#357 ‒ 长寿科学的新纪元：衰老模型、雷帕霉素人体试验、生物钟、潜力化合物与生活方式干预 | Brian Kennedy博士

所以当你生病时，你会看起来更老，而当你康复时，年龄又会回落。

So that's why when you get sick, you look older, and then you get better, you come back down.

第一个驱动因素并没有改变。

That first driver's not changing.

是第二个因素在波动。

It's the second one that's oscillating.

大多数干预措施似乎都影响了第二个因素，这表明我们目前的做法基本上是在边缘修修补补——我要这么说，但接下来我要加以说明。

And most of the interventions seem to affect the second one, which suggests that what we're doing right now is all right, I'm going say this, then I'm going to qualify it it suggests that what we're doing right now is sort of working around the edges.

我们正在做的一些事情可能对健康寿命产生五到十年的影响，而如果成功，这本身就是一场革命。

We're doing things that may have five or ten years impact on health span, which by the way is a revolution if that's successful.

如果我们能为每个人延长五到十年的健康寿命，我认为这将是医学上的重大突破。

I think that's a major breakthrough in medicine if we can give everybody five or ten years of extra health span.

但这些方法可能不会影响人类的最大寿命，也无法让我们活到150岁或200岁。

But these things may not impact maximum lifespan in humans, and they may not get us to one fifty or 200.

而要实现这一目标，可能需要完全不同的干预方式。

And the kinds of ways to get there may be totally different kinds of intervention.

所以我们现在和彼得一直在深入思考这个问题。

So we're thinking about that a lot with Peter right now.

我把我的研究翻译成了一个更好的术语。

And I translated my research in translated as a better term.

大约十年前，我转而投身转化研究，因为我当时想，我不想在80岁退休后，坐在门廊上无所作为，对人类毫无影响。

I switched my research into translation about ten years ago because I was like, I don't want to be retired and 80 on a porch somewhere and not have any impact on humans.

但现在，我开始回过头思考基础科学，因为我逐渐意识到，如果我们真想实现重大突破，我们所需的干预手段尚未被开发出来，我们必须回归到一些发现型科学来实现这一点。

But now I'm starting to think back a little bit to basic science because I'm starting to think that the interventions that we need to develop if we really want to have the big changes are not being done yet and we have to go back to some discovery science to do that.

所以，布莱恩，这里有

So Brian, there's a

你刚才说的很多内容都非常有趣，我想逐一拆解，不仅为了我自己，也为了听众。

lot you said there that's really interesting and I'd like to unpack it both for myself and for the listener.

你提到的第一点，实际上我不太确定是否理解正确：我们有一个线性过程，我们宽松地使用‘损伤’这个词。

The first thing you said, actually, I'm not sure I understand is, we have a linear process of we're gonna use the word damage loosely.

随着时间推移，这种损伤是单调且线性增加的。

And over time, that is increasing monotonically and linearly.

而且是不可改变的。

And not alterably.

不，正是如此。

No, exactly.

在此基础上，我们看到损伤以这种方式发生。

Superimposed on that, so we have damage occurring this way.

在此基础上，还叠加了周期性、突发性、波动性的变化，这可能解释了你所看到的两位50岁人群之间的巨大差异。

Superimposed on that, we have cyclic episodic volatile change that probably explains a lot of the difference between two 50 year olds that you might see.

你可能会看到一位50岁的人，状态非常好。

You might see a 50 year old, they look great.

你看到另一位50岁的人，却看起来像75岁。

You see a 50 year old, they look like they're 75.

为什么？

Why?

或者你甚至可能在同一个人身上看到这种差异。

Or you might see it even within an individual.

天啊，50岁的时候我看起来糟透了，但我后来调整过来了，到55岁的时候，我看起来简直像45岁。

Boy, at 50 I looked horrible but I got my act together and by 55, I actually looked like I did ten years sooner.

所以这就是这个叠加的曲线。

So that's this superimposed curve.

你说的是，从转化应用的角度来看，我们所做的一切——顺便说一下，彼得为此写了一整本书——是如何影响这种波动的？

And you're saying, look, everything we're doing from a translational perspective, all the stuff Peter talks about, by the way, wrote a whole book on this topic is how do you impact the oscillation?

如果你这样睡觉，这样锻炼，这样饮食，服用这种补充剂或药物，管理好所有这些因素，你绝对会让自己处于更好的波动波段上。

Well, if you sleep this way, if you exercise this way, if you eat this way, if you take this supplement, this drug, manage all of these factors, you are absolutely gonna put yourself on the better wave here.

但你并没有影响到这个人。

But you are not impacting this guy.

这正是我担心正在发生的事。

That's what I'm afraid is happening.

是的。

Yeah.

但你刚才说了一句话，我想确认一下我有没有理解对。

But then you said something a moment ago that I just want make sure I understand.

你对衰老遵循冈珀茨曲线而非线性曲线的解释是什么？

Is your explanation for why aging follows a Gompertz curve as opposed to a linear curve.

这是由于叠加在线性曲线之上的那个波造成的，还是有其他原因导致衰老遵循指数型的冈珀茨定律？

Is that all due to the superimposed wave that goes on top of the linear curve or was there another reason that aging follows exponential Gompertz law?

不，我认为我把两个概念混在一起了。

No, I think I had conflated two ideas at once.

好的。

Okay.

