阿尔茨海默病：病因、生物标志物与治疗 | Karl Herrup 教授

你好。

Hello.

欢迎回来，感谢你的参与。

Welcome back, and thanks for joining me.

今天，我将为你带来与卡尔·哈罗普教授关于阿尔茨海默病对话的第二部分。

Today, I bring you part two of my conversation about Alzheimer's disease with professor Carl Harrop.

如果你错过了第一部分，建议你先从那里开始。

If you missed part one, I'd start there.

我已经在节目笔记中附上了链接。

I've linked to it in the show notes.

让我们继续和卡尔交流。

Let's get back to Carl.

之前你提到了DNA损伤——嗯。

Earlier, you mentioned DNA damage Mhmm.

以及它在衰老大脑中的作用。

And the roles of that in the aging brain.

你能详细谈谈这个吗？

Can you talk a bit more about that?

好的。

Okay.

众所周知，我们的DNA是双螺旋结构，意味着两条链相互缠绕，DNA承载着制造我们体内所有蛋白质的指令。

So our DNA is is as famously a double helix, meaning it has two strands that wrap around each other, and our DNA is the holder of the instructions for how to make every protein in our body.

所以任何合成过程都离不开它。

So you need it if you're going to do any synthetic process.

双链断裂是最具破坏性的。

A double strand break is the most damaging.

当螺旋的两条链在同一位置或相近位置断裂时，会导致螺旋结构分裂成两部分。

It's when both strands of the helix break at the same spot or near the same spot, and that allows the helix to separate into two pieces.

修复这种损伤非常困难。

Fixing that damage is hard.

单链断裂则更为常见。

A single strand break is far more common.

虽然危险，但修复起来相对容易些，因为螺旋结构尚未完全分离。

It's dangerous, but a repair is a little easier because the helix hasn't come apart.

它仍由那条完整的单链维系着结构。

It's still held together by the single strand, the single intact strand.

这时可以利用完整的那条链重建另一条链应有的编码，然后像用胶带粘合一样修复它，继续正常运作。

And now you can use that intact strand to recreate the code that should be on the other strand and then scotch tape it up and and go about your business.

衰老的问题在于单链和双链断裂开始累积，且以无法修复的方式堆积。

The problem with aging is that both single and double strand breaks begin to accumulate, and they accumulate in ways that can't be repaired.

这背后具体的化学机制或许并不重要，关键在于损伤会不断累积，不仅无法修复，还会使神经元运作越来越困难。

And the detailed chemistry behind that is maybe not important, but the point is that the damage becomes cumulative, and rather than being able to be fixed, it just makes the neuron more and more difficult to operate successfully.

你正在撰写一本关于衰老的综合性著作。

You're working on your book on aging in general.

所谓的基因组不稳定性是衰老的另一标志性特征，其中就包含了DNA损伤。

So called genomic instability is another of the hallmarks of aging, and that subsumes DNA damage.

DNA损伤还有其他多种发生方式。

There are other ways that DNA damage can occur.

不仅仅是像辐射这样的各种不同压力。

It's not just through various different stresses like radiation.

也可能发生在错误的复制过程中等等。

It can be during faulty copying and so on.

你认为DNA损伤在衰老生物学中是一个特别重要的因素吗？

Do you see DNA damage as a particularly important player in the biology of aging.

如果你考虑所有导致衰老的不同因素，那么你会认同那种基于损伤的理论，还是认为它只是众多促成因素中的一部分？

If you think about all the different factors that are driving aging, then would you say that you subscribe to that type of damage based theory, or do you think that it's just one of a mosaic of different factors that contribute?

我称之为假说，因为证据并不严谨，但我认同未修复DNA损伤的积累是我们所认知的衰老驱动因素这一观点。

I'm gonna call it a hypothesis because the proof is not rigorous, but I subscribe to the view that that accumulation of unrepaired DNA damage is the driver of aging as we recognize it.

是的。

Yeah.

没错。

Yeah.

因此这个话题极为重要，不仅对阿尔茨海默症，对整体衰老而言都是如此，这意味着它关系到一系列与年龄相关的疾病。

So that makes this topic hugely important, not just for Alzheimer's, but for aging in general, which means for a whole host of age related diseases.

据估计，每个细胞每天大约会发生一万次DNA损伤。

I think it's been estimated that there are roughly ten thousand DNA lesions per cell per day.

想想你体内数万亿的细胞，每天需要修复的DNA损伤量是巨大的。

So you think about the trillions of cells in your body, that's a lot of DNA damage that has to be repaired each day.

所以这些损伤会随时间积累也就不足为奇了。

So it's no great surprise that these different lesions can accumulate over time.

确实如此。

Exactly.

确实如此。

Exactly.

因此当损伤发生时，大脑需要修复机制来修复它。

And so when that damage takes place, the brain needs repair mechanisms to fix it.

正如你指出的，DNA损伤是细胞正常存在的一部分，既来自外部伤害、辐射，也来自化学物质和致癌物。

So as you pointed out, DNA damage, it's part of the normal existence of a cell, both from external injury, radiation as you point out, but also chemicals, carcinogens.

但还有——这真是极具讽刺意味——正常的细胞活动本身也可能引发DNA损伤。

But also, and this is, you know, of course, irony of ironies, just normal cellular activity, is able to induce DNA damage.

这甚至包括像转录这样简单的过程，即根据DNA模板生成RNA。

And that includes just something as simple as transcription, which is making RNA off the DNA template.

此外，神经元活动也会以我们尚未完全理解的机制导致DNA损伤。

But also in ways we don't quite understand, neuronal activity can induce DNA damage.

因此我们的基因组每天都在遭受攻击，而我们拥有大量专门用于检测和修复DNA损伤的蛋白质。

So our genome is assaulted every day, every hour, every minute, and we have a huge, armamentarium of proteins whose function is to detect that DNA damage and fix it as best as possible.

我们具备所有这些修复机制，但它们并非完美无缺。

We've got all those repair mechanisms, but they're not flawless.

