Skulachev M V, Skulachev V P
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
Biochemistry (Mosc). 2017 Dec;82(12):1403-1422. doi: 10.1134/S000629791712001X.
(i) In 2015-2017 we compared possible reasons for longevity of two mammalian highly social species, i.e. naked mole rats and humans. We proposed that in both cases longevity is a result of neoteny, prolongation of youth by deceleration of late ontogeny (Skulachev, V. P. (2015) Abst. 11th Conf. on Mitochondrial Physiology (MiP2015), Lucni Bouda, Czech Republic, pp. 64-66; Skulachev, V. P., Holtze, S., Vyssokikh, M. Y., Bakeeva, L. E., Skulachev, M. V., Markov, A. V., Hildebrandt, T. B., and Sadovnichii, V. A. (2017) Physiol. Rev., 97, 699-720). Both naked mole rats and humans strongly decreased the pressure of natural selection, although in two different manners. Naked mole rats preferred an "aristocratic" pathway when reproduction (and, hence, involvement in evolution) is monopolized by the queen and her several husbands. Huge number of subordinates who have no right to take part in reproduction and hence in evolution serves the small queen's family. Humans used an alternative, "democratic" pathway, namely technical progress facilitating adaptation to the changing environmental conditions. This pathway is open to all humankind. (ii) As a result, aging as a mechanism increasing evolvability by means of facilitation of natural selection became unnecessary for naked mole rats and humans due to strong attenuation of this selection. This is apparently why aging became a counterproductive atavism for these two species and was strongly shifted to late ages. This shift is direct evidence of the hypothesis that aging is programmed, being the last step of late ontogeny. (iii) Further deceleration of aging for humans by means of neoteny is unrealistic since the development of neoteny probably takes million years. (iv) However, if biological aging is a program, an alternative and much simpler way to avoid it seems possible. We mean inhibition of an essential step of this program. (v) At present, the most probable scheme of the aging program assumes that it is a mechanism of slow poisoning of an organism by reactive oxygen species produced by mitochondria. If this is the case, a mitochondria-targeted antioxidant might be an inhibitor of the aging program. During the last 12 years, such an antioxidant, namely SkQ1, was synthesized and studied in detail in our group. It consists of plastoquinone and decyltriphenylphosphonium (a penetrating cation responsible for electrophoretic accumulation of SkQ1 in mitochondria). It was shown that long-term treatment with SkQ1 increased the lifespan of plants, fungi, invertebrates, fish, and mammals. Moreover, SkQ1 is effective in the therapy of various age-related diseases. It was also shown that a single SkQ1 injection could save life in certain models of sudden death of animals. (vi) A tentative scheme is proposed considering aging as a process of chronic phenoptosis, which eventually results in initiation of acute phenoptosis and death. This scheme also suggests that under certain conditions chronic phenoptosis can be neutralized by an anti-aging program that is activated by food restriction regarded by an organism as a signal of starvation. As for acute phenoptosis, it is apparently controlled by receptors responsible for measuring key parameters of homeostasis. The first experimental indications have been already obtained indicating that both chronic and acute phenoptosis are suppressed by SkQ1.
（i）在2015 - 2017年期间，我们比较了两种高度社会化哺乳动物——裸鼹鼠和人类——长寿的可能原因。我们提出，在这两种情况下，长寿都是幼态持续的结果，即通过减缓个体发育后期进程来延长青春时期（Skulachev, V. P.（2015年），第11届线粒体生理学会议（MiP2015）摘要，捷克共和国卢奇尼布达，第64 - 66页；Skulachev, V. P., Holtze, S., Vyssokikh, M. Y., Bakeeva, L. E., Skulachev, M. V., Markov, A. V., Hildebrandt, T. B., 和Sadovnichii, V. A.（2017年），《生理学评论》，97卷，699 - 720页）。裸鼹鼠和人类都极大地降低了自然选择的压力，不过方式有所不同。裸鼹鼠选择了一条“贵族式”途径，即繁殖（进而参与进化）由王后及其几只配偶垄断。大量无权参与繁殖因而也无权参与进化的从属个体为王后的小家庭服务。人类则采用了另一种“民主式”途径，即技术进步促进对不断变化的环境条件的适应。这条途径对全人类开放。（ii）结果，由于自然选择的强烈减弱，衰老作为一种通过促进自然选择来增加进化能力的机制，对裸鼹鼠和人类来说变得不再必要。这显然就是为什么衰老对这两个物种而言变成了一种适得其反的返祖现象，并被强烈推迟到了老年期。这种转变是衰老被编程这一假说的直接证据，衰老被认为是个体发育后期的最后一步。（iii）通过幼态持续进一步减缓人类衰老并不现实，因为幼态持续的发展可能需要数百万年。（iv）然而，如果生物衰老有一个程序，那么似乎有一种替代且简单得多的方法来避免它。我们指的是抑制该程序的一个关键步骤。（v）目前，衰老程序最可能的方案假定它是线粒体产生的活性氧对生物体进行慢性毒害的一种机制。如果是这样，一种靶向线粒体的抗氧化剂可能是衰老程序的抑制剂。在过去12年里，我们团队合成并详细研究了这样一种抗氧化剂，即SkQ1。它由质体醌和癸基三苯基鏻（一种负责SkQ1在线粒体内电泳积累的穿透性阳离子）组成。研究表明，长期用SkQ1处理可延长植物、真菌、无脊椎动物、鱼类和哺乳动物的寿命。此外，SkQ1对各种与年龄相关的疾病治疗有效。还表明，单次注射SkQ1能在某些动物猝死模型中挽救生命。（vi）提出了一个初步方案，将衰老视为慢性自然凋亡的过程，最终导致急性自然凋亡的启动和死亡。该方案还表明，在某些条件下，慢性自然凋亡可被一种抗衰老程序中和，这种程序由生物体视为饥饿信号的食物限制所激活。至于急性自然凋亡，显然由负责测量体内平衡关键参数的受体控制。已经获得了首批实验迹象，表明SkQ1能抑制慢性和急性自然凋亡。
