《自然》期刊：破解免疫系统，实现长生不老？

The human immune system is a complex beast whose multitudinous cellular and molecular components work together to shape development, protect against infections, help wounds to heal and eliminate cells that threaten to become cancerous. But it becomes less effective as people age and the system’s composition starts to change. In older age, people become susceptible to a range of infectious and non-infectious diseases — and more resistant to the protective power of vaccines.

人体免疫系统是一个复杂的野兽，其众多的细胞和分子成分共同作用，以塑造发育、防止感染、帮助伤口愈合并消除有癌变危险的细胞。但随着人们年龄的增长以及系统的组成开始发生变化，它的效率就会降低。随着年龄的增长，人们变得容易感染一系列传染性和非传染性疾病，并且对疫苗的保护能力产生更强的抵抗力。

The immune system has two main components: a fast-acting innate system, which destroys invading pathogens indiscriminately, and a more-precise adaptive immune system, whose components learn to recognize specific foreign bacteria and viruses and generate antibodies against them. The HS cells in the bone marrow spawn the immune cells of both arms of the system. They differentiate into two main classes — lymphoid and myeloid — which go on to differentiate further. Lymphoid cells are mostly responsible for adaptive immunity, and include: B cells, which produce antibodies; T cells, which help to attack invaders and orchestrate complex immune responses; and natural killer cells, which destroy infected cells. Myeloid cells include a raft of cell types involved mostly in innate immunity.

免疫系统有两个主要组成部分：快速作用的先天系统，它不加区别地消灭入侵的病原体；以及更精确的适应性免疫系统，其组件学会识别特定的外来细菌和病毒并产生针对它们的抗体。骨髓中的 HS 细胞产生系统双臂的免疫细胞。它们分化成两个主要类别——淋巴和骨髓——并进一步分化。淋巴细胞主要负责适应性免疫，包括： B 细胞，产生抗体； T 细胞，有助于攻击入侵者并协调复杂的免疫反应；和自然杀伤细胞，它可以破坏受感染的细胞。骨髓细胞包括大量主要参与先天免疫的细胞类型。

Proteins inside immune-cell-generating stem cells become more symmetrical with age (right). Credit: Eva Mejia-Ramirez

One of the earliest changes in the immune system as people age is the shrinking of the thymus, which begins after puberty. This organ is the crucible for T cells, but a lot of the tissue has turned to fat by the time people hit their 30s, slashing the production of new T cells and diminishing the power of the immune system. What’s more, the function of T cells alters as they age and become less specialized in their ability to recognize infectious agents. The proportions of different types of immune cell circulating in the blood also changes. The ratio of myeloid to lymphoid cells skews markedly towards myeloid cells, which can drive inflammation. Moreover, increasing numbers of immune cells become senescent, meaning that they stop replicating but don’t die.

随着人们年龄的增长，免疫系统最早的变化之一是胸腺萎缩，这种情况在青春期后开始。这个器官是 T 细胞的熔炉，但到了 30 多岁时，许多组织已经变成脂肪，从而减少了新 T 细胞的产生并削弱了免疫系统的力量。更重要的是，T 细胞的功能会随着年龄的增长而改变，识别传染源的能力也会变得不那么专业。血液中循环的不同类型免疫细胞的比例也会发生变化。骨髓细胞与淋巴细胞的比例明显偏向骨髓细胞，这会引发炎症。此外，越来越多的免疫细胞开始衰老，这意味着它们停止复制但不会死亡。

Any cell in the body can become senescent, typically when damaged by a mutation. Once in this state, cells start to secrete inflammatory signals, flagging themselves for destruction. This is an important anticancer and wound-healing mechanism that works well in youth. But when too much damage accumulates with ageing — and immune cells themselves also become senescent — the mechanism breaks down. Senescent immune cells, attracted by the inflammatory signals from senescent tissue, secrete their own inflammatory molecules. So not only do they fail to clean up properly, but they also add to the inflammation that damages surrounding healthy tissue. The phenomenon is known as ‘inflammaging’.

体内的任何细胞都可能衰老，通常是在因突变而受损时。一旦进入这种状态，细胞就会开始分泌炎症信号，标记自己即将被破坏。这是一种重要的抗癌和伤口愈合机制，在年轻人中效果很好。但当随着年龄的增长而积累过多的损伤时——免疫细胞本身也会衰老——这一机制就会崩溃。衰老的免疫细胞受到衰老组织炎症信号的吸引，分泌自己的炎症分子。因此，它们不仅无法正确清理，而且还会加剧炎症，损害周围的健康组织。这种现象被称为“炎症”。

Many scientists are trying to do just that, from very different angles. Lots of the approaches hint that very short treatments of the immune system might have long-term effects, keeping side effects to a more manageable minimum.

许多科学家正试图从不同的角度做到这一点。许多方法表明，对免疫系统进行非常短期的治疗可能会产生长期影响，将副作用控制在更容易控制的最低限度。

One approach is to tackle senescent immune cells head on, using drugs to either remove them or block the inflammatory factors they secrete. “Senescent immune cells have long been known to be very modifiable in humans,” says Niedernhofer. “They go up if you smoke and down if you exercise.”