特别是在双链断裂的情况下，螺旋结构分离时可能丢失中间片段，这种修复往往比较粗糙。

And sometimes the repair especially with double strand breaks where you helix comes apart and you don't quite know if maybe a little piece came out of the middle there, the repair is kinda slipshod.

把螺旋结构重新拼合起来，可能比完全精确修复更为重要。

And putting the helix back together, maybe that's more important than getting it exactly right.

或许99%的情况下确实如此，但很多时候并非这样。

Probably 99 times out of 100, that's true, but lots of times it isn't.

这些DNA双螺旋上的'疤痕'会不断累积。

And these scars, if you will, on the DNA double helix, accumulate.

从单个细胞的角度来看，它们使细胞功能变得越来越困难。

And on a cell by cell basis, they make cellular function more and more difficult.

我们可以从中得出几点结论。

We could argue from that a couple of things.

其中一点我在书中确实有论证，即所有这些损伤对每个细胞来说都是独特的。

One I think I do argue in the book, which is that all of this damage is going to be unique to every single cell.

辐射损伤是随机的。

Radiation damage is is random.

初步近似来看，它不会优先攻击螺旋结构的任何特定部分。

It doesn't strike any particular part of the helix preferentially to a first approximation.

化学诱变剂也是如此。

And the same with chemical mutagens.

虽然对神经元活动来说不完全适用，但对转录和RNA合成过程来说基本成立。

Not it's a little less true for neuronal activity, but certainly not much less true for transcription, RNA synthesis.

简而言之，损伤对每个细胞都是独特的，但平均而言，随着年龄增长每个细胞都会积累伤痕。

So it's a long winded way of saying the damage is going to be unique to each cell, but on average, each cell is going to accumulate scars as we age.

这意味着衰老实际上发生在细胞层面。

But the implication is that aging therefore occurs at the level of the cell.

因此每个细胞都会衰老，而我们感知到的衰老现象——白发、皱纹——实际上是众多细胞行为的总和，每个细胞都在尽其所能应对基因组完整性的丧失。

So each cell ages, and what we perceive as aging, the graying of hair, the wrinkling of skin, is actually a sum of the behaviors of a lot of individual cells, each of them dealing with the loss of their genomic integrity as best they can.

这也说明我们的大脑会衰老，身体其他部分同样如此。

But what that also says is that our brains age, but then so does the rest of our body.

正如之前所说，大脑不是孤岛，它存在于包含肝脏、胆囊、肌肉等器官的代谢环境中。

And as we said before, the brain is not an island, it exists in a metabolic context that includes the liver, the gallbladder, the muscles, what have you.

因此，不仅大脑中的单个神经元在经历自身的老化过程，它们还处在一个随着老化持续而变得越来越不友好的环境中。

So not only are the individual neurons of the brain undergoing their own aging process, but they're dealing with an environment that is increased less and less friendly as the aging process persists.

将这一点与整体免疫活动联系起来，身体其他部位的免疫活动也会影响大脑中的情况。

Tying that into immune activity in general, immune activity elsewhere in the body is going to influence what's going on in the brain too.

所以如果你感染了病原体，就像不幸的是，卡尔，我想你最近在中国又感染了SARS-CoV-2。

And so if you contract a pathogen, as unfortunately, I think you did recently, Carl, I think while you're in China, you picked up SARS CoV two again.

是这样吗？

Is that right?

是在

Was in

芝加哥机场。

the Chicago Airport.

我不会抓到你。

I'm not gonna catch you.

那里又挤又热，我一时疏忽没戴口罩。

It's crowded and hot, and and I I got sloppy and didn't wear my mask.

所以就是那一次。

So So it's that one time.

是的。

Yeah.

嗯，一次就够了。

Well, that's all it takes.

说到这个，包括SARS-CoV-2在内的各种感染都会增加患痴呆症的风险。

On that note, various different infections, including SARS CoV two, you have been released to an increased risk of dementia.

显然，虽然它出现的时间不长，但新冠肺炎和长期新冠似乎显著增加了患某些类型痴呆症的风险。

And, obviously, it hasn't been around that long, but COVID nineteen and long COVID seem to quite substantially affect risk of developing certain forms of dementia.

那么你能举些例子说明人们感染后如何影响患阿尔茨海默病的风险吗？

So can you give some examples of people picking up infections and then that affecting risk of Alzheimer's?

这些数据是否让你信服？

And are you compelled by those data?

我无法给出具体案例，但越来越多的数据表明，不仅像新冠这样让你卧床几天的显性感染，还包括我们一生中通常无症状积累的内源性病毒。

I can't give specific examples, but there's increasing volumes of data that link not only overt infections like COVID that, you know, throw you into bed for a couple of days, but also just endogenous viruses that, you know, we accumulate during life often asymptomatically.

这些病毒的存在总是难以评估。

The presence of these, it's always hard.

这是阿尔茨海默病研究中非常困难的领域，因为我们所有人都携带病毒载量，生活在一个生物世界而不仅是物理世界。

This is a very difficult area of Alzheimer's research because all of us carry viral loads, and we live in a biological world, not just a physical world.

我们被这些病原体包围，它们之所以存在是因为它们非常擅长侵入我们体内并进行复制。

We are surrounded by these pathogens, and these pathogens are still around because they're very good at getting into us and and replicating.

它们用于复制的场所之一就是我们的大脑。

And one of the sites they use to replicate is our brains.

这意味着即使你非常健康且完全没有反应，你体内很可能仍残留某种EB病毒感染痕迹。

So that means that even if you're perfectly healthy and and not at all responding, you very likely have remnants of some sort of Epstein Barr virus infection.

如果你没得阿尔茨海默病，那当然没问题。

If you don't get Alzheimer's, fine.

但如果你患病了，这是否可能是诱因之一？

But if you do, does that maybe contribute?

越来越多的证据表明，确实可能存在这种关联。

The evidence is piling up that, yeah, maybe it does.

