医学考博题源报刊选读：Nipping ageing in the bud(2)

Potent cocktail

（烈性鸡尾酒，在这指强效混合化合物，比如后边提到的D+Q。针对前几个段落中叙述的衰老细胞其产生的危害，如毒性作用和远程破坏，研究学者最终找到了能够激活细胞凋亡的化合物）

Senescence was initially (and correctly) assumed to have evolved as an intrinsic defense against cancer: if old or damaged cells can no longer replicate, they can’t proliferate uncontrollably. But it was a mystery why they didn’t just activate a type of programmed cell death called apoptosis. The answer turned out to be that—in people roughly under 50 at least—senescent cells play a key role in the repair of damaged tissues. They enter this zombie-like state to take one last hit for the team, calling in an immune response that kill them and cleans up wider damage to the tissue, clearing the way for replacement by new cells.

衰老最初（并且正确地）被认为是一种对抗癌症的内在防御：如果衰老或受损细胞无法再复制，它们就不能不受控制地增殖。但它们为什么不直接激活一种叫做细胞凋亡的程序性死亡，这是一个谜。答案是，至少在大约50岁以下的人群中，衰老细胞在受损组织的修复中起着关键作用。他们进入这种类似僵尸的状态，为团队承受最后一次打击，召唤免疫反应杀死他们并清理更大范围的组织损伤，为新细胞更替扫清道路。

intrinsic defense 内在防御

replicate v.复制

proliferate v.增殖

activate v.激活

replacement n.代替，替换

This process is initiated by the senescent cells secreting a complex cocktail of signaling molecules which mobilizes nearby immune cells and promotes inflammation This potent stew is called the senescence-associated secretory phenotype (SASP).

这一过程最初衰老细胞会分泌一种复杂的信号分子混合物，该信号分子可以动员附近的免疫细胞并促进炎症，这种强有力的混合物被称为衰老相关分泌表型（SASP）。

As we get older, however, this process gradually diminishes and eventually backfires. As more and more cells reach the Hayflick limit or get damaged and enter senescence—including the immune cells that perform the clean-up—the sheer quantity of senescent cells overwhelms the body’s ability to clear them out and they accumulate. “They just sit there making a nuisance of themselves,” says Linda Partridge at the Max Planck Institute for Biology of Ageing in Cologne, Germany.

然而，随着年龄增长，这个过程逐渐减弱，最终适得其反。随着越来越多的细胞达到海弗利克极限或受损衰老，包括负责清理的免疫细胞，衰老细胞的数量超过了身体清除它们的能力，它们就会累积起来。在德国科隆马克斯·普朗克衰老生物学研究所工作的琳达·帕特里奇说，它们只是坐在那里自生自灭。

backfire v. 发生意外, 产生事与愿违的后果

clean-up 打扫

overwhelm v.压倒，打败

nuisance n.讨厌的东西（人，行为）

That is bad news because compounds in the SASP are toxic to healthy tissues. Left lingering inside cells, they induce DNA damage, mitochondrial dysfunction, the slowdown of processes that normally recycle bits of old cells and a host of other troubles. Outside cells, they cause prolonged inflammation and the overproduction of proteins that lead to a type of thickening of tissue in various organs, called fibrosis.

这是个坏消息，因为SASP中的化合物对健康组织存在毒性作用。如果留在细胞内徘徊，它们会导致DNA损伤、线粒体功能障碍、正常旧细胞的循环过程减慢以及一系列其他问题。在细胞外，它们会引起长时间的炎症和蛋白质过量产生，导致各种器官的组织增厚，也称为纤维化。

Cells damaged by the SASP often turn senescent themselves, so senescence creeps throughout the body with age. This is what Kirkland calls the threshold theory of senescent cell burden—once senescent cells exceed a certain level, they start to self-amplify. The SASP’s reach also travels far and wide via the bloodstream. And the longer the cells persist, the more toxic they become. “They start having mutations after a month or two and the SASP gets more and more damaging over time,” says Kirkland.

被SASP破坏的细胞本身往往会衰老，因此衰老随着年龄增长蔓延至全身。这就是柯克兰所说的衰老细胞负荷阈值理论，一旦衰老细胞超过一定水平，它们就开始自我扩增。SASP的作用范围也通过血液广泛传播。细胞存在时间越长，毒性越大。柯克兰说，它们在一两个月后开始发生突变，随着时间增长，SASP的破坏性越来越大。

amplify v. 扩增（基因，DNA序列）

persist v.持续，存留

mutation n.突变，变化

Indeed, the SASP is so toxic that it only takes a small dose of senescent cells to cause trouble. In a 2018 study, Kirkland’s team took young, healthy mice and transplanted a million senescent cells into each of them, giving them an overall senescent cell burden of 1 per10, 000 cells. The mice aged and died prematurely, of the same age-related conditions that kill naturally aged mice. The transplanted cells didn’t move far from where they were injected into the abdominal cavity, but senescent cells showed up in the limbs of the mice, confirming that the SASP can act at long distances.

