Rewinding the Clock 时钟倒转

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Treatment restores blood vessel growth, muscle vitality, boosts exercise endurance in aging animals

治疗恢复血管生长,肌肉活力,增强老化动物的运动耐力By EKATERINA PESHEVA 作者: EKATERINA PESHEVA March 22, 2018 2018年3月22日 Research 研究2.3K 2.3 k

Rewinding the Clock

Scientists have reversed vascular atrophy, restored vessel growth in mice. Photo: Kevin Krull, for HMS. Video: Rick Groleau and Ekaterina Pesheva. 科学家们逆转了血管萎缩,恢复了老鼠血管的生长。图片来源: Kevin Krull,HMS。视频: Rick Groleau 和 Ekaterina Pesheva

We are as old as our arteries, the adage goes, so could reversing the aging of blood vessels hold the key to restoring youthful vitality? 

The answer appears to be yes, at least in mice, according to a new study led by investigators at Harvard Medical School.

The research, published March 22 in Cell, identifies the key cellular mechanisms behind vascular aging and its effects on muscle health and has successfully reversed the process in animals.

俗话说,我们和我们的动脉一样老,所以逆转血管的老化是恢复青春活力的关键吗?根据哈佛医学院研究人员的最新研究,答案似乎是肯定的,至少在老鼠身上是这样。这项研究发表在3月22日的《细胞》杂志上,确定了血管老化背后的关键细胞机制及其对肌肉健康的影响,并成功地逆转了动物的这一过程。

The findings pinpoint a glitch in the normal crosstalk that occurs between muscles and blood vessels and keeps both tissues healthy.

这些发现指出了正常的肌肉和血管之间发生的相互干扰的一个小故障,这个小故障可以保持两个组织的健康。

Using the synthetic precursors of two molecules naturally present in the body, the scientists also managed to reverse blood vessel demise and muscle atrophy in aging mice, boosting their exercise endurance in the process. 

The achievement, the team said, paves the way to identifying related therapies for humans.

“We’ve discovered a way to reverse vascular aging by boosting the presence of naturally occurring molecules in the body that augment the physiological response to exercise,” said study senior investigator David Sinclair, professor in the Department of Genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School.

通过使用体内自然存在的两种分子的合成前体,科学家们还成功地逆转了老鼠的血管死亡和肌肉萎缩,在这个过程中提高了它们的运动耐力。研究小组说,这一成就为确定人类的相关治疗方法铺平了道路。哈佛医学院遗传学系教授、哈佛医学院保罗 · f · 格伦衰老生物学中心联合主任、资深研究员大卫 · 辛克莱说: “我们发现了一种逆转血管衰老的方法,即通过增加体内自然存在的分子来增强对运动的生理反应。”。

“The approach stimulates blood vessel growth and boosts stamina and endurance in mice and sets the stage for therapies in humans to address the spectrum of diseases that arise from vascular aging,” added Sinclair, who is also a professor at the University of New South Wales School of Medical Sciences in Sydney, Australia.

辛克莱同时也是澳大利亚悉尼新南威尔士大学医学院的教授,他补充说: “这种方法刺激了小鼠的血管生长,提高了小鼠的耐力和耐力,为人类治疗血管衰老引起的疾病创造了条件。”。

The researchers caution that many promising treatments in mice don’t have the same effect in humans due to critical differences in biology. However, the results of the experiments were dramatic enough to prompt the research team to pursue experiments in humans. Clinical trials for safety are already under way, Sinclair said. 

研究人员警告说,由于生物学上的关键差异,许多有前景的小鼠治疗方法在人类身上并没有同样的效果。然而,实验的结果是戏剧性的,足以促使研究小组进行人体实验。辛克莱说,安全性的临床试验已经在进行中。

As old as our blood vessels

和我们的血管一样古老

Sinclair and team set out to unravel the mechanisms behind one of biology’s inevitabilities: aging. 