当然，其中一个讽刺之处在于，现有文献中有证据表明，淀粉样肽本身的功能之一实际上是作为保护大脑免受这些病毒侵害的外衣。

Of course, one of the the ironies is that as part of this literature, there's evidence that one of the functions of the amyloid peptide itself is to actually serve as a coat to protect the brain against these viruses.

因此，如果这是真的，清除它可能并非好事。

And so getting rid of it might not be good if that's true.

谈到清除机制，大脑拥有这种宏观的废物处理系统，即所谓的类淋巴系统（glymphatic system，源于神经胶质细胞与淋巴系统的结合），这一系统直到近年才被真正认识。

Speaking about getting rid of things, the brain has this macroscopic waste disposal system, the so called glymphatic system, as in glial cells, lymphatic system, that has only really been recognized in relatively recent years.

这确实是我特别感兴趣的睡眠研究领域的真实情况。

Certainly, that's true of the field of sleep research that I've had a particularly strong interest in.

过去十年左右，人们越来越关注睡眠与该系统的关系，以及它对清除清醒时大脑中积累的某些废物的重要性。

For the last decade or so, people have increasingly focused on how sleep relates to that system and the importance of it to clearing certain wastes that accrue during wakefulness from the brain.

举例来说，我们需要记住，驱动阿尔茨海默病的未必是淀粉样蛋白，但梅根·内德加德已证明，仅仅一夜的睡眠缺失就能显著增加大脑中的淀粉样蛋白。

Just as an example of this, and we need to bear in mind that it's not necessarily amyloid that is driving Alzheimer's disease, but Megan Nedergard has shown that a single night of sleep loss can measurably increase amyloid in the brain.

你认为这个类淋巴系统的重要性有多大？

How important a player do you think this glymphatic system is?

与此相关的是，你是否认为这开始凸显了睡眠在痴呆症病理学中的普遍重要性？

And then I suppose related to that, do you think that this is starting to highlight the importance of sleep in dementia pathology in general?

对问题的第二部分，答案无疑是肯定的。

So certainly a resounding yes to the second part of that question.

睡眠障碍是阿尔茨海默病的常见症状，甚至可能是其诱因之一。

Sleep disruption is a common symptom, if not a contributor to Alzheimer's disease.

如果情况确实如此，这无疑是个令人担忧的因素。

It's certainly a worrisome factor if if if that's what's going on.

正如你指出的，我们刚刚开始认识的类淋巴系统，利用睡眠时段进行废物清理活动，清除大脑和身体不再需要、甚至不希望积累的物质。

And as you point out, the glymphatic system, which we're only now learning to appreciate, uses that period of sleep as an opportunity to do some waste disposal activities and get rid of things that the brain and the body don't need anymore, and in fact don't want accumulated.

流行病学证据相当有力，表明睡眠障碍与阿尔茨海默病存在相关性，生物学机制也很明确。

So the epidemiologic evidence is pretty strong, that sleep disruption and Alzheimer's disease are correlated, and the biology is also strong.

类淋巴系统利用睡眠时段完成大量重要工作。

The glymphatic system uses the period of sleep to do a lot of its important work.

所以，我认为这里存在关联是毋庸置疑的。

So, yeah, I think there's no question that there's a connection here.

回到您之前提到的内容，我不确定我们是否具体说明了相关结构。

Returning to something that you mentioned earlier, I'm not sure that we named the specific structures that are at play.

细胞中某些细胞器对废物处理至关重要，您在书中讨论的溶酶体就是其中之一。

There are certain organelles in cells that are key to waste disposal, and one of those that you discuss in the book is the lysosome.

能否请您简要说明溶酶体与阿尔茨海默病的关系，以及当细胞功能异常时，某些有害物质如何积累并阻碍细胞运作？

If you could just touch on how that relates to Alzheimer's and some of the nasties that can accumulate in cells and basically back cells up when they don't function correctly.

溶酶体就像是我们的垃圾处理器。

So the lysosomes are kind of our garbage disposals.

它们是充满酶的小囊泡，能将蛋白质DNA等大分子切割成小片段，使这些片段得以重新利用来组装新的蛋白质。

They're little vesicles that are full of enzymes that cut up large macromolecules like protein DNA into smaller pieces and allows those small pieces to be reused to reassemble fresh proteins.

这是更大规模的宏观结构清理系统的一部分，即我们所说的自噬作用。

It's part of a larger system of macrostructural janitorial work, if you will, known as autophagy.

自噬的字面意思就是自我吞噬。

Literally autophagy means self eating.

它使细胞能够收集较大结构，用膜包裹它们，将这些膜与溶酶体融合，然后让溶酶体继续工作，将物质分解成基本组成部分。

What it allows the cell to do is to pick up larger structures, package them in membranes, fuse those membranes with the lysosomes, and then allow the lysosomes to go ahead and do their job of breaking things down into component parts.

多年前就发现，在电子显微镜下，伴随阿尔茨海默病发展会出现溶酶体结构异常。而最近研究发现，维持溶酶体腔内的酸碱平衡正是早老素基因的功能——该基因正是阿尔茨海默病的遗传风险因素之一。

It's been known for years that there are, at the electron microscope level, there are structural abnormalities in lysosomes that accompany the progression of Alzheimer's disease, and more recently maintaining acidic balance within the lysosomal compartment turns out to be a function of none other than the presenilin gene, which is one of the genetic risk factors for Alzheimer's.

因此我们关注早老素，它是从APP前体蛋白生成淀粉样肽所需的酶之一。

So we focus on presenilin as one of the enzymes required to generate the amyloid peptide from the APP precursor protein.

但可以确定的是，这些不同突变带来的问题之一就是破坏了溶酶体内pH值维持的平衡。

But it's certainly plausible that one of the problems with these different mutations is that they upset the balance of pH maintenance within the lysosome.

所以当pH值失衡时，那些负责分解有害物质的酶就无法正常工作。

So then when the pH is off, the enzymes that break down, the stuff that you don't want don't work so well.

