Metformin, AMPK, and Aging
Nir Barzilai and the TAME study that has major implications for longevity
尼尔 · 巴兹莱和 TAME 研究对长寿有重要影响
The key to longevity is balance.
After reading the paper Hallmarks of Aging, which I would say is the hallmark paper of longevity, that was my main takeaway. For the majority of the therapies, whether it came down to stem cell repletion, senescent cell eradication, or inhibition of mTOR, the key was to have the right amount of the given substance. There seems to be a “Goldilocks zone” for every hallmark and the key to longevity is maintain our bodies in that zone for as long as possible.
在阅读了《衰老的特征》这篇文章之后，我的主要收获就是这篇文章，我认为这篇文章是长寿的标志性文章。对于大多数的治疗，无论是干细胞的充实，衰老的细胞根除，抑制 mTOR，关键是有适量的给定的物质。似乎每个标志都有一个“适居带” ，而长寿的关键是尽可能长时间地保持我们的身体在这个区域内。
This principle holds true for AMPK and metformin which is the topic of this article. AMPK is one of the “big three” longevity pathways along with mTOR inhibition and sirtuin activation. They all play a big role in metabolic functions in the cell and they are key “nodes” many biological pathways.
这个原则适用于 AMPK 和二甲双胍，这也是本文的主题。AMPK 与 mTOR 抑制和 sirtuin 激活一起，是“三大”长寿途径之一。它们都在细胞的代谢功能中发挥着重要作用，是许多生物学途径的关键“节点”。
Alteration of these nodes is a good way to extend lifespan as shown in many studies on model organisms like C.elegans, and mice. Small molecules that target these three proteins have had the lion’s share of focus in the longevity world.
What is AMPK and What Does it Do?
AMPK otherwise known as AMP activated kinase is a key node in the pathway in how cells regulate metabolism based on nutrient availability. AMPK is known as the “guardian of metabolism” for its importance.
AMPK 又称 AMP 激活的激酶，是细胞基于营养物质利用率调节新陈代谢途径中的关键节点。AMPK 因其重要性被称为“新陈代谢的守护者”。
AMPK does this by sensing the AMP : ATP ratio. ATP as we all know is the energy currency of the cell which is largely produced in the mitochondria or the “power plant of the cell”. When ATP is used it is broken down into ADP, which can further break down into AMP. When there is a high concentration of AMP relative to ATP it means that cellular energy levels have gone down. AMPK can sense when this occurs because it has a binding spot for AMP which would alarm the AMPK when there is too much AMP.
AMPK 通过感知 AMP: ATP 的比例来做到这一点。众所周知，ATP 是细胞的能量货币，主要产生于线粒体或“细胞的发电厂”。当 ATP 被使用时，它被分解成 ADP，进一步分解成 AMP。当有一个高浓度的 AMP 相对 ATP，这意味着细胞能量水平已经下降。AMPK 可以感觉到这种情况发生，因为它有一个结合点的 AMP，这将警报 AMPK 时，有太多的 AMP。
AMPK is a kinase, meaning it can phosphorylate other protiens. The phosphorylation transmits signals to other protiens and can activate them to carry out certain functions. The proteins that AMPK phosphorylates key pathway in metabolism are shown here.
AMPK 是一种激酶，这意味着它可以磷酸化其他原核。磷酸化作用将信号传递给其它蛋白质，并激活它们以执行某些功能。AMPK 磷酸化代谢关键途径的蛋白质如图所示。
Most Important Functions
- inhibits mTOR → tells the cell to stop growing 抑制 mTOR →告诉细胞停止生长
- activates ULK1 → activates autophagy(breakdown of cellular/organelle junk) 激活 ULK1→激活自噬(细胞/细胞器垃圾的分解)
- activates ATGL→ fatty acid catabolism (breakdown) 激活 ATGL →脂肪酸分解代谢(分解)
- inhibits ACC→ stops fatty acid synthesis 抑制 ACC →停止脂肪酸合成
- inhibits HMG-CoA reductase → stops cholestorol synthesis 抑制羟甲基戊二酸单酰辅酶A还原酶→阻止胆固醇合成
- activates TBC1D1 → more glucose uptake + glycolysis 激活 TBC1D1→更多的葡萄糖摄取 + 糖酵解
The diagram above showcases all of the different ways that AMPK can influence metabolism. What all of these pathways have in common though is that the promote catabolism : the breakdown of materials in the cell. Opposite of anabolism, which is the build up of things in the cell, AMPK acts as like a switch to go into a catabolic state.
