Quercetin

Researching the immune system in space could have payoffs for human aging on earth. Scientists have revealed how the lack of gravity affects the cells of the immune system at single cell resolution. As long as humans have been traveling into space, astronauts have experienced significant health effects from the extreme conditions of space flight, notably the reduction of gravity. Two Buck scientists led a team that has revealed for the first time how the lack of gravity affects the cells of the immune system at single cell resolution. As co-senior authors, along with Christopher E. Mason, PhD of Weill Cornell Medical College, Associate Professor David Furman, PhD and Associate Professor Daniel Winer, MD, published in the June 11, 2020 issue of Nature Communications an extensive survey of how gravity affects immune cells, and the identification of "space nutraceuticals" to counter aberrant effects of microgravity on these cells. "We show how simulated microgravity shapes immune cells and how the changes in force alter the cells' function at the single cell level," said Winer. "This level of resolution is new and exciting in understanding the effects of microgravity on cells." Using cells in simulated microgravity, combined with data from space flight from astronauts and mice on the International Space Station, the researchers created a complete picture of how the different cells of the immune system in the peripheral blood are shaped by reduced gravity. These cells include lymphocytes and monocytes, which are the main players in immunity. The study has potential implications for immune aging on Earth since the changes observed during aging resemble those captured during space travel. The team additionally outlines a pathway for identifying compounds that can reverse the effects of near zero gravity, and demonstrates that one of the compounds, quercetin, shows promise for mitigating the damage caused by spaceflight and during normal aging on the ground. "Our work provides a resource to better understand how and why the immune system changes in simulated microgravity and spaceflight," said Furman. "We also provide a way to develop countermeasures to maintain normal immunity under these harsh conditions." Astronauts in low earth orbit, such as on the International Space Station, suffer from immune system problems, especially infections, latent viruses reactivating, and skin sensitivity. These reactions occur even on short-term spaceflights. Previous studies using actual or simulated microgravity conditions have found impaired function of various immune cells. However, the fundamental mechanisms, genes, and pathways that explain immune dysfunction in microgravity were mostly unclear, the researchers said. They wanted to understand what was happening on a cellular level to explain the changes. The team, led by the study's co-first authors Buck postdoctoral researcher Fei Wu, PhD and graduate student Huixun Du, examined in depth how 25 hours of simulated microgravity affects the human peripheral blood mononuclear immune system, using samples from 27 healthy human donors between the ages of 20 and 46. To simulate an environment with almost no gravity, the team grew the cells inside of a Rotating Wall Vessel, a device developed by NASA to simulate microgravity conditions. To explore the changes caused by reduced gravity, the team used a number of techniques, including sequencing and super-resolution microscopy. They then validated their findings by comparing their data with other space studies done in humans and mice, including the JAXA (Cell-Free Epigenome study) mission, SpaceX's Inspiration 4 mission, NASA's Twins Study, and spleens from mice housed on the International Space Station. "Interestingly, changes in mechanical forces appear to orchestrate immune cell function," said Winer, whose interest in studying space medicine grew from him delving into the emerging field of mechanoimmunology, or how environmental forces affect immune cell function. Parts of astroimmunology are related to mechanoimmunolgy, but it is proving its own as a new field, he said, paving the way to better understand how to help the immune system survive in space. After unearthing several genes and biochemical pathways that are affected by microgravity, the team wanted to see if they could find any specific drugs or supplements that could protect the immune cells. To help them search, they used machine learning technology developed by Furman at the Buck, which can detect more than 2 million interactions between genes and different drugs and foods. They identified dozens of potential compounds and chose one, the plant pigment quercetin (often found in red onions, grapes, berries, apples and citrus fruits among others) to explore further since it is widely available as an antioxidant and anti-aging supplement. Quercetin turned out to reverse approximately 70 percent of the changes caused by lack of gravity and protected the cells from reactive oxygen species excess. "These findings define hallmarks of immune cell alteration in simulated microgravity, with correlation to spaceflight exposures in mice and humans," said Winer. "This work helps define avenues for future research in mechanoimmunology and astroimmunology and provides opportunities to develop countermeasures to maintain normal cellular function in space." Furman adds that this publication sets the standard for how to analyze the physiological changes that accompany space travel. "This is the first comprehensive study that provides the scientific community worldwide with an atlas to understand human biology in this extreme condition," he says. "The implications are huge, beyond humans in space," he adds. The researchers are excited to explore the parallel changes they are finding that occur in aging humans on the ground, and to use the knowledge to design interventions that can potentially reverse the immune dysfunction that accompanies aging.