正确。

Correct.

然后垃圾就会堆积起来。

And then garbage can accumulate.

而且确实如此。

And does.

说到这些垃圾，有些人特别关注脂褐素的问题。

Speaking of that garbage, some people focus on lipofuskin as a particular problem.

或许你该解释下它是什么，我相信你会比我描述得更清楚。

You might want to describe what it is because I'm sure you'll do a better job than I would.

它本质上是垃圾，主要是无法被分解的脂质废物。

It's basically garbage, and it's largely lipid garbage that just is unable to be broken down.

它们倾向于在曾是溶酶体的结构中积聚，形成这些团块。

And it tends to accumulate inside structures that were once lysosomes and form these blobs.

如果你对衰老的人类大脑进行显微镜观察，特别是神经元部分，它们简直是个麻烦——因为当你尝试做荧光显微镜时，脂褐素会在所有波长下发出荧光，导致你无法透过脂褐素的荧光看到抗体标记。

If you do microscopy of the aging human brain, and in particular if you're interested in neurons, they're a damn nuisance because if you're trying to do fluorescence microscopy, lipofusion will fluoresce in all wavelengths, so you can't see your antibody for the fluorescence from the lipofusion.

抛开显微镜技术不谈，这反映了蛋白质稳态系统的崩溃。

But microscopy aside, it's a reflection of the breakdown of the proteostasis system.

这反映了我们保持自我更新的能力随着年龄增长而衰退。

It's a reflection of how our ability to keep ourselves fresh and new degrades with age.

无论是β-淀粉样蛋白沉积、tau蛋白堆积，还是其他上百种蛋白质的积聚，细胞处理这些物质的能力会随时间衰退，这不仅损害细胞本身，也对整个机体有害。

Whether it's the buildup of amyloid or the buildup of tau, or the buildup of a 100 other proteins, your cell's ability to take care of that is lost over time to the cell's detriment, but also to the detriment of the entire organism.

与此相关的是，某些细胞会面临所谓的铁死亡现象，这是由于铁离子过量积累导致脂质发生过氧化损伤。

Somewhat related to this, another issue that some cells will face is so called pheroptosis, which relates to oxalated damage to lipids as a result of excess iron accumulation.

你认为这也是阿尔茨海默症的诱因之一吗？就像整个团队里另一个微不足道的队员？

Do you think that that also is a contributor to Alzheimer's, another very minor player within the whole team?

确实是个影响因素。

It's certainly a player.

铁死亡这个概念相对较新。

This whole concept of ferroptosis is relatively new.

这个概念引起我共鸣，因为铁元素在细胞能量代谢中处于核心地位。

It resonates with me because of the centrality that iron has as a part of our cell's energy metabolism.

铁及含铁酶的使用在进化史上非常古老，因此建立铁转运和代谢的调控机制至关重要，一旦这些机制被破坏，就需要清除相关细胞。

The use of iron and iron containing enzymes are evolutionarily ancient, and so having ways of dealing with iron transport and metabolism are important, and their disruption would be one that you would want to make sure you got rid of get rid of a cell where that was lost.

这就是铁死亡的简要原理。

So that's ferroptosis in a nutshell.

顺便说，可能应该叫'铁死亡'才对。

And by the way, it probably should be ferroptosis.

也可能是细胞凋亡。

Might be apoptosis.

不，不该是细胞凋亡。

Well, it shouldn't be apoptosis.

是的。

It yes.

细胞凋亡。

Apoptosis.

确实。

Exactly.

不是细胞凋亡。

Not not apoptosis.

应该是的。

It should yeah.

所以我会采纳这个建议继续推进。

So I'll take that going forward.

呃，不行。

Well, no.

整个领域还有其他类似现象，我们...我们得学会选择战场。

The the other the entire field also paraphosis, and I I we're there let's choose our battles.

这个不在考虑范围内。

That isn't one of them.

这

The

卡尔，对我这样的人来说问题在于要花大量时间研读这些资料。

problem for people like me, Carl, is that you spend lots of time reading about this stuff.

但事实上，当需要讨论时，由于已不在学术机构任职，我只能通过播客获取相关信息。

But, actually, when it comes to discussing it, not being part of an academic institution anymore, I get that through the podcast.

所以有时候，这些只是我读到的东西，然后我会和像你这样知道正确发音的人交流。

So, occasionally, these are just times that I've read, and then I speak with people like you that know how to pronounce them.

然后

And

我想，哦，原来应该这么说，而不是我刚才说的那样。

I think, oh, that's how you say it, not the way that I just said it.

不。

No.

我会坚持用你说的方式说，因为这个领域的人会对你指指点点，他们会从眼镜上方俯视你。

I would keep saying it the way you said it because the field would call you you know, the field would look down over their glasses at you.

关于铁元素，有一个我觉得非常有趣的研究问题，在我看来尚未被充分探索。

On the subject of iron, there's a research question that I find very interesting that, to my eye, just hasn't been explored.

我认为这个问题可能很容易回答，并且在人口层面上可能具有重要意义。

I think it's probably quite easy to answer and could be meaningful at the population level.

但近年来已有一些研究关注不同身体部位（包括脑脊液）中的铁浓度，并将其与痴呆症发病率上升前瞻性关联。

But there's been some research in recent years looking at iron concentrations in different bodily compartments, including the CSF, the cerebrospinal fluid, and then associating that prospectively with an increased incidence of dementia.

这可能部分与铁死亡有关。

And this probably in part relates to ferroptosis.

如果是这样，那么降低体内铁储存的方法可能具有保护作用。

So if that's the case, then it follows that ways to reduce iron stores in the body could have some protective effects.

如果我们看关于献血的研究，它会受到所谓的健康用户偏见的干扰，因为献血者通常是更健康的人群。

And if we look at research on blood donation, then it's confounded by the so called healthy user bias in which people who give blood are generally healthier individuals.

不献血的人更可能锻炼身体，更少吸烟等等。

People who don't give blood, they're more likely to exercise, they're less likely to smoke, and so on.