上面的图表展示了 AMPK 影响新陈代谢的所有不同方式。所有这些通路的共同点是促进分解代谢: 细胞内物质的分解。与合成代谢相反，合成代谢是细胞内物质的积累，AMPK 作为一个开关进入分解代谢状态。
Pretty much all the foremost longevity molecules goal is to do this — enter the catabolic state or what David Sinclair calls the “survival circuit”. The position at which most of our bodies are in due to our lifestyle is normally anabolic because of the things we eat, low amount of exercise etc. By pushing ourselves into a catabolic state it forces our body to cut out some of the junk and stay lean.
几乎所有最重要的长寿分子的目标都是做到这一点ー进入分解代谢状态，或者 David Sinclair 所说的“生存回路”。由于我们的生活方式，我们身体的大部分位置通常是合成代谢，因为我们吃的东西，少量的运动等等。通过促使我们自己进入分解代谢状态，它迫使我们的身体去除一些垃圾并保持苗条。
Caloric restriction, exercise, and hot/cold therapies have been shown to activate this process. But doing those things is hard and requires a lot of effort that not everyone is willing to put in. The key to research today is how can we augment those results with pharmacological agents with higher efficacy.
How Does Metformin Effect AMPK?
You probably know metformin as the drug that is used for type 2 diabetes. Chances are you probably know someone who is on metformin as 78million Americans were prescribed the drug in 2017. In type 2 diabetes, metformin is used to increase insulin sensitivity but research has shown it has effects that can increase longevity as well.
The mechanism of action for metformin works by inducing energy stress on complex 1 of the mitochondria which reduces the amount of ATP levels. With the concentration of ATP to AMP diminished by the metformin which in turn activates AMPK. With AMPK activated all the functions are carried out by the various pathways and the survival circuit is turned on.
二甲双胍的作用机制是通过诱导能量应激作用于线粒体复合体1，从而降低 ATP 水平。随着 ATP 到 AMP 的浓度减少，二甲双胍反过来激活 AMPK。随着 AMPK 的激活，所有的功能都通过各种途径进行，生存电路被打开。
Out of all of the potential drugs to extend longevity, metformin has been shown a increased amount of attention due to the large amount of data that has already been collected on its usage. Scientists have looked at longitudinal human data to examine metformin’s effect on lifespan which other drugs simply do not have.
Unlike the other molecules, metformin has been used widely for decades and in addition is very cheap to source. There are less safety concerns with metformin and there is less procedural concerns which can take a long chunk of the development process.
This is why one of the most groundbreaking longevity trials is being done with metformin. TAME (Targeting Aging with Metformin Trial) is the first in its kind clinical trial that is testing over 3,000 individuals. It is spearheaded by Nir Barzilai of the Albert Einstein College of Medicine and one of the most important people in the longevity field. What is most important about this study is that if it succeeds, it will be the first clinical trial approved by the FDA that includes aging as the indication.
这就是为什么最具开创性的长寿试验之一是用二甲双胍进行的。TAME (二甲双胍针对衰老试验)是第一个对3000多人进行同类临床试验的试验。这项研究由阿尔伯特·爱因斯坦医学院的 Nir Barzilai 领导，他是长寿领域的重要人物之一。这项研究最重要的一点是，如果成功，它将是第一个由 FDA 批准的临床试验，其中包括年龄作为适应症。
The TAME study will pave the way for more aggressive therapies like senolytics and rapamycin to have large scale clinical trials like TAME. Metformin likely will not add many years to total lifespan (~2 years), but the progress of this study will open the gates for bigger and better ones.
这项 TAME 研究将为更积极的治疗方法铺平道路，比如使用敏感药物和雷帕霉素进行大规模的临床试验，比如 TAME。二甲双胍可能不会增加多少年的总寿命(~ 2年) ，但这项研究的进展将打开更大和更好的大门。