的确，SASP的毒性很强，只需要少量的衰老细胞就能造成麻烦。在2018年的一项研究中，柯克兰的研究小组选取年轻健康的老鼠，并将100万个衰老细胞移植到每只老鼠身上，占其体内总细胞的万分之一。这些老鼠衰老并过早死亡，与自然衰老的老鼠死于相同的与年龄相关的疾病。移植的细胞并未远离注入腹腔的位置，但却在老鼠的四肢上出现了衰老细胞，这证实SASP可以远程发挥作用。

transplant v.移植

prematurely adv.过早地

abdominal cavity 腹腔

show up 出现，露面

limb n.四肢

Recall that one of the key features of senescent cells is that they have switched off apoptosis. “They are very resistant to dying,” says Kirkland. So, in an attempt to clear them out of the body, he and his team set out to discover compounds that could reactivate apoptosis, focusing on safe, natural compounds and drugs already approved for human use. In 2005, they reported a double success, with a cancer drug called dasatinib (D) and a plant compound called quercetin (Q). Both killed senescent cells in cell culture, and a combination of the two was more powerful than either alone. When old mice were given D+Q, it significantly rejuvenated them. Two years later, the researchers found similar success with the combination of another cancer drug, navitoclax, and a plant compound, fisetin. Together, these treatments were dubbed senolytics.

回想一下，衰老细胞的一个关键特征是它们关闭了细胞凋亡。柯克兰说，它们对死亡有很强的抵抗力。因此，为了将它们从体内清除出去，他和他的团队开始寻找能够重新激活细胞凋亡的化合物，重点是安全、天然的化合物和已获批用于人类的药物。2005年，他们宣布取得双重胜利——一种叫做达沙替尼(dasatinib)的抗癌药物和一种叫做槲皮素(quercetin)的植物化合物。它们都能杀死细胞培养中的衰老细胞，两者结合比单独使用更有效。当年老的老鼠被给予D+Q时，它大幅恢复了它们活力。两年后，研究人员发现另一种抗癌药物navitoclax和植物化合物非瑟酮的组合也取得了类似的成功。这些疗法合在一起被称为“抗衰老疗法”。

switch off 关闭

be resistant to 对…有抵抗力；耐…

in an attempt to do 企图做，尝试做

set out to do 着手做

dub v.把……称为

In animals, senolytics were found to be effective at extending both healthspan and lifespan. They also slowed the progression of numerous age-related conditions or reversed the damage caused by them, including dementia, frailty and cardiovascular disease, among others.

在动物实验中，人们发现抗衰老药能有效延长健康寿命和寿命，还减缓了许多与年龄有关疾病的进展，或逆转了由这些疾病引起的损害，包括痴呆、虚弱和心血管疾病等。

In 2016, senolytics moved into clinical trials in humans. The first to report results was for a rare and debilitating lung disease called idiopathic pulmonary fibrosis (IPF). Its cause is unknown, but it is associated with a high senescent cell burden. The researchers gave 14 people with the condition nine doses of D+Q over three weeks. Five days after the last dose, the participants could walk further and faster and rise from a chair more easily, though measures of lung function hadn’t improved.

2016年，抗衰老药物进入了人体临床试验阶段。第一个报告结果是针对一种罕见的、使人衰弱的肺部疾病——特发性肺纤维化(IPF)。其原因尚不清楚，但它与衰老细胞负担高有关。研究人员在三周内给14名患有这种疾病的人注射了九剂D+Q。最后一次服药后5天，参与者可以行走更远更快，从椅子上站起来也更容易，但肺功能没有改善。

rare adj/罕见的

debilitating adj.使衰弱的

progression n.发展，前进

IPF isn’t technically an age-related condition, despite it usually developing only after the age of 50. But the trial is proof of principle that senolytics can help with conditions in which senescent cells are a problem. “That looks as though it might be a success story,” says Patridge.

从技术上讲，IPF并非一种与年龄有关的疾病，尽管它通常在50岁以后才出现。但该试验证明了衰老药物可以帮助解决细胞衰老问题的原理。帕特里克说，这看起来似乎是一个成功的故事。

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