然而，已有对照试验研究了献血对各种不同健康结果的急性影响。

However, there are controlled trials looking at the acute effects of blood donation on various different health outcomes.

显然，这是一个自我限制的过程。

Obviously, this is a self limiting process.

如果你来献血，而你的铁蛋白储备指标低于某个阈值，你就不能献血。

If you turn up to give blood and some proxy of your ferritin stores is below a certain threshold, you can't give blood.

如果指标足够，你就可以献血。

If it's sufficient, you can give blood.

当这种情况发生并且你随后献血时，我们会看到血压在短期内出现相当大幅度的下降。

When that's the case and you then give blood, we see quite a substantial drop in blood pressure acutely.

某些代谢健康指标也有轻微改善，比如一些致动脉粥样硬化的脂质。

There are some minor improvements in some markers of metabolic health too, such as some atherogenic lipids.

献血还可以作为一种排出异生物质的方式——那些来自环境、否则很难解毒的外来化学物质。

And giving blood as a way to offload some xenobiotics, some foreign chemicals that you get from the environment that would otherwise be very hard to detoxify.

几年前澳大利亚有一项关于消防员的有趣研究，他们通过捐献血浆（因为血浆可以比全血更频繁地捐献）发现，定期捐献血浆能使体内PFASs的浓度随时间显著下降。

There was an interesting study of firefighters in Australia a few years ago looking at giving plasma because you can donate plasma more frequently than whole blood, showing that when they gave plasma regularly, their bodily concentrations of PFASs decline meaningfully over time.

这个发现，加上流行病学研究表明献血者患某些心血管疾病的风险更低、全因死亡率略低，使我认为对于铁储备过高的人群，献血也可能降低痴呆风险。

That, plus the fact that the epidemiology suggests that people who give blood have a lower risk of certain cardiovascular diseases and have slightly lower all cause mortality suggests to me that for people with high iron stores, giving blood is something that could reduce risk of dementia too in people who are prone to high iron stores.

显然，作为男性，我们一生中从不会定期失血，所以我预计这可能对女性群体更具相关性。

And obviously, as men, at no point in our life do we lose blood on a regular basis, so I'd expect this to possibly have more relevance to the less fair sex.

当我寻找关于献血与痴呆风险的研究时，总是没有任何相关文献。

When I've looked for work looking at blood donation and dementia risk, there's always nothing out there.

嗯。

Mhmm.

这让我觉得简直是双赢，因为你必须记住献血也是一种亲社会行为。

And it just strikes me as such an easy win win because you've got to bear in mind that blood donation is something that's also prosocial.

当你献血时，你可能正在拯救某个人的生命。

You could be saving someone's life when you give blood.

对你我而言，如果我们体内铁蛋白储备过高而不自知，献血就是一种零成本的干预方式——除了你花时间去献血的机会成本。

And for you and I, if we had high ferritin stores without realizing it and we gave blood, it's a free intervention minus the opportunity cost of time that you spend going to give blood.

所以不知道是不是我漏掉了什么，但我觉得居然没人深入研究过这点，实在很不可思议。

So I don't know if I'm just missing something, but I find it bizarre that nobody has looked at that thoroughly.

我已经在PubMed上多次检索过这个主题的研究，每次真的都一无所获。

And I have scanned PubMed for work on that subject several times, and each time I really come up dry.

这是个...这是个有趣的想法。

It's an it it it's an interesting idea.

我只想补充一点，这要追溯到大概一二十年前，当时有人做过所谓螯合疗法的研究。

The only thing I would add is that there and this now goes back, oh, maybe one or two decades, is that there was work done on what was called chelation therapy.

嗯。

Mhmm.

那个理念是针对所有重金属，不仅仅是铁。

And the idea was all heavy metals, not not just iron.

那些前瞻性试验最终毫无结果。

Those prospective trials ended up drawing a blank.

我可能会和你一样认为试验周期可能不够长。

I would probably join you in arguing they may not have been long enough.

但问题在于——这是我的旧记忆了——当他们使用螯合这种粗暴手段时，最终出现了不良反应事件。

But the problem, I think, and this is old memories of mine, was that they ended up with, adverse incidents when they did some used basically a blunt instrument of trying to do chelation.

螯合疗法基本上就是往血液里注入某种物质，它能结合重金属并使其失去活性。

And chelation is basically you put something in the blood that will bind up heavy metals and make them inactive.

除此之外，我的意思是，确实，这很有说服力。

Other than that, I mean, yeah, it's it's compelling.

我确实同意你的观点，这是一个尚未被研究的领域。

And I I do agree with you that it's an area that has not been looked at.

利用像英国生物银行这样的资源来研究会很容易

It'd be very easy to look at with resources like the UK Biobank and

是的。

Yeah.

对。

Yeah.

没错。

Yeah.

根据你所说的螯合疗法，我在想如果结合其他某些干预措施是否可能增强其效果。

Based on what you're saying about chelation therapy, I wonder if its effects could be potentiated by combining it with certain other interventions too.

酮体铁解是通过谷胱甘肽失调来减轻铁引起的氧化应激，而有些方法可以提升谷胱甘肽水平。

So keto ferrotysis is some sort of dysregulation of glutathione to reduce the oxidative stress from the iron, and there are ways that you can boost glutathione.

例如，补充甘氨酸加N-乙酰半胱氨酸似乎就能做到，有研究表明静脉注射N-半胱氨酸确实能增加大脑中的谷胱甘肽。

For example, it seems that supplementing glycine plus n acetylcysteine can do that, and there's some work showing that giving n cysteine intravenously does actually increase glutathione in the brain.

所以我在想这是否能形成一种双重打击机制，既具有很好的安全性，又避免了螯合疗法那样的脱靶效应。

So I wonder if that could be a kind of double whammy there with a really good safety profile without some of the off target effects of something like chelation therapy.

但我就在想，难道没人研究过这个吗？

But I just thought, has no one looked at this?

看起来不是。

It seems like No.