As we grow old, we become weak and frail. A constellation of physiological changes—some subtle, some dramatic—precipitate this inevitable decline. What exactly happens inside our cells to cause the biological shifts that lead to aging? It’s a question that has vexed Sinclair and team for years.

As we age, our tiniest blood vessels wither and die, causing reduced blood flow and compromised oxygenation of organs and tissues. Vascular aging is responsible for a constellation of disorders, such as cardiac and neurologic conditions, muscle loss, impaired wound healing and overall frailty, among others. Scientists have known that loss of blood flow to organs and tissues leads to the build-up of toxins and low oxygen levels. The so-called endothelial cells, which line blood vessels, are essential for the health and growth of blood vessels that supply oxygen-rich and nutrient-loaded blood to organs and tissues. But as these endothelial cells age, blood vessels atrophy, new blood vessels fail to form and blood flow to most parts of the body gradually diminishes. This dynamic is particularly striking in muscles, which are heavily vascularized and rely on robust blood supply to function.

Muscles begin to shrivel and grow weaker with age, a condition known as sarcopenia. The process can be slowed down with regular exercise, but gradually even exercise becomes less effective at holding off this weakening.

Sinclair and team wondered: What precisely curtails the blood flow and precipitates this unavoidable decline? Why does even exercise lose its protective power to sustain muscle vitality? Is this process reversible?

In a series of experiments, the team found that reduced blood flow develops as endothelial cells start to lose a critical protein known as sirtuin1, or SIRT1. Previous studies have shown that SIRT1 delays aging and extends life in yeast and mice. 

SIRT1 loss is, in turn, precipitated by the loss of NAD+, a key regulator of protein interactions and DNA repair that was identified more than a century ago. Previous research by Sinclair and others has shown that NAD+, which also declines with age, boosts the activity of SIRT1.

辛克莱尔和他的团队着手揭开生物学中一个不可避免的机制: 衰老。随着年龄的增长,我们变得虚弱。一系列的生理变化ーー有些微妙,有些戏剧性ーー促成了这种不可避免的衰退。我们的细胞内究竟发生了什么,导致了导致衰老的生物学变化?这个问题困扰了辛克莱尔和他的团队多年。随着年龄的增长,我们最细小的血管会萎缩和死亡,导致血液流量减少,器官和组织的氧化作用受到损害。血管老化是一系列疾病的罪魁祸首,比如心脏和神经系统疾病,肌肉萎缩,伤口愈合受损,整体虚弱等等。科学家已经知道,血液流向器官和组织的损失会导致毒素和低氧水平的积累。所谓的血管内皮细胞,即血管的内皮细胞,对于血管的健康和生长至关重要,为器官和组织提供富含氧气和营养的血液。但是随着这些内皮细胞的老化,血管萎缩,新的血管无法形成,流向身体大部分部位的血液逐渐减少。这种动力在肌肉中尤其明显,因为这些肌肉有着大量的血管供应,并且依赖于强健的血液供应来维持功能。随着年龄的增长,肌肉开始萎缩,变得越来越脆弱,这种情况被称为骨骼肌减少症。这个过程可以通过有规律的锻炼来减缓,但是渐渐地,即使是锻炼也不能有效地延缓这种减弱。辛克莱和他的团队想知道: 到底是什么抑制了血液流动,促使了这种不可避免的衰退?为什么即使是运动也会失去保护肌肉活力的能力?这个过程可逆吗?在一系列的实验中,研究小组发现,当内皮细胞开始失去一种被称为 sirtuin1或 SIRT1的关键蛋白质时,血流量就会减少。先前的研究表明,SIRT1延缓衰老,延长酵母菌和小鼠的寿命。一个多世纪以前,人们就发现了 NAD + 是蛋白质相互作用和 DNA 修复的关键调节因子,它的缺失反过来又加速了 SIRT1的缺失。先前辛克莱和其他人的研究表明,NAD + 也会随着年龄的增长而减少,它会增强 SIRT1的活性。

A stimulating conversation 

一次激动人心的谈话

The study reveals that NAD+ and SIRT1 provide a critical interface that enables the conversation between endothelial cells in the walls of blood vessels and muscle cells.