一种方法是正面应对衰老的免疫细胞，使用药物去除它们或阻止它们分泌的炎症因子。 “长期以来，人们都知道衰老的免疫细胞在人类中是非常容易改变的，”尼德恩霍夫说。 “如果你吸烟，它们就会上升，如果你运动，它们就会下降。”

Some drugs — such as dasatinib, which is approved for the treatment of some cancers, and quercetin, which is marketed as an antioxidant dietary supplement but not approved as a drug — are known to reduce the age-related acceleration of senescence, and dozens of clinical trials are testing their impact on various age-related diseases. Niedernhofer herself is involved in a small clinical trial on older people with sepsis, a condition that becomes more deadly with age. Her team is also doing experiments to assess which of the many types of immune cells is the most important in driving senescence in the body, which should help in the design of more precise therapies. Two types — T cells and natural killer cells — are emerging as key contenders, she says. She plans to screen natural products and drugs already approved for use by the US Food and Drug Administration for their ability to interact with those types of immune cells in senescence.

一些药物——例如被批准用于治疗某些癌症的达沙替尼，以及作为抗氧化剂膳食补充剂销售但未被批准作为药物的槲皮素——已知可以减少与年龄相关的衰老加速，并且有数十种药物可以减少与年龄相关的衰老加速。临床试验正在测试它们对各种与年龄相关的疾病的影响。尼德恩霍夫本人参与了一项针对患有脓毒症的老年人的小型临床试验，这种疾病随着年龄的增长而变得更加致命。她的团队还在进行实验，以评估多种类型的免疫细胞中哪一种对于驱动体内衰老最重要，这应该有助于设计更精确的疗法。她说，T 细胞和自然杀伤细胞这两种细胞正在成为主要竞争者。她计划筛选美国食品和药物管理局已批准使用的天然产物和药物，以确定它们与衰老过程中这些类型的免疫细胞相互作用的能力。

The value of priming the aged immune system before administering a vaccine has been demonstrated in a series of clinical trials led by researcher Joan Mannick, chief executive of Tornado Therapeutics, which is headquartered in Boston, Massachusetts. Those trials tested analogues of the drug rapamycin and other drugs with similar mechanisms, which target the immune system and are approved for prevention of organ transplant rejection and for the treatment of some cancers. The drugs block an enzyme, called mTOR, that is crucial for many physiological functions and which becomes dysregulated in old age. For several weeks before receiving their influenza vaccinations, trial participants were treated with doses of the drugs that were low enough to avoid side effects. This treatment regimen improved their responses to the vaccine, and boosted the ability of their immune systems to resist viral infections in general.

总部位于马萨诸塞州波士顿的 Tornado Therapeutics 公司首席执行官、研究员 Joan Mannick 领导的一系列临床试验已经证明了在注射疫苗之前启动老年免疫系统的价值。这些试验测试了雷帕霉素的类似物以及具有类似机制的其他药物，这些药物以免疫系统为目标，并被批准用于预防器官移植排斥和治疗某些癌症。这些药物会阻断一种名为 mTOR 的酶，这种酶对于许多生理功能至关重要，但在老年时会变得失调。在接受流感疫苗接种前的几周内，试验参与者接受了足够低剂量的药物治疗，以避免副作用。这种治疗方案改善了他们对疫苗的反应，并增强了他们的免疫系统抵抗病毒感染的能力。

Vaccines tend to work less efficiently in older adults, but new approaches could boost their power.Credit: Hector Vivas/Getty

One other way is to try to restore the function of the thymus to maintain the production of new T cells. Immunologist Jarrod Dudakov at the Fred Hutchinson Cancer Center in Seattle, Washington, is researching the basic biology of thymus cells to try to work out how they regenerate themselves after stressful assaults. “It’s all a bit early to see how this understanding will translate into the clinic,” he says. But he thinks that maintaining the ability of the thymus to generate a broad repertoire of T cells will be “foundational”.

另一种方法是尝试恢复胸腺的功能以维持新 T 细胞的产生。华盛顿州西雅图 Fred Hutchinson 癌症中心的免疫学家 Jarrod Dudakov 正在研究胸腺细胞的基础生物学，试图弄清楚它们在压力攻击后如何自我再生。 “现在判断这种理解如何转化为临床还为时过早，”他说。但他认为维持胸腺产生广泛 T 细胞库的能力将是“基础”。

Others are trying to combat ageing by generating thymic tissue from pluripotent stem cells for eventual transplantation. But Greg Fahy, chief scientific officer at Intervene Immune in Torrance, California, says he sees no need to wait for these long-term prospects to come to fruition, because an available drug — synthetic growth hormone — is already known to regenerate thymus tissue. He is doing a series of small studies on healthy volunteers using growth hormone as part of a cocktail of compounds. Early results indicate that the participants show increased levels of functional thymic tissue, and that their epigenetic clock — a biomarker of ageing — reverses by a couple of years6. Fahy is now extending the trial to look at whether the drug cocktail also improves physical fitness in a larger group of volunteers.