这这这确实是个有趣的提问方向。

It's it's it's certainly an interesting line of questioning.

我一时想不出有什么理由会反对进行这类实验。

I can't think of anything offhand that would mitigate against, doing this kind of an experiment.

所以

So

题外话结束。

tangent over.

从痴呆症的诱因转到最后几个相关话题。

Moving on from the drivers of dementia to couple subjects to finish.

我很想听听您对预测痴呆症风险的看法。

One of the things I'd love your opinions on is forecasting dementia risk.

我注意到最近几年出现了许多试图建立阿尔茨海默病风险预测模型的尝试。

It strikes me that in the last few years, there have been many attempts to try to build models that better predict Alzheimer's risk.

其中很多模型都采用了多模态组合方法，包括从认知测试到脑部扫描再到血浆生物标志物——如今这些标志物已涵盖蛋白质组学指标，而不仅限于常规临床化学标志物。

And a lot of these rely on multimodal combinations of everything from cognitive tests to brain scans to plasma biomarkers, which nowadays include things like proteomics as opposed to just routine clinical chemistry markers.

这些模型的预测能力似乎越来越强，但问题是大多数听众无法接触到这类技术。

And they seem to be better and better at predicting risk, but the problem is that most people listening to this won't have access to those types of technologies.

基于此，您认为是否存在几种对普通人实际可行的生物标志物，能帮助识别阿尔茨海默病风险？

So based on that, do you think that there are a few biomarkers that can help people identify their Alzheimer's risk that are gonna be practical for most people?

那我可能要冒险说——没有。

So if I'm gonna go out on a limb here and say no.

有意思。

Interesting.

我希望我那些正前往多伦多参加AAIC会议的朋友们没在听，因为最近会议上很多讨论都围绕着各种生物标志物打转。

I hope all of my friends on their way to Toronto to the AAIC meeting aren't listening Because a lot of the, churn in in recent meetings has been, you know, talking about this or that biomarker.

其中绝大多数——90%的生物标志物研究——都是基于淀粉样蛋白级联假说的。

The vast majority, 90% of those biomarkers are based on the amyloid cascade hypothesis.

假说。

Hypothesis.

所以，是的。

So Yeah.

众所周知，我是这个假说的著名怀疑论者，所以在我看来，这些特定标志物作为阿尔茨海默病诊断依据的价值相当薄弱。

Since I'm, you know, a well acknowledged, skeptic of that hypothesis, the value of those particular markers as diagnostic of Alzheimer's disease, is kind of weak in my mind.

看来我的下一笔拨款要泡汤了。

And there goes my next grant.

不过话说回来，我认为是时候思考这些研究实际测量的到底是什么了。

But having said that, I think it's time to think about what these studies are actually measuring.

所以我真正好奇的是，他们有多少研究是在关注健康衰老的动态过程。

So what I do wonder is how much they're looking at dynamics of aging, healthy aging.

抱歉这可能听起来像循环论证，但这就是我们正在面对的逻辑。

I mean, I'm sorry if it sounds like circular logic, but that is the logic we're dealing with.

年龄越大，患阿尔茨海默病的风险就越高。

So if you are older, your risk for Alzheimer's goes up.

数据已经相当明确了。

You know, the data's pretty clear.

65岁后，你的风险每五年翻一番。

After age 65, your risk doubles every five years.

如果这些是衰老的标志，那么它们当然能衡量你患阿尔茨海默病的风险——不是因为它们直接与阿尔茨海默病相关，而是因为它们与衰老这一最大风险因素相关。

So if those are markers of aging, yes, of course they are going to give you a measure of your risk of Alzheimer's, not because they're related to Alzheimer's disease directly, but because they're related to its greatest single risk factor, which is aging.

我认为我们还没理清这个问题。

I don't think we've sorted that out yet.

好的。

Okay.

虽然会遭到朋友同事的强烈反对，但我最近一直在推广一个观点框架——不是模型，而是一个讨论方向。

And I would get robust and legitimate arguments from friends and colleagues on this, but I've been promoting a model not a model, but a but a a talking point recently.

这关乎功能退化，我们称之为随年龄增长的认知功能衰退。

It's about the loss of function, let's call it cognitive function, with aging.

我们的认知功能在四十多岁时达到顶峰，之后便开始衰退。

So our our cognitive function pretty much peaks when we're in our forties and declines after that.

反应速度变慢，执行处理能力下降。

Reaction time slows, executive processing.

这些都是健康的衰老现象，无需担忧。

That's all healthy aging, and there's nothing to be concerned about.

当然，除非你极度恐惧死亡——那我会担心你。

Well, I mean, unless you're terrified of death, which, then I would be concerned.

但这并非疾病。

But it's not a disease.

这只是衰老而已。

It's just aging.

阿尔茨海默病会以更快的速度损害这些认知功能。

Alzheimer's begins to degrade those very features at a more rapid pace.

因此一旦患上阿尔茨海默病（暂且不谈具体定义），认知能力衰退速度会急剧加快。

So if you kick into Alzheimer's disease, let's leave the definition alone for now, your rate of cognitive decline increases dramatically.

但有趣的是，当你进入所谓的阿尔茨海默病状态后，认知功能实际上遭受着双重损害。

However, the interesting thing is that then if you think about it, once you've entered into that state where you've, got what we are going to call Alzheimer's disease, your cognitive function is actually suffering from two deficits.

第一重是疾病本身的生物学机制，第二重则是40岁后正常衰老过程带来的功能减退。

The first is the biology of the disease itself, but the second is the decrement you suffered from when you were 40 just due to the process of normal aging.

为什么这很重要？

Why is that important?

这很重要——让我们以单克隆抗体为例来说明。

It's important because let's use the monoclonals as a lovely example.

如果使用单克隆抗体后认知衰退减缓，我们无法区分这是修复了阿尔茨海默病的病理机制，还是延缓了大脑衰老进程。

If I give you a monoclonal and your cognition begins to decline more slowly, we don't know if that was rescuing the biology of Alzheimer's disease or slowing the process of brain aging.