研究表明 NAD + 和 SIRT1提供了一个关键的界面,使血管壁和肌肉细胞内的内皮细胞之间的对话。

Specifically, the experiments reveal that in young mouse muscle, SIRT1 signaling is activated and generates new capillaries, the tiniest blood vessels in the body that supply oxygen and nutrients to tissues and organs. However, as NAD+/SIRT1 activity diminishes over time, the study found, so does the blood flow, leaving muscle tissue nutrient-deprived and oxygen-starved. 

Indeed, when researchers deleted SIRT1 in the endothelial cells of young mice, they observed markedly diminished capillary density and decreased number of capillaries, compared with mice that had intact SIRT1. Mice whose endothelial cells lacked SIRT1 had poor exercise tolerance, managing to run only half the distance covered by their SIRT1-intact peers.  

具体来说,实验表明,在小鼠的肌肉中,SIRT1信号被激活并产生新的毛细血管,毛细血管是身体中为组织和器官提供氧气和营养的最小血管。然而,研究发现,随着 NAD +/SIRT1活性随着时间的推移而减少,血流量也随之减少,导致肌肉组织缺乏营养和缺氧。事实上,当研究人员删除年轻小鼠内皮细胞的 SIRT1时,他们观察到毛细血管密度明显减少,毛细血管数量减少,与完整的 SIRT1小鼠相比。内皮细胞缺乏 SIRT1的小鼠运动耐受力较差,只能跑完 SIRT1完整小鼠一半的距离。

To determine SIRT1’s role in exercise-induced blood vessel growth, the researchers observed how SIRT1-deficient mice responded to exercise. After a month-long training regimen, the hind-leg muscles of SIRT1-deficient mice showed markedly diminished ability to form new blood vessels in response to exercise compared with same-age mice that had intact SIRT1 in their endothelial cells.

Exercise-induced blood vessel formation is known to occur in response to growth-stimulating proteins released by muscles under strain. SIRT1, however, appears to be the key messenger relaying growth-factor signaling from muscles to blood vessels, the study found.  

Experiments showed that endothelial cells lacking SIRT1 were desensitized to the growth-stimulating proteins released by exercised muscles.

“It’s as if these cells had grown deaf to the signals that muscles sent their way,” Sinclair said.

The observation, he added, explains why age-related loss of SIRT1 leads to muscle atrophy and blood vessel demise.

Since the experiments revealed the critical role of SIRT1 in exercise-induced blood vessel formation, the researchers wondered whether boosting SIRT1 levels would stimulate blood vessel growth and stave off muscle wasting.

为了确定 SIRT1在运动诱导的血管生长中的作用,研究人员观察了 SIRT1缺陷小鼠对运动的反应。经过一个月的训练后,SIRT1基因缺陷小鼠的后腿肌肉与同龄小鼠的内皮细胞中有完整 SIRT1基因的小鼠相比,在运动后显示出明显的减少形成新血管的能力。众所周知,运动诱导的血管形成是由于肌肉在压力下释放刺激生长的蛋白质而发生的。然而,研究发现,SIRT1似乎是将生长因子信号从肌肉传递到血管的关键信使。实验表明,缺乏 SIRT1的内皮细胞对运动后肌肉释放的刺激生长蛋白失敏。“这就好像这些细胞对肌肉发出的信号变得失聪了,” Sinclair 说。他补充说,这一观察结果解释了为什么与年龄相关的 SIRT1缺失会导致肌肉萎缩和血管死亡。由于实验揭示了 SIRT1在运动诱导的血管形成中的关键作用,研究人员想知道提高 SIRT1水平是否会刺激血管生长并延缓肌肉萎缩。

Exercise in a pill?

吃药锻炼?