▎药明康德内容团队编辑根据世界卫生组织的估计，到2050年，年龄超过60岁的人口将占据全球人口的近四分之一。随着全球老龄化进程的不断加速，“健康老龄化”也成为世界上各个国家共同关注的焦点。驱动人体衰老的因素中，衰老细胞（senescent cells）近年来成为抗衰老研究的热点之一。针对性清除衰老细胞的抗衰老药物（senolytics）已经进入临床开发阶段并且表现出可喜的效果。近日，顶尖学术期刊《自然》杂志上发表的文章对这一领域的最新进展进行了盘点。图片来源：123RF残留在身体里的“僵尸”细胞衰老细胞常被比喻成人体中的“僵尸“细胞，它们就像恐怖电影中的僵尸一样，虽然不会死去，但是也无法行使正常细胞的功能。那么这些功能失常的细胞为什么不像身体中受损的一些其它细胞一样，通过程序性死亡（又称为细胞凋亡）或者其它形式死去呢？此前的研究发现，衰老细胞之所以不死是因为它们能够提供重要的预警功能。这些细胞会分泌包括白细胞介素6（IL-6） 和干扰素γ（IFN γ）在内的大量炎症信号。它们会刺激免疫系统清除受损的细胞和组织，为组织修复和再生铺平道路。然而随着人们年龄的增长，免疫系统功能逐渐下降。衰老细胞积累得越来越多，并且导致炎症水平的过度升高。多项研究已经显示，衰老细胞的积累和炎症水平的提高与多种疾病具有相关性，包括骨质疏松、糖尿病、心脏病和阿尔茨海默病等等。因此，这也激发科学家专注于开发清除衰老细胞的方法。消灭衰老细胞的策略小分子药物衰老细胞之所以不会死去，是因为它们身体中引发细胞死亡的程序被打断，导致“该死“的细胞不死。因此，清除衰老细胞的一个方法就是恢复细胞对程序性死亡的敏感性。采用这一策略的药物研发项目已经进入临床开发阶段。例如，位于美国旧金山的UNITY Biotechnology公司开发的UBX1325（foselutoclax）是一款靶向Bcl-2家族凋亡调节蛋白成员Bcl-xL的高效小分子抑制剂。Bcl-xL在视网膜的病态血管中高度表达，促进刺激炎症和损伤血管完整性的衰老细胞的积累。通过抑制Bcl-xL的活性，UBX1325可以选择性地杀死病态血管中的衰老细胞，促进健康血管的再生和重组。去年4月，该公司公布的2期临床试验BEHOLD的长期随访试验结果显示，单次UBX1325的治疗让糖尿病黄斑水肿（DME）患者在试验期间的视力获得显著改善。48周时患者的视力与接受治疗前相比，在视力表上平均可以多看到6.2个字母。该公司的首席执行官Anirvan Ghosh博士在接受《自然》杂志采访时表示，有的患者仅接受治疗两周后就发现生活质量和颜色视觉得到显著提升。目前，该公司正在进行一项2b期临床试验，在DME患者中评估UBX1325与标准治疗相比的疗效和安全性。从头开发创新药物之外，研究人员也在探索“老药新用”的策略，利用已经获得FDA批准抗癌药物清除衰老细胞。去年9月发表在Nature Medicine上的一项临床试验中，科学家将一种已获得美国FDA批准用于治疗慢性髓系白血病和急性淋巴细胞白血病的酪氨酸激酶抑制剂dasatinib，与一种天然植物提取的黄酮类化合物——槲皮素联用（下面简称D+Q疗法），治疗5名早期阿尔茨海默病患者。这项1期临床试验结果显示，D+Q联合疗法的耐受性良好，没有发生提前停药的不良事件。研究人员在4名受试者的脑脊液中检测到dasatinib，不过未检测到槲皮素。在生物标志物方面，受试者脑脊液中的IL-6和胶质纤维酸性蛋白（GFAP）的水平升高，衰老相关细胞因子和趋化因子呈下降趋势，Aβ42水平呈上升趋势。研究人员正在进行一项包含安慰剂的更大规模的临床试验，在患有或未患阿尔茨海默病的参与者中检验D+Q组合的效果。近日，加州大学圣地亚哥分校的研究团队还开发出一种高通量筛选的技术，能够特异性针对疾病组织中的衰老细胞，筛选杀死这些细胞的抗衰老药物。在发表在Journal of Clinical Investigation上的研究中，科学家们利用这一技术，成功筛选出靶向特发性肺纤维化（IPF）患者中衰老肺细胞的候选药物。CAR-T细胞疗法CAR-T细胞疗法已经在治疗血液癌症方面展现了出色的疗效，不过它的治疗潜力远不止对抗癌症。今年在Nature Aging上发表的一篇研究中，美国冷泉港实验室（CSHL）的科学家找到了一种重编程T细胞的方法，可以让CAR-T细胞对抗衰老。