换句话说，它作用的是健康组织还是病变组织？

In other words, was it dealing with the healthy stuff, or was it dealing with the disease biology?

对痴呆症患者而言，这其实无关紧要。

If you're a person with dementia, that actually doesn't matter.

只要病情好转，就该积极治疗。

You're better than you would have been, so bring it on.

但对研究者来说至关重要——我们必须明确研究的是衰老机制还是疾病机制，若不能区分二者就无法取得进展。

But if you're a researcher, it matters a whole lot because we need to know when we're studying aging and when we're studying disease biology because, we're not going to make progress if we can't untangle the two of them.

更深入地理解大脑衰老过程非常重要，这样才能区分这两种发展轨迹。

It's really important to better understand brain aging because then you can decompose those two trajectories.

这让我回到了那个统一假说。

And brings me back to my, you know Unifying hypothesis.

就像持续不断的打击。

Like to beat constantly.

是啊。

Yeah.

那么可以公平地说，你对磷酸化tau蛋白217的潜在预后价值并不像大多数人那样热衷？

So it's fair to say that you're not as enthused about the potential prognostic value of phospho tau two seventeen as most people?

不。

No.

我不热衷。

I'm not.

我是说，这是疾病的症状表现吗？

I mean, is it symptomatic of the disease?

是的。

Yeah.

当然。

Sure.

它是一个有用的生物标志物吗？

Is it a useful biomarker?

当然。

Sure.

它的用处就像淀粉样蛋白扫描一样有用。

It's useful the same way an amyloid scan is useful.

你患有一种严重疾病的概率可能更高，但我并不认为它们是确凿的诊断工具。

The probability that you're suffering from a demanding illness is probably higher, but I don't find them as definitive diagnostic tools.

现在把注意力转向治疗方面，我发现一些被重新利用的药物在帮助人们预防甚至治疗阿尔茨海默症方面可能具有巨大潜力。

Now focusing on the treatment side of things, it strikes me that some medications that are being repurposed could have substantial potential in helping people prevent or even treat Alzheimer's.

这个播客是我帮助大家活得更长久、更幸福、更美好生活目标的一部分。

This podcast is part of my goal to help us all live longer, happier, better lives.

如果你觉得这个节目有趣或有帮助，我有个小请求。

If you find the show interesting or helpful, I've got a small favor to ask.

你可以通过关注节目并留下评论来帮助我帮助更多人。

You can help me help more people by following the show and leaving a review.

当然是五星好评。

Five star one, obviously.

如果你是通过Spotify或其他平台收听，也可以在那里关注节目。

If you're tuning in from Spotify or another platform, you can follow the show there too.

要获取节目更新并了解我正在学习的内容，请关注Instagram账号greg potter p h d，并订阅YouTube频道greg potter p h d。

For updates about the show and check out what I'm learning about, follow the Instagram handle at greg potter p h d, and subscribe to the YouTube channel at greg potter p h d.

非常有创意。

Very creative.

最后，如果这个播客确实为你的生活增添了价值，而你想进一步支持节目，何不把它分享给你认为也会受益的朋友或家人呢？

Finally, if this podcast has genuinely added value to your life and you want to support the show further, why not share it with a friend or family member you think will benefit from it too?

非常感谢你的支持。

Thanks so much for your support.

现在回到节目内容。

Now back to the episode.

你已经多次提到单克隆抗体，所以我其实不想在这上面多费口舌，我会在节目说明中推荐并链接你参与撰写的几篇深思熟虑的论文，这些论文基本上将它们与现有药物进行比较，展示了它们的劣势，同时也表明它们在副作用方面可能更不安全。

You've already mentioned the monoclonal antibodies a couple of times, So I actually don't want to dwell on those, and I'll refer people and link in the show notes to a couple of thoughtful papers that you contributed to where you're basically comparing them to existing medications, showing their inferiority and also showing the fact that they're probably less safe in terms of side effects.

不用说，它们价格昂贵得多。

Needless to say, they're far more expensive.

所以它们没能通过你所说的'祖母测试'——即你是否会把它用在你祖母身上，我认为这是探讨这个话题的绝佳方式。

So they don't pass what you call the grandmother test, which is would you give it to your grandmother, which I think is a great way of framing the subject.

但回到药物再利用的话题，我今天刚看到《细胞》期刊发表的一篇论文，研究的是胶质细胞和神经元的基因表达数据，比较健康个体与年龄匹配的阿尔茨海默病患者之间的差异，然后将其与现有药物对这些细胞类型基因表达的影响进行映射，最终提出了两种不同癌症药物的组合作为阿尔茨海默病的潜在疗法。

But going back to repurposing medications, I just today saw a paper that came out in Cell that was looking at gene expression data from, I think it was glial cells and neurons, and how those differ between healthy individuals and age matched individuals who have Alzheimer's disease, and then mapping that to how existing drugs affect gene expression in those cell types, and then coming up with a combination of two different cancer medications as a potential therapy for Alzheimer's disease.

我认为这是用这种统计方法识别新型干预措施的潜力的一个有趣案例。

Which I thought was an interesting example of the potential of that type of statistical approach to identifying novel interventions.

但你在书中也强调了一些现有药物可能具有潜力。

But there are also some existing medications that you highlight in your book as maybe having some potential.

所以我想先从这些药物开始讨论。

So I just wanted to start with those instead.

考虑到你对少突胶质细胞的关注，你提到我们或许可以采用多发性硬化症(MS)的药物。嗯。

Given your focus on oligodendrocytes, you mentioned that it could be that we could take multiple sclerosis, MS medications Mhmm.

鉴于这是一种由这些细胞遭受自身免疫攻击导致髓鞘丧失引发的疾病。

Given the fact that that is a disease that is driven by autoimmune attack on those cells and hence loss of myelin.

我们目前是否有证据表明这些多发性硬化症药物对阿尔茨海默病可能有效？

Do we have any evidence yet that any of those MS medications could be helpful in Alzheimer's?