The scientists set their sights on NAD+, a molecule conserved across many life forms, known to decline with age and previously shown to stimulate SIRT1 activity.

科学家们把目光投向了 NAD + ,这是一种存在于许多生命形式中的分子,已知它会随着年龄的增长而衰退,并且以前曾被证明会刺激 SIRT1的活性。

“We reasoned that declining NAD+ levels reduce SIRT1 activity and thus interfere with aging mice’s ability to grow new blood vessels,” said study first author Abhirup Das, who conducted the work as a post-doctoral fellow in Sinclair’s lab, currently a visiting scholar in genetics at Harvard Medical School and a post-doctoral research fellow at the University of South New Wales School of Medical Sciences. 

“我们的理由是 NAD + 水平的下降降低了 SIRT1的活性,从而干扰了衰老老鼠生长新血管的能力,”该研究的第一作者 Abhirup Das 说,他是 Sinclair 实验室的博士后研究员,目前是哈佛医学院的遗传学访问学者和南新威尔士大学医学院的博士后研究员。

To test this premise, scientists used a chemical compound called NMN, a NAD+ precursor, previously shown to play a role in repairing cellular DNA and maintaining cell vitality.

In lab dish experiments, endothelial cells from humans and mice treated with NMN showed enhanced growth capacity and reduced cell death.

Next, the team gave NMN over two months to a group of mice that were 20 months old—the rough equivalent of 70 in human years. NMN treatment restored the number of blood capillaries and capillary density to those seen in younger mice. Blood flow to the muscles also increased and was significantly higher than blood supply to the muscles seen in same-age mice that didn’t receive NMN.

为了验证这一假设,科学家们使用了一种叫做 NMN 的化合物,这是一种 NAD + 的前体,以前被证明在修复细胞 DNA 和维持细胞活力方面起着重要作用。在实验室的培养皿实验中,来自人和小鼠的内皮细胞经 NMN 处理后表现出增强的生长能力和减少的细胞死亡。接下来,研究小组在两个月内给一组20个月大的老鼠注射 NMN ーー大致相当于人类年龄的70只。NMN 治疗使小鼠毛细血管数量和毛细血管密度恢复到年轻小鼠的水平。流向肌肉的血流量也增加了,明显高于未接受 NMN 的同龄小鼠的肌肉供血量。

The most striking effect, however, emerged in the aging mice’s ability to exercise. These animals showed between 56 and 80 percent greater exercise capacity, compared with untreated mice the study showed. The NMN-treated animals managed to run 430 meters, or about 1,400 feet, on average, compared with 240 meters, or 780 feet, on average, for their untreated peers. 

To see whether the effects of NMN could be further augmented, the researchers added a second compound to the treatment regimen. The compound, sodium hydrosulfide (NaHS), is a precursor to hydrogen sulfide, which also boosts the activity of SIRT1. 

然而,最显著的效果出现在衰老老鼠的运动能力上。研究显示,与未经治疗的老鼠相比,这些老鼠表现出了56% 到80% 的运动能力。接受 nmn 治疗的动物平均可以跑430米,即1400英尺,相比之下,没有接受 nmn 治疗的动物平均可以跑240米,即780英尺。为了观察 NMN 的作用是否可以进一步增强,研究人员在治疗方案中加入了第二种化合物。这种化合物,硫氢化钠(NaHS) ,是硫化氢的前体,也能增强 SIRT1的活性。

A group of 32-month-old mice—the rough equivalent to 90 in human years—receiving the combo treatment for four weeks were able to run, on average, twice as long as untreated mice. In comparison, mice treated with NMN alone ran 1.6 times farther, on average, than untreated animals.

