不过即使如此,去年还是刊登了对中国计划生育政策起源和效果进行批评的一组文章。而这一期专辑文章的基调虽然是渲染人口压力,仍然包含了一篇评价中国计生效果的一篇文章,提到了中国人口未来面临的挑战: Xizhe Peng:China’s Demographic History and Future Challenges 这个作者彭希哲留学英国学习人口学,现在复旦大学。对于中国的人口学研究者该如何评价,请参见易富贤的文章。彭希哲这篇文章的结论是: Demographic changes in China will have important global impacts. Given all of the factors discussed above, a future population decline may be desirable for China. But rapid or even sudden population decline would be disastrous, and it would be very difficult to stop. Maintaining the present low fertility would be worrisome. Overall, it would be rational for China to modify its current population policy and to relax the rigid control on childbearing sooner rather than later, and to allow the TFR to grow and be maintained at around 1.8 in the near future. Then the country’s population would decline and its aging process would be slower in the future, which would provide more time and a better social environment for China to cope with future population-related socioeconomic changes. China’s population issues should be dealt with in an integrated and balanced way. (译:中国的人口变化对世界有重要影响。按照上述讨论的因素,将来人口的降低对中国可能是必须的。但是快速的、甚至突然的人口降低会是灾难性的,而且这种降低很难停止。继续保持现有的低生育率【译注:即第六次人口普查再次印证的不到1.5的总和生育率】值得担忧。总之,中国理性的做法是,尽早而不拖延地修改现行的人口政策、放松严格的生育控制,容许总和生育率的上升,在近期维持在1.8左右【译注:现在中国人口是一半城市一半农村,考虑到生活压力,城市即使放开平均生育率也不过是1,而如果想达到全国平均1.8的生育率,则农村必须达到2.6,这怎么可能】。这样的话,中国的人口会降低,而老龄化过程在未来会减缓,这会为中国处理未来与人口有关的社会经济变化提供更多的时间和更好的社会环境。中国的人口问题应该用整体和平衡的方法来处理。) 看到了吧,官拜“国家人口与计划生育委员会人口专家委员会委员”的彭希哲可以到科学上发文章呼吁尽早而不拖延地放松人口政策(如上所述,任何人如果诚心希望中国总和生育率回到1.8,必须承认只能彻底废除计划生育政策),而六次人口普查之后,主管部门和人口专家面对彻底暴露的中国人口灾难前景,却一直处于“不战不和不守、不降不死不走”的假死状态(典故见 http://news.china.com/zh_cn/history/all/11025807/20051212/12937977.html )。这就是内外有别的中国人口学。
Communiqué of the National Bureau of Statistics of People's Republic of China on Major Figures of the 2010 Population Census (No. 1) April 28, 2011 In accordance with the Regulations on National Population Census and the Circular of the State Council on the Conduct of the 6th National Population Census,Chinacarried out its 6th national population census with zero hour of November 1, 2010 as the reference time . The field enumeration of the census has been successfully completed through the leadership of the State Council and governments at all levels, the support and cooperation from people of various nationalities, and the painstaking efforts and hard work of nearly 10 million census workers. Results on major figures obtained through advance tabulation are released as follows: I. Total Population Total population ofChinawas 1370536875 persons. Of which: The population of the 31 provinces, autonomous regions and municipalities and of servicemen on the mainland ofChinathrough census enumeration was 1339724852 persons. The population of Hong Kong Special Administrative Region was 7097600 persons. The population of Macao Special Administrative Region was 552300 persons. The population ofTaiwan was 23162123 persons. II. Population Growth Compared with the population of 1265825048 from the 2000 population census (zero hour of November 1, 2000), the total population of the 31 provinces, autonomous regions and municipalities and the servicemen of the mainland of China increased by 73899804 persons, or 5.84 percent over the past 10 years. The average annual growth rate was 0.57 percent. III. Population of Family Households In the 31 provinces, autonomous regions and municipalities of the mainland ofChina, there were 401517330 family households with a population of 1244608395 persons. The average size of family household was 3.10 persons, or 0.34 person less as compared with the 3.44 persons in the 2000 population census. IV. Sex Composition Of the population enumerated in the 31 provinces, autonomous regions and municipalities and servicemen of the mainland ofChina, 686852572 persons or 51.27 percent were males, while 652872280 persons or 48.73 percent were females. The sex ratio (female=100) declined from 106.74 to 105.20. V. Age Composition Of the population enumerated in the 31 provinces, autonomous regions and municipalities and servicemen of the mainland of China, 222459737 persons were in the age group of 0-14, accounting for 16.60 percent of the total population; 939616410 persons in the age group of 15-59, accounting