不，我们没有。

No, we don't.

我的意思是，我提出这个主要是作为一个假设性的例子。

I mean, I threw it out as mostly a hypothetical example.

我是说，我会坚持这个观点。

I mean, I'll stand by it.

我认为这条路值得走下去。

I think it's worth going down that road.

但我有点喜欢你提到的那篇细胞论文的方法，因为它确实触及了我们反复讨论的核心——这是一种多因素疾病。

But I kinda like the approach of the cell paper that you mentioned because it's it it really gets at the core of of what we've talked about repeatedly during our conversation, which is that this is a multifactorial disease.

这是一种与新陈代谢密切相关的疾病。

It is a disease that is intimately rooted in metabolism.

因此要通过组合多种因素来微调控键，使功能回归到我们认为更健康的状态。

And so to use a combination of factors to tweak the tweak the control knobs and get function back towards a what we think of as a healthier state.

我喜欢这种总体思路。

I like that general approach.

我认为可以借鉴这篇论文，在实验层面进行扩展。

I think it could be expanded, you know, experimentally, taking the lead from this paper.

我预见的问题是，FDA的传统架构向来不青睐组合疗法。

The problem that I foresee is that the FDA, as it has been at least structured traditionally, does not like combinatorial approaches.

每种投入人体的药物都必须单独评估安全性和有效性。

Each drug that you put into a human has to be separately evaluated as being safe and efficacious.

而组合疗法的核心在于：单一药物可能安全，但未必有效。

And the whole point of combinatorial therapy is that any one drug is not it may be safe, but it's not efficacious.

这需要药物审批流程——我不想只说审批流程，但暂且这么简称——发生根本性变革。

So it's going to require, I think, sort of a sea change in the drug I don't want to just call it the drug approval process, but we'll use that as shorthand.

这需要从疗法审批方式、试验推进许可标准到成功证据认定等各个层面进行彻底改革。

It's going to take a sea change in how those therapies are approved, and even how trials are approved to go forward, and what constitutes evidence of success.

那么如何将这两种抗癌药物推进临床试验呢？

So how do you take the two cancer drugs to clinical trial?

我记不清具体数据了，但70岁以上的美国成年人平均服用多少种药物？

I forget the statistics regarding this, but past the age of 70, how many medications is the average US adult taking now?

五种左右？

Five or something?

我数字，

I numbers,

但我有朋友。

but I have friends.

嗯，是的。

And yeah.

对。

Yeah.

这是个正确的观察。

And it goes correct observation.

是的。

Yes.

我们或许应该研究这些药物的组合使用。

We probably should be studying these in combination with each other.

哦，没错。

Oh, yeah.

不过这会很有趣，因为显然在特朗普和RFK掌舵下，事情可能在24小时内发生变化。

It'll be interesting, though, because obviously with Trump and RFK at the helm, things can change in twenty four hours at the moment.

所以我认为这在一定程度上也取决于他们的喜好。

So I suppose it it depends in part on what they fancy too.

抗炎药怎么样？

What about anti inflammatory drugs?

书中提到的另一类是NSAIDs，即非甾体抗炎药。

Another category that came up in the book is NSAIDs, non steroidal anti inflammatory drugs.

与大多数药物相比，它们已被大量研究。

Been studied quite a lot compared to most medications.

确实如此。

They have.

我在书中提到，当我查阅临床数据时有多么沮丧——前瞻性试验表明我们无法证明它们的疗效。

And I think I say in the book how just crestfallen I was when I, you know, look over the in the clinical data, which says in prospective trials, we can't prove their efficacy.

我会坚持流行病学的观点。

I will stick by the epidemiology.

炎症确实在起作用。

Something is going on with the inflammation.

而且不仅仅是流行病学证据。

And it's not just the epidemiology.

我们在病理学中也观察到了。

We see it in the pathology.

在实验系统中同样能看到这种现象。

We see it in our experimental systems as well.

因此炎症过程确实参与其中，但任何免疫学学生都会告诉你，从细胞和激素角度来看，炎症过程都是非常复杂的。

So somehow the inflammatory process is involved, but any student who immunology will tell you that the inflammatory process is a very complicated business, both from a cellular and a hormonal point of view.

我认为例外的是，有一种类固醇在非常早期的短期临床试验中被尝试过。

The exception, I think, of a steroid that was tried very early in a very short clinical trial.

大多数试验都集中在环氧化酶抑制剂上，或许我们找错了方向——炎症过程的这一方面并非阿尔茨海默病的关键驱动因素。

Most of the trials have been on on cyclooxygenase inhibitors, and maybe we're barking up the wrong tree that that's not the it's a facet of the inflammatory process that really is the key driver of Alzheimer's.

这让我们回到衰老理论——这些衰老神经元释放出细胞因子和趋化因子的混合物，它们被统称为促炎物质，但它们并非环氧化酶。也许我们需要针对这些化合物，而不是简单地服用布洛芬然后观察效果。

Then we can bring it back to the senescence argument where these senescent neurons are putting out this cocktail of cytokines and chemokines, which are as a group called pro inflammatory, but they are not cyclooxygenase, maybe we need to address those compounds and not just throw in ibuprofen and see what happens.

如果我说错了请纠正，但据我所知，James Kirkland可能正在主导筛选潜在抗衰老物质的研究，比如非瑟酮、槲皮素联合达沙替尼，包括几项针对痴呆患者的小型先导试验。

Correct me if I'm wrong, but I think that James Kirkland is probably doing most of the work looking at candidate senolytic substances like Facetin and Quercetin plus Dasatinib, including a couple of small pilot trials of patients with dementia.

但截至目前，这些研究主要还集中在安全性评估上。

But so far, a lot of the research on those is basically just focused on safety.

嗯。

Mhmm.

所以我们确实还不清楚它们是否具有临床显著效果。

And so we we really don't know about whether they have any clinically significant effects yet.

这个说法很公允。

I think that's fair.