正向抗衰极客进阶的你，心中是否总是有那么几个别人都说效果好，但是自己却又不敢尝试的选项，诸如红外线、高压氧、冰水浴乃至雪地“裸奔”？你是否总是担心这些手段可能会刺激身体，引起损害，“抗衰不成反折寿”？
1月25日（下周四）晚20点至21点，派派荣幸地邀请到美国毒理学家、2009年居里夫人奖获奖者、马萨诸塞大学阿默斯特分校Edward Calabrese教授为我们直播连线，讲解如何利用毒物兴奋效应延寿、如何规避生活中的致癌物以及如何全面、精准地进行癌症风险评估和筛查等。
图注：Edward Calabrese教授
Edward Calabrese教授曾任美国低剂量暴露生物学效应委员会主席，是畅销科普读物《毒物兴奋：生物学、毒理学和医学的革命》的作者，并在学术期刊上发表1000多篇论文、出版10多本书。
本次直播连线活动面向时光派极客联盟成员开放免费现场观摩名额（地址：上海市杨浦区大学路248号3楼Timecure综合抗衰中心），现场仅设15席。参与活动的朋友，有任何与主题相关的疑惑都可现场直接与Edward Calabrese教授连麦交流，机会宝贵不容错过！
如未报满，剩余名额将开放给对毒理学与毒物兴奋效应延寿感兴趣的时光派T1会员与T2会员（须缴纳基础运维成本）。
有意参与本次活动的极客联盟成员与时光派会员可扫描海报上的二维码咨询详情，或在相应群内直接提问。
接下来，我们一起来看看所谓的毒物兴奋效应是什么，又是如何被生命利用，变成延寿助力的。
近日，意大利Vittorio Calabrese教授的研究团队在Ageing Research Reviews杂志上发表了有关毒物兴奋效应（毒物指提到的诸如红外线、热量限制、冷热甚至是超重等外界环境刺激）的最新综述 ，并指出，无论是哪种刺激，其对生物体的健康状态以及寿命的最大影响均维持在30%-60%的范围中[1]。
毒物兴奋效应，又称激效反应，它的英文名Hormesis（源自希腊语hormáein ）[2]，有“激活”之意。顾名思义，毒物兴奋效应所描述的正是从细菌到人类的各种生物系统面对外界刺激时高度激活机体保护和修复功能，从而保障生存的一套反应系统。
图片来源：https://www.wondriumdaily.com/ecosystems-and-their-six-characteristics/
对于生物体而言，毒物兴奋效应就好比是隐藏在它们体内的一根根弹簧，帮助机体更好地对抗外界的压力刺激 [3-10]。然而，一定的压力固然可以帮助弹簧维持形状，不至于太松散，过高的压力却可能把弹簧给一下子压扁，再也“抬不起头”。
毒物兴奋效应也有类似的特点，这种现象被科学家们称为双相剂量效应。
具体来说，就是低水平的生物、化学、物理和心理刺激会上调机体的适应性反应，不仅能让受损的组织/器官有更好的应对策略，如预处理、修复和恢复正常功能，还会通过适度地过度补偿，比如过量产生某些有益因子，减少持续损伤，从而改善机体健康状况，而高剂量的这种刺激往往会有害无益。
从上图中的曲线波峰也可以看出来，毒物兴奋效应的最大特点就是受刺激影响的范围不大，各类刺激对机体造成有益影响的最大值均比正常状态高出约30到60% [11-13]，这也暗示着那暗藏在这些刺激背后的统一性。
不仅如此，科学家们还发现，毒物兴奋效应在几乎所有生命形式和所有细胞类型中均有体现，并且影响从早期胚胎内细胞团阶段到生命的老年阶段的整个生命周期，但会随着衰老而逐渐减弱，从而影响机体对抗疾病的能力 [5,14,15]。
不过，也有研究证实，我们可以通过饮食和或运动干预组合来给这根弹簧抹点“油”，恢复其弹性，从而修复老年动物由于衰老退化的适应性毒物兴奋效应 [16]。
那毒物兴奋效应到底和我们的寿命有着怎样的关联呢，他们又是怎样影响我们的寿命打的呢？且听派派一一为你介绍 [17]。
热量限制（CR）
作为我们熟悉的老朋友，热量限制在包括酵母、昆虫、大鼠、小鼠和猴子等多种生物体中均被证明可以延缓衰老、延长寿命 [18-31]，也有部分研究证实了饮食限制对人类有益，可以促进健康，并可能延长寿命 [32,33]。
图注：两只都是27岁的猴子，右图中的这只在过去20年中一直接受热量限制干预，其面部特征、姿态和皮毛都明显更年轻 [34]
例如，持续六个月的相对较短时间的热量限制被认为可降低空腹胰岛素水平、体温和DNA 损伤 [35]，并且可以预防神经退行性疾病方面 [36,37]。
最初，科学家们还没有将热量限制与毒物兴奋效应联想到一起，但随着后来科学家们发现，热量限制引起的寿命延长可能与增加皮质酮浓度的应激反应相关 [38]，且热量限制和辐射一样具备双相剂量效应，他们最终便还是将热量限制纳入了毒物“刺激”的大家族 [9,39]。
运动
在毒物“刺激”大家族中，运动同样是一个非常有代表性的成员。
早在20世纪初，科学家们就已经发现，尽管长时间的运动会导致酸性物质、过氧化物等强力破坏因子的过量产生，而反复适量的运动却有促进健康作用 [40-43]，这与毒物应激效应的特征完全一致。
运动的毒物兴奋效应主要涉及三个途径：
