白藜芦醇和NMN的研究细节

《Lifespan》关于白藜芦醇和NMN的研究细节

David Sinclair 是谁？

David Sinclair是哈佛医学院遗传学系的教授，也是哈佛医学院保罗.格伦老龄生物学中心的主任，在过去的20多年一直致力于抗衰老研究。他被《时代》评为“全球100位最具影响力人物”和“医疗保健领域最具影响力50人”。他在他的新书《Lifespan》中提出：人类如何衰老，以及人类可以如何减缓甚至逆转衰老。

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THE THREE MAIN LONGEVITY PATHWAYS, mTOR, AMPK, AND SIRTUINS, EVOLVED TO PROTECT THE BODY DURING TIMES OF ADVERSITY BY ACTIVATING SURVIVAL MECHANISMS. When they are activated, either by low-calorie or low-amino-acid diets, or by exercise, organisms become healthier, disease resistant, and longer lived. Molecules that tweak these pathways, such as rapamycin, metformin, resveratrol, and NAD boosters, can mimic the beneЙts of low-calorie diets and exercise and extend the lifespan of diverse organisms.进化出三种主要的长寿途径，即mTOR，AMPK和SIRTUINS，以在逆境中通过激活生存机制来保护身体。当通过低热量或低氨基酸饮食或通过运动激活它们时，有机体变得更健康，抗病且寿命更长。调节这些途径的分子，例如雷帕霉素，二甲双胍，白藜芦醇和NAD促进剂，可以模仿低热量饮食和运动的益处，并延长多种生物的寿命。In 2002, antioxidants were all the rage. They might not have been the antiaging and health panaceas some believed them to be, but that wasn’t yet known. One of the antioxidants, scientists from the Karol Marcinkowski University of Medical Sciences (now Poznan University of Medical Sciences in Poland) had learned, was resveratrol, a natural molecule that is found in red wine and that many plants produce in times of stress. 28 A few researchers had suggested that resveratrol might explain the “French paradox,” the fact that the French have lower rates of heart disease, even though their diet is relatively high in foods containing saturated fat, such as butter and cheese.

在2002年，抗氧化剂风行一时。它们可能不是某些人认为的抗衰老和健康灵丹妙药，但这还不为人所知。来自Karol Marcinkowski医科大学（现为波兰的波兹南医科大学）的科学家了解到，其中一种抗氧化剂是白藜芦醇，白藜芦醇是一种在红酒中发现的天然分子，许多植物在压力下都会产生这种抗氧化剂。一些研究人员认为，白藜芦醇可能解释了“法国悖论”，即法国人的心脏病发病率较低，尽管他们的饮食中富含饱和脂肪的食物（例如黄油和奶酪）相对较高。

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As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the human gut, two attributes that most medicines need to be eАective at treating diseases. Despite its limitations as a drug, it did serve as an important Йrst proof that a molecule can give the beneЙts of calorie restriction without the subject having to go hungry, and it set off a global race to Йnd other molecules that might delay aging. Finally, at least in scientiЙc circles, slowing aging with a drug was no longer considered bonkers.事实证明，白藜芦醇不是很有效，也不易溶于人体肠道，这是大多数药物在治疗疾病时需要有效的两个属性。尽管它作为一种药物有局限性，但它确实是一个重要的第一个证据，即一个分子可以在不使受试者饥饿的情况下限制卡路里的摄入，它为寻找其他可能延缓衰老的分子提供了全球竞争。最后，至少在科学界，不再考虑用药物来延缓衰老。By studying resveratrol, we also learned that it is possible to activate sirtuins with a chemical. This prompted a ood of research into other sirtuin-activating compounds, called STACs, that are many times more potent than resveratrol at stimulating the survival circuit and extending healthy lifespans in animals. They go by names such as SRT1720 and SRT2104, both of which extend the healthy lifespan of mice when given to them late in life. There are, today, hundreds of chemicals that have been demonstrated to have an eect on sirtuins that are even more eective than resveratrol’s and some that have already been demonstrated in clinical trials to lower fatty acid and cholesterol levels, and to treat psoriasis in humans.