一组32个月大的老鼠(大约相当于人类年龄的90岁)在接受四周的联合治疗后,能够平均比未接受治疗的老鼠跑两倍的时间。相比之下,单独使用 NMN 的老鼠比未使用 NMN 的老鼠平均多跑1.6倍。

“These are really old mice so our finding that the combo treatment doubles their running capacity is nothing short of intriguing,” said study co-author James Mitchell, associate professor of genetics and complex diseases at the Harvard T. H. Chan School of Public Health.  Research led by Mitchell and published in the same issue of Cell also found sodium hydrosulfide to augment blood vessel formation in the muscles of mice.

Interestingly, the NMN treatment did not improve blood vessel density and exercise capacity in young sedentary mice. However, it did boost blood vessel formation and exercise capacity in young mice that had been exercising regularly for a month.

“This observation underscores the notion that age plays a critical role in the crosstalk between blood vessels and muscles and points to a loss of NAD+ and SIRT1 as the reason behind loss of exercise effectiveness after middle age,” Das said.

这项研究的合著者、哈佛大学公共卫生学院(Harvard t. h. Chan School of Public Health)遗传学和复杂疾病副教授詹姆斯 · 米切尔(James Mitchell)说: “这些老鼠实在太老了,所以我们发现这种混合疗法可以使它们的运动能力增加一倍,这简直是耐人寻味。”。由 Mitchell 领导并发表在同一期《细胞》杂志上的研究也发现硫氢化钠可以增加老鼠肌肉中血管的形成。有趣的是,NMN 治疗并没有改善血管密度和运动能力的年轻久坐小鼠。然而,它确实促进了经常锻炼一个月的小白鼠的血管形成和运动能力。“这一观察结果强调了年龄在血管和肌肉之间的相互作用中起着关键作用的观点,并指出 NAD + 和 SIRT1的缺失是中年以后运动效率下降的原因,” Das 说。

The researchers say their findings may pave the way to therapeutic advances that hold promise for the millions of older people for whom regular physical activity is not an option.

研究人员说,他们的研究结果可能为治疗方面的进步铺平道路,这些进步为数百万老年人带来了希望,对他们来说,有规律的身体活动是不可能的。

“Even if you’re an athlete, you eventually decline,” Sinclair said. “But there is another category of people—what about those who are in a wheelchair or those with otherwise reduced mobility?”

“即使你是一个运动员,你最终也会衰退,”辛克莱说。“但还有另一类人——那些坐轮椅的人或者行动不便的人怎么办? ”

The team’s ultimate goal is to replicate the findings and, eventually, move toward developing small-molecule, NMN-based drugs that mimic the effects of exercise—enhanced blood flow and oxygenation of muscles and other tissues. Such therapies may even help with new vessel growth of organs that suffer tissue-damaging loss of blood supply and oxygen, a common scenario in heart attacks and ischemic strokes, the team said.

Neo-vascularization—the formation of new blood vessels—should be treated with caution, the researchers say, because increased blood supply could inadvertently fuel tumor growth.

该团队的最终目标是复制这些发现,并最终开发小分子的、基于 nmr 的药物,模拟运动的效果ーー增强肌肉和其他组织的血液流动和氧合作用。研究小组说,这种疗法甚至可能有助于器官的新血管生长,这些器官遭受组织损伤性血液供应和氧气丧失,这是心脏病发作和缺血性中风的常见情况。研究人员说,对于新血管形成(即新血管的形成)应该谨慎对待,因为血液供应的增加可能在无意中促进肿瘤的生长。

“The last thing you want to do is provide extra blood and nourishment to a tumor if you already have one,” said study co-author Lindsay Wu, at the University of New South Wales School of Medical Sciences.

新南威尔士大学医学院的研究合著者林赛 · 吴说: “如果你已经有了肿瘤,你最不想做的就是为它提供额外的血液和营养。”。

Sinclair and Wu point out that experiments done as part of the current study provide no evidence that treatment with NMN stimulated tumor development in animals treated with the compound.

Sinclair 和 Wu 指出,作为当前研究的一部分所做的实验并没有提供证据证明 NMN 治疗会刺激用该化合物治疗的动物的肿瘤发展。

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