for 70.14 percent, and 177648705 persons in the age group of 60 and over, accounting for 13.26 percent, of which 118831709 persons were in the age group of 65 and over, accounting for 8.87 percent. As compared with the results of the 2000 population census, the share of people in the age group of 0-14 was down by 6.29 percentage points, that of the age group of 15-59 was up by 3.36 percentage points, that of the age group of 60 and over was up by 2.93 percentage points, and that of the age group of 65 and over was up by 1.91 percentage points. VI. Composition of Nationalities Of the population enumerated in the 31 provinces, autonomous regions and municipalities and servicemen of the mainland ofChina, 1225932641 persons or 91.51 percent were of Han nationality, and 113792211 persons or 8.49 percent were of various national minorities. Compared with the 2000 population census, the population of Han nationality increased by 66537177 persons, or 5.74 percent; while the population of various national minorities increased by 7362627 persons, or 6.92 percent. VII. Composition of Educational Attainment Of the population enumerated in the 31 provinces, autonomous regions and municipalities and servicemen of the mainland of China, 119636790 persons had finished university education (referring to junior college and above); 187985979 persons had received senior secondary education (including secondary technical school education); 519656445 persons had received junior secondary education and 358764003 persons had primary education (the persons with various educational attainment included graduates and students in schools). Compared with the 2000 population census, following changes had taken place in the number of people with various educational attainments of every 100,000 people: number of people with university education increased from 3611 to 8930; number of people with senior secondary education increased from 11146 to 14032; number of people with junior secondary education increased from 33961 to 38788; and number of people with primary education decreased from 35701 to 26779. Of the population enumerated in the 31 provinces, autonomous regions and municipalities and servicemen of the mainland ofChina, 54656573 persons were illiterate (i.e. people over 15 years of age who can not read). Compared with the 2000 population census, the size of illiterate population dropped by 30413094 persons, and the illiterate rate declined from 6.72 percent to 4.08 percent, or down by 2.64 percentage points. VIII. Urban and Rural Population Of the population enumerated in the 31 provinces, autonomous regions and municipalities and servicemen of the mainland ofChina, 665575306 persons were urban residents , accounting for 49.68 percent; and 674149546 persons were rural residents, accounting for 50.32 percent. Compared with the 2000 population census, the number of urban residents increased by 207137093 persons, and the number of rural residents dropped by 133237289 persons. The proportion of urban residents rose by 13.46 percentage points. IX. Migration of Population Of the population enumerated in the 31 provinces, autonomous regions and municipalities and servicemen of the mainland ofChina, 261386075 persons lived in places other than the towns (townships or streets) of their household registration where they had left for over 6 months. Of this total, 39959423 were persons with current residence different from the place of their household registration in the same city , and the remaining were 221426652 persons. Compared with the 2000 population census, population in this category increased by 116995327 persons, or up by 81.03 percent. X. Error of Enumeration After field enumeration, a total of 402 enumeration blocks were randomly selected to conduct post-enumeration survey, resulting in a population undercount rate of 0.12 percent. Notes: 1. All figures in the Communiqué are preliminary results. 2. The population census covers all natural persons residing in the territory of the People's Republic of China and the Chinese citizens residing outside but not permanently settled down in locations beyond the territory of the People’s Republic of China at the census reference time, excluding residents of Hong Kong, Macao and Taiwan and foreigners temporarily staying in the territory of the People’s Republic of China. Territory here refers to the territory of the customs. 