概念验证实验结果显示，只要注射一针，这种CAR-T细胞就能带来长期好处，帮助年轻小鼠延缓衰老，或是帮助老年小鼠恢复青春活力，减少“老年病”。研究人员发现，在衰老细胞表面高度表达着一种名为uPAR（尿激酶型纤溶酶原激动剂受体）的受体，多个组织的老化过程中都可以看到uPAR阳性的衰老细胞随着年龄增长而不断增加。因此，他们设计了一种靶向uPAR的CAR-T细胞疗法，在小鼠实验中，3个月大的年轻小鼠接受了一剂靶向uPAR的CAR-T细胞，此后一生中都可检测到这种CAR-T细胞在其体内持续存在并扩增。而从多项代谢指标和体能指标来看，这种预防性给药给年轻小鼠带来了延缓衰老的效果，还能使年轻小鼠在高脂肪饮食的情况下避免早早出现肥胖、糖尿病等加速衰老的代谢功能障碍。▲接受过抗衰CAR-T细胞治疗的年轻小鼠衰老较慢，并且可以预防高脂肪饮食诱导的肥胖、糖尿病等疾病（图片来源：参考资料[4]）基因疗法位于美国西雅图的Oisín Biotechnologies则选择了基因疗法来消灭衰老细胞。该公司的研究人员发现，衰老细胞高度表达p16或p53。因此他们设计了一种基因疗法，将表达引发细胞程序性死亡的caspase-9蛋白的转基因送到动物体内，这一转基因只在高度表达p16的细胞中生产caspase-9蛋白，从而选择性杀死衰老细胞。在临床前研究中，科学家们让接受治疗的小鼠寿命延长20%，一次治疗可以清除高达70%的衰老细胞。“我相信抗衰老药终将影响临床应用……未知的是它会以那种形式出现”不管以哪种方式消灭衰老细胞，最关键的挑战是如何确保抗衰老药物杀死的是衰老细胞，而不是健康的细胞。超过200多名科学家已经成立了称为SenNet的合作研究项目，旨在为小鼠和人类中的衰老细胞“画像”，生成描述这些细胞特征的生物标志物图谱。而针对衰老细胞生物标志物的研究，将进一步催生更安全有效的抗衰老药物，未来有望预防或治疗年龄相关疾病。UNITY Biotechnology公司的首席执行官Ghosh博士对此充满信心。“我相信抗衰老药终将影响临床应用，”他在接受《自然》采访时表示，“现在还不清楚的是它会以什么形式出现，那款疗法将最先获得批准。”▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放题图来源：123RF参考资料：[1] How to kill the ‘zombie’ cells that make you age. Retrieved May 17, 2024, from https://www-nature-com.libproxy1.nus.edu.sg/articles/d41586-024-01370-4[2] Ageing and health. Retrieved May 17, 2024, from https://www-who-int.libproxy1.nus.edu.sg/news-room/fact-sheets/detail/ageing-and-health[3] New Technique to Identify Anti-Aging Molecules. Retrieved May 17, 2024, from https://www.ucsf.edu/news/2024/04/427496/new-technique-identify-anti-aging-molecules[4] With modification, CAR T cells can attack senescent cells, leading to slower aging in mice. Retrieved Jan 25, 2024 from https://www.cshl.edu/the-fountain-of-youth-is-a-t-cell/[5] Promising restorative therapy potentially 5 years away. Retrieved May 18, 2024, from https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新