其他人则试图通过利用多能干细胞产生胸腺组织以进行最终移植来对抗衰老。但加州托兰斯 Intervene Immune 首席科学官格雷格·法伊 (Greg Fahy) 表示，他认为没有必要等待这些长期前景的实现，因为已知有一种药物——合成生长激素——可以再生胸腺组织。他正在对健康志愿者进行一系列小型研究，使用生长激素作为混合物的一部分。早期结果表明，参与者的功能性胸腺组织水平有所增加，并且他们的表观遗传时钟（衰老的生物标志物）逆转了几年6。 Fahy 现在正在扩大试验范围，看看这种药物混合物是否也能改善更多志愿者的身体健康。

Another approach, not yet in the clinic, is to partially reprogram immune cells, to try to turn back the clock in cells that have become senescent. This involves transiently exposing the cells in a dish to a cocktail of transcription factors known to induce a pluripotent state in adult cells.

另一种尚未进入临床的方法是对免疫细胞进行部分重新编程，试图使衰老细胞的时钟倒转。这涉及将培养皿中的细胞短暂暴露于已知可诱导成体细胞多能状态的转录因子混合物中。

Florian’s approach, aims to produce healthier immune cells — inside the body1,2. HS cells in the blood rack up epigenetic changes, and their environment also changes as they age. This causes proteins in the cells to arrange themselves more symmetrically — a process known as polarization — which shifts the balance of stem-cell differentiation in favour of myeloid cells over lymphoid cells. Florian’s studies used a four-day treatment with a compound, called CASIN, that inhibits one part of this process to correct the polarization, and helped the mice to live longer. The team saw the same life-extending effects when HS cells from old mice given CASIN were transplanted into old mice that hadn’t received the treatment. “This very small step had a large impact,” says Florian. She next hopes to bring her work to the clinic. As a first case study, she thinks her drug might support the regeneration of the immune system after people receive chemotherapy for cancer.

弗洛里安的方法旨在在体内产生更健康的免疫细胞1,2。血液中的 HS 细胞会发生表观遗传变化，它们的环境也会随着年龄的增长而发生变化。这导致细胞中的蛋白质排列得更加对称——这一过程被称为极化——这改变了干细胞分化的平衡，有利于骨髓细胞而不是淋巴细胞。弗洛里安的研究使用了一种名为 CASIN 的化合物进行为期四天的治疗，该化合物抑制这一过程的一部分以纠正极化，并帮助小鼠延长寿命。当将接受 CASIN 治疗的老年小鼠的 HS 细胞移植到未接受治疗的老年小鼠体内时，研究小组发现了同样的延长寿命的效果。 “这一很小的一步产生了很大的影响，”弗洛里安说。她下一步希望将她的工作带到诊所。作为第一个案例研究，她认为她的药物可能支持人们接受癌症化疗后免疫系统的再生。

Research on immune ageing faces some fundamental challenges. One is shared with ageing studies in all organs — the inability to measure ageing precisely. “We don’t know in a quantitative, measurable, predictive way what ageing means at the molecular level in different cell types,” says Sebastiano. “Without those benchmarks, it is very hard to show rejuvenation.” Last year, a consortium of academics got together to begin developing a consensus on biomarkers of ageing — which will be essential when scientists come to seek approval from regulatory agencies for anti-ageing therapies.

免疫衰老研究面临一些根本性挑战。其中一个与所有器官的衰老研究共有——无法精确测量衰老。 “我们不知道以定量、可测量、预测的方式，衰老在不同细胞类型的分子水平上意味着什么，”塞巴斯蒂亚诺说。 “如果没有这些基准，就很难展现出复兴的活力。”去年，一个学术联盟聚集在一起，开始就衰老生物标志物达成共识——当科学家们寻求监管机构批准抗衰老疗法时，这一点至关重要。

Another challenge is the difficulty in pinning down what makes one immune cell unique. Until recently, it has been hard to demonstrate which subtypes of immune cells live where, and how they change with time. But technologies such as single-cell RNA sequencing, which quantitatively measures the genes being expressed in individual cells, have tightened up analysis. A large study of immune cells in the blood of mice and humans across a range of ages published last November, for example, revealed 55 subpopulations. Just twelve of those changed with age.

另一个挑战是很难确定一种免疫细胞的独特之处。直到最近，还很难证明哪些免疫细胞亚型生活在哪里，以及它们如何随时间变化。但单细胞 RNA 测序等技术可以定量测量单个细胞中表达的基因，从而加强了分析。例如，去年 11 月发表的一项针对不同年龄段小鼠和人类血液中免疫细胞的大型研究揭示了 55 个亚群。其中只有 12 个随着年龄的增长而改变。

With so many strands of research coming together, scientists are cautiously hopeful that the immune system will indeed prove to be a key lever in healthy ageing. Don’t expect an elixir of youth any time soon, says Florian — by definition, ageing research takes a long time. “But there is such great potential for translation.”

随着如此多的研究结合在一起，科学家们谨慎地希望免疫系统确实会被证明是健康老龄化的关键杠杆。弗洛里安说，不要指望很快就会有长生不老药——根据定义，衰老研究需要很长时间。 “但破译的难度十分巨大。”