3. The population of the 31 provinces, autonomous regions and municipalities and servicemen on the mainland ofChinadoes not include residents ofHong Kong,MacaoandTaiwanand foreigners staying in the territory of the People’s Republic ofChinaat the time of the census. 4. Population of Hong Kong SAR refers to data at the end of 2010 provided by Hong Kong SAR government. 5. Population of Macao SAR refers to data at the end of 2010 provided by Macao SAR government. 6. Population ofTaiwanrefers to population at the end of 2010 released by relevant authorities ofTaiwan. 7. Population of family households refer to households consists of persons, bonded by family relations, staying under the same roof and sharing living arrangement. 8. Illiterate rate refers to the population over 15 years of age who can not read divided by the population of the 31 provinces, autonomous regions and municipalities and servicemen on the mainland ofChina. 9. Urban and rural population refer to population living in urban or rural areas within the territory of China, which are classified based on Regulation on Statistical Classification of Urban and Rural Areas issued by the National Bureau of Statistics in 2008. 10. Persons with current residence different from the place of their household registration in the same city refer to persons in a city whose current residence is one town or street when their household registration is in another town or street of the same municipality or prefecture-level city 2010 年第六次全国人口普查主要数据公报 (第 1 号) 中华人民共和国国家统计局 2011 年 4 月 28 日 根据《全国人口普查条例》和《国务院关于开展第六次全国人口普查的通知》,我国以 2010 年 11 月 1 日 零时为标准时点进行了第六次全国人口普查 。在国务院和地方各级人民政府的统一领导下,在全体普查对象的支持配合下,通过广大普查工作人员的艰苦努力,目前已圆满完成人口普查任务。现将快速汇总的主要数据公布如下: 一、 总人口 全国总人口为 1370536875 人。其中: 普查登记的大陆 31 个省、自治区、直辖市和现役军人的人口 共 1339724852 人。 香港特别行政区人口 为 7097600 人。 澳门特别行政区人口 为 552300 人。 台湾地区人口 为 23162123 人。 二、人口增长 大陆 31 个省、自治区、直辖市和现役军人的人口,同第五次全国人口普查 2000 年 11 月 1 日 零时的 1265825048 人相比,十年共增加 73899804 人,增长 5.84% ,年平均增长率为 0.57% 。 三、家庭户人口 大陆 31 个省、自治区、直辖市共有家庭户 401517330 户,家庭户人口为 1244608395 人,平均每个家庭户的人口为 3.10 人,比 2000 年第五次全国人口普查的 3.44 人减少 0.34 人。 四、性别构成 大陆 31 个省、自治区、直辖市和现役军人的人口中,男性人口为 686852572 人,占 51.27% ;女性人口为 652872280 人,占 48.73% 。总人口性别比(以女性为 100 ,男性对女性的比例)由 2000 年第五次全国人口普查的 106.74 下降为 105.20 。 五、年龄构成 大陆 31 个省、自治区、直辖市和现役军人的人口中, 0-14 岁人口为 222459737 人,占 16.60% ; 15-59 岁人口为 939616410 人,占 70.14% ; 60 岁及以上人口为 177648705 人,占 13.26% ,其中 65 岁及以上人口为 118831709 人,占 8.87% 。同 2000 年第五次全国人口普查相比, 0-14 岁人口的比重下降 6.29 个百分点, 15-59 岁人口的比重上升 3.36 个百分点, 60 岁及以上人口的比重上升 2.93 个百分点, 65 岁及以上人口的比重上升 1.91 个百分点。 六、民族构成 大陆 31 个省、自治区、直辖市和现役军人的人口中,汉族人口为 1225932641 人,占 91.51% ;各少数民族人口为 113792211 人,占 8.49% 。同 2000 年第五次全国人口普查相比,汉族人口增加 66537177 人,增长 5.74% ;各少数民族人口增加 7362627 人,增长 6.92% 。 七、各种受教育程度人口 大陆 31 个省、自治区、直辖市和现役军人的人口中,具有大学(指大专以上)文化程度的人口为 119636790 人;具有高中(含中专)文化程度的人口为 187985979 人;具有初中文化程度的人口为 519656445 人;具有小学文化程度的人口为 358764003 人(以上各种受教育程度的人包括各类学校的毕业生、肄业生和在校生)。 同 2000 年第五次全国人口普查相比,每 10 万人中具有大学文化程度的由 3611 人上升为 8930 人;具有高中文化程度的由 11146 人上升为 14032 人;具有初中文化程度的由 33961 人上升为 38788 人;具有小学文化程度的由 35701 人下降为 26779 人。 大陆 31 个省、自治区、直辖市和现役军人的人口中,文盲人口( 15 岁及以上不识字的人)为 54656573 人,同 2000 年第五次全国人口普查相比,文盲人口减少 30413094 人,文盲率 由 6.72% 下降为 4.08% ,下降 2.64 个百分点。 八、城乡人口 大陆 31 个省、自治区、直辖市和现役军人的人口中,居住在城镇的人口 为 665575306 人,占 49.68% ;居住在乡村的人口为 674149546 人,占 50.32% 。同 2000 年第五次全国人口普查相比,城镇人口增加 207137093 人,乡村人口减少 133237289 人,城镇人口比重上升 13.46 个百分点。 九、人口的流动 大陆 31 个省、自治区、直辖市的人口中,居住地与户口登记地所在的乡镇街道不一致且离开户口登记地半年以上的人口为 261386075 人,其中市辖区内人户分离的人口 为 39959423 人,不包括市辖区内人户分离的人口为 221426652 人。同 2000 年第五次全国人口普查相比,居住地与户口登记地所在的乡镇街道不一致且离开户口登记地半年以上的人口增加 116995327 人,增长 81.03% 。 十、登记误差 普查登记结束后,全国统一随机抽取 402 个普查小区进行了事后质量抽样调查。抽查结果显示,人口漏登率为 0.12% 。 注释: 本公报中数据均为初步汇总数。 普查登记的对象是指普查标准时点在中华人民共和国境内的自然人以及在中华人民共和国境外但未定居的中国公民,不包括在中华人民共和国境内短期停留的港澳台居民和外籍人员。“境内”指我国海关关境以内,“境外”指我国海关关境以外。 大陆 31 个省、自治区、直辖市和现役军人的人口数据不包括居住在境内的港澳台居民和外籍人员。 香港特别行政区的人口数为香港特别行政区政府提供的 2010 年底的数据。 澳门特别行政区的人口数为澳门特别行政区政府提供的 2010 年底的数据。 台湾地区的人口数为台湾地区有关主管部门公布的 2010 年底的户籍登记人口数据。 家庭户是指以家庭成员关系为主、居住一处共同生活的人组成的户。 文盲率是指大陆 31 个省、自治区、直辖市和现役军人的人口中 15 岁及以上不识字人口所占比重。 城乡人口是指居住在我国境内城镇、乡村地域上的人口,城镇、乡村是按 2008 年国家统计局《统计上划分城乡的规定》划分的。 市辖区内人户分离的人口是指一个直辖市或地级市所辖的区内和区与区之间,居住地和户口登记地不在同一乡镇街道的人口。