通过研究白藜芦醇，我们还了解到可以用一种化学物质激活沉默调节蛋白。这促使人们对其他沉默调节蛋白的活化化合物（称为STAC）进行了大量研究，其在刺激动物的生存回路和延长健康寿命方面的功效比白藜芦醇高出许多倍。它们以SRT1720和SRT2104之类的名字命名，当它们在生命的晚期被赋予时，它们都可以延长小鼠的健康寿命。如今，已经有数百种化学物质被证明对Sirtuins具有影响，甚至还可以起到抑制作用, 比白藜芦醇更有效，在临床试验中已经证明它们可以降低脂肪酸和胆固醇水平并治疗人类牛皮癣。

Another STAC is NAD, sometimes written as NAD+.39 NAD has an advantage over other STACs because it boosts the activity of all seven sirtuins.

另一个STAC是NAD，有时也写为NAD +。NAD比其他STAC更具优势，因为它可以增强所有7个沉默调节蛋白的活性。

NAD was discovered in the early twentieth century as an alcoholic fermentation enhancer. …… It turned out that NAD is a product of the vitamin niacin, a severe lack of which causes inamed skin, diarrhea, dementia, skin sores, and ultimately death. And because NAD is used by over ve hundred dierent enzymes, without any NAD, we’d be dead in thirty seconds.

NAD在20世纪初被发现是一种酒精发酵促进剂。…… 事实证明，NAD是维生素烟酸的产物，严重缺乏会导致皮肤受损，腹泻，痴呆，皮肤疮甚至最终死亡。而且由于NAD被超过200种不同的酶所使用，而没有任何NAD，因此我们将在30秒内死亡。

…..That all changed in the 1990s, when we began to realize that NAD wasn’t just keeping things running;it was a central regulator of many major biological processes, including aging and disease. That’s because Shin-ichiro Imai and Lenny Guarente showed that NAD acts as fuel for sirtuins. Without sucient NAD, the sirtuins don’t work eciently: they can’t remove the acetyl groups from histones, they can’t silence genes, and they can’t extend lifespan. And we sure wouldn’t have seen the lifespan-extending impact of the activator resveratrol. We and others also noticed that NAD levels decrease with age throughout the body, in the brain, blood, muscle, immune cells, pancreas, skin, and even the endothelial cells that coat the inside of microscopic blood vessels.

….. 这一切在1990年代发生了变化，当我们开始意识到NAD不仅使事情保持运转；它还是许多主要生物过程（包括衰老和疾病）的中央调节器。那是因为今井伸一郎和兰尼·瓜伦特（Lenny Guarente）表明，NAD充当sirtuins的燃料。没有有效的NAD，sirtuins不能有效地发挥作用：它们不能从组蛋白中除去乙酰基，它们不能使基因沉默，也无法延长寿命。而且我们肯定不会看到白藜芦醇活化剂能延长使用寿命。我们和其他人也注意到，随着年龄的增长，整个身体，大脑，血液，肌肉，免疫细胞，胰腺，皮肤，甚至覆盖了显微血管内部的内皮细胞的NAD含量都会下降。

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Meanwhile, on a parallel path, researchers, including us, were homing in on a chemical called nicotinamide mononucleotide, or NMN, a compound made by our cells and found in foods such as avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD. Give an animal a drink with NR or NMN in it,40 and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.同时，在平行的道路上，包括我们在内的研究人员正在研究一种名为烟酰胺单核苷酸或NMN的化学物质，这种化合物是由我们的细胞产生的，并在鳄梨，西兰花和卷心菜等食物中发现。在体内，NR转换为NMN，然后再转换为NAD。给动物喝其中含有NR或NMN的饮料，其体内NAD的水平在接下来的几个小时内上升约25％，就好像它在禁食或进行大量运动时一样。

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Every day I’m asked by members of the public, “Which is the superior molecule: NR or NMN?” We find NMN to be more stable than NR and see some health benets in mouse experiments that aren’t seen when NR is used.每天都有公众问我：“哪个是更好的分子：NR或NMN？” 我们发现NMN比NR更稳定，并且在老鼠实验中发现了一些健康优势，而使用NR则看不到。