1.激活核因子NF-kB通路，其中包含各种应激激酶和抗氧化基因 [40,44]。
2.通过蛋白酶体和溶酶体途径增加受损蛋白质和其他大分子的降解 [42,45]。
3.激活热休克蛋白（HSP）合成途径，防止分子损伤的发生和积累 [46-50]。
温度刺激
冷刺激和热刺激均已被发现可以延缓生物体衰老，延长其寿命。
No.1
热刺激
热刺激主要通过热休克反应（HSP）发挥作用 [46]。大量研究均证实，不超过2小时的热刺激会延长动物的寿命，与之相反的是，更长时间的热刺激要么没有影响，要么甚至对机体有害 [51-53]。
科学家们对反复轻度热刺激正常人表皮角质细胞影响的研究则从另一个角度证实了热刺激的毒物兴奋效应 [54]。研究发现，细胞在反复暴露于41°C 的温和恒温恒湿条件下也表现出多种抗衰老效应，而在反复暴露于43°C时则看不到类似的结果。
总得来说，毒物兴奋效应的双相剂量效应特征在刺激时间和刺激强度两个维度均得到了体现，这便启示着我们，当我们试图从某个维度尝试毒物刺激而发现自身无法承受时，或许可以换个维度再试试。
像日本人民酷爱的桑拿活动，就是热刺激中较为容易被人接受的一种，已经被科学家们证明可以降低全身炎症水平以及老年痴呆的发病风险 [55, 56]，或许这也是日本人民长寿的密码之一吧。
No.2
冷刺激
相比热刺激，冷刺激的毒物兴奋效应更晚才被逐渐证实 [54]，可能与通过激活PA28γ/PSME3 激活胰蛋白酶样活性有关。
尽管极端低温对生物体有害，但适度降低体温对生物体也有好处 [57]。经大量研究报道，降低体温可延长食肉动物 [58-63]和啮齿动物等恒温动物的寿命 [64]。
另一个有趣的事实是，自工业革命以来，人类体温每十年单调下降0.03°C，有研究证实，这与过去160 年人类寿命的逐步延长有潜在联系 [65]。
图注：如图，随着时代变化，人类的平均体温始终呈现下降态势 [65]
膳食营养物质
多种膳食成分如维生素、抗氧化剂、微量元素、矿物质、乙醇，都被证明具有典型的毒物剂量反应 [66]。
甚至还有研究发现，我们平时畏之如虎的农药百草枯，其在低浓度下也可以轻度诱导秀丽隐杆线虫体内的氧化应激，延长其寿命 [67]。
所有这些化合物（天然的或合成的）都通过一种或多种维持和修复途径以及应激反应途径产生有益的生物效应 [13]。
辐射
高剂量辐射当然会缩短寿命，但科学家们也发现，低剂量辐射可以延长果蝇 [68, 69]和家蝇 [70]以及大鼠和小鼠 [71,72]等生物的寿命。
有趣的是，据报道，英国原子能管理局所有工人的死亡率低于全国的死亡率 [73]。且核工作人员的全因死亡率和全因癌症（白血病和前列腺癌）也明显低于非辐射工作人员 [73]。不知道会不会有抗衰极客看到这些报道，跑去福岛定居呢（开玩笑）。
相关研究表明，低剂量辐射的延寿作用可能与调节免疫反应、刺激造血系统、抗氧化、减少DNA损伤以及提高DNA损伤修复能力有关 [74]。
超重力、种群密集压力、精神和心理压力
要说派派最感兴趣的一类毒物刺激，那真得是包括超重力、心理压力在内的多种压力刺激。
No.1
超重力
相关研究证实，啮齿动物和果蝇终生暴露在超重力环境中会缩短寿命，而在生命早期阶段暴露在3或5克重力环境中2周，雄性黑腹果蝇的寿命会延长 15% [75,76]。
No.2
种群密集压力
也有一些科学家异想天开，将生命早期阶段的种群密度压力也放进了研究范畴。然而出人意料的是，这异想天开还成真了。例如，有报告称，尽管存活率急速下降，但随着种群密度的增加，果蝇的发育时间、抗饥饿能力、相对脂肪含量和寿命也会增加 [77]。
No.3
精神和心理压力
尽管慢性和急性精神压力对生活功能、生活质量和生存的有害影响已得到充分证实 [78,79]，但周期性低水平精神压力的有益影响得到了科学家们的关注。
例如，一些初步研究表明，通过心理挑战 [79,80]和集中精神的冥想技术 [53,81-84]可能有助于刺激应激反应以及细胞间和细胞内碎片清除过程。
时光派点评
说了这么多，大家应该都已经意识到了毒物兴奋效应对于生物体寿命的有益影响，但不幸的是，这个大自然赐予生命的进化利器同时也可能是束缚寿命的绳索。
正如这篇论文的标题Hormesis defines the limits of lifespan所言，毒物兴奋效应决定了寿命的上限，在毒物兴奋效应法则的束缚之下，无论那种刺激都只能让我们最多延长30到60%的寿命。
不过，派派认为我们大家不必太过悲观，大家不妨想想，我们的祖先在猛兽口中过着朝不保夕，寿命只有三十几年甚至十几年的生活的时候，会想到如今某些国家的平均寿命已经接近80岁了吗？
我们目前还不清楚为什么毒物兴奋效应的有益影响会局限在30-60% 的范围之中，或许随着我们对生命系统乃至进化法则的深入理解，一切束缚人类长生的枷锁，都将像那端粒一样，逐渐被挣脱。
还是那句话，“那些杀不死我的，都将让我更加强大”。
—— TIMEPIE ——
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