你对这个波的描述比我更清楚，我们就此打住吧。

So let me associate You described the wave better than I do, so we'll leave it at that.

我觉得你是对的。

I think that you're right.

这几乎就像我们试图在当前受损的状态下，达到最佳状态。

It's almost like we're trying to get to the best state we can be at for the damaged state we're in.

顺便说一句，布莱恩，我从未这样想过。

By the way, I have never thought of it that way, Brian.

我喜欢这个描述。

I love that description.

这实际上也是我对我的病人说的话，因为有人来找我，说：彼得，我真的想活到150岁。

And it's actually what I say to my patients because I get people that come to me and they say, Peter, I really want to live to a 150.

听说你就是那个能人。

I'm told you're the guy.

我会说：其实我不是那个能人。

And I say, actually, I'm not the guy.

我不认为这是可能的。

I don't believe it's possible.

我认为可能实现的是多活七到十年，而且生活质量大幅提升。

What I believe is possible is seven to ten more years of infinitely higher quality life.

如果你不想要这些，而想要远超于此的东西，那你得去找那些能提供确凿证据证明他们能做到的人。

And if that's not what you want, if you want something that is far in excess of that, you're gonna have to go to somebody who's got proof that they can do different.

是的，我认为没有任何证据支持这一点。

Yeah, and I don't think there is any proof

对，我显然也不认为这是可能的。

right I obviously don't think there is either.

我仍然保留这种可能性存在的想法。

I do leave the idea open that it could be possible.

我认为做到这一点可能是可行的，但我认为目前没有任何东西

I think it may be feasible to do that, but I don't think anything

我看不出有任何证据表明现在有什么东西在实现这一点。

I would don't see any evidence that there's anything that's doing it now.

是的。

Yeah.

从转化医学的角度，我同意你的看法。

Translationally, I agree with you.

我认为从线性到指数的转变，就是所谓的‘山丘’理念。

I think the linear to exponential is the idea of the hills.

你有一个球。

You've got a ball.

如果你在二维中做这个，你会得到一条像这样的曲线，这里有一个球。

If you do it at two dimension, you've got a curve that looks like this, and you've got a ball here.

而损伤导致这个东西下降，因此球越过的概率实际上是指数级的。

And the damage is causing the thing to come down, and so the chances of the ball going over is actually exponential.

嗯。

Yep.

嗯。

Yep.

嗯。

Yep.

嗯。

Yep.

所以，即使你降低了山的高度，是的。

So even if you have reduction in the height of the hills Yeah.

活化能会增加，而且概率呈指数增长；顺便说一下，我只是在思考为什么会这样。

The activation energy will increase And probability exponentially the by the way, I'm just trying to think through why that's the case.

这是不是因为如果我们将它建模为实际的球体，越过山丘涉及的是速度平方的问题？

Is that the case because of is it a V squared problem in getting over the hill if we were to model it out as actual balls?

是的。

Yeah.

我有一张图。

I have a graph.

我们有一个关于电影的模型，它能很好地帮助那些不是数学家的人理解。

We have a model of a movie that really helps people that are not mathematicians.

我想我们两人都对数学有一定理解，但很多人确实觉得情况就是这样。

I think both of us have some understanding of the math, but And a lot of people I think that, yeah, it's something like that.

我认为这也能很好地解释为什么治疗疾病往往无效，因为你可能陷入50种不同的失败状态。

I think also it explains very well why treating disease doesn't work because you have 50 failure states you can go into.

每个人由于基因和生活方式的不同，需要跨越的失败状态之山的高度可能略有差异。

Each person, based on their genetics and their lifestyle, the hill to go over that failure state may be a little bit different.

有时候一个人可能无法跨越这一个障碍，但你有很大几率会跨越许多其他不同的失败状态。

Sometimes a person's not going to go over this one, but there's a chance you're going to go over a lot of different failures.

如果你阻断了其中一种，比如治疗糖尿病，你仍然会面临其他失败状态。

And if you block one of them, say you treat diabetes or something, you're still gonna go over the other ones.

真正减缓衰老的唯一方法是让这座山保持更高。

The only way to really slow aging is to keep the hill higher.

是的。

Yeah.

这既是一个非常美妙的思维模型，帮助我们理解这个问题，但同样令人沮丧，因为我不知道为什么这些墙正在倒塌。

Again, that's both a beautiful model, a mental model for how to think about it, and yet still equally infuriating because I don't know why the walls are coming down.

是的。

Yeah.

为什么这些山会降低？

Why are the hills coming down?

根本原因是什么？

What is the fundamental reason?

墙高下降的粒子层面原因是什么？

What's the particle reason for the wall height coming down?

我认为这些山丘代表韧性。

I think the hills are resilience.

韧性是亚洲最重要的术语。

Resilience is the most important term in Asia.

没人理解

Nobody understands

它。

it.

是的。

Yeah.

没错。

Exactly.

好吧。

Alright.

我会给你一个不完整的答案，因为这已经是我能给你的全部了。

I'll give you a half baked answer because it's all I can give you.

我认为正在发生的是，这种损伤正在影响维持你健康的网络，也就是这种稳态网络。

I think that what's happening is this damage is impacting this network that's keeping you healthy, this homeostatic network.

损伤以零星的方式不断发生，网络会对此进行补偿，勉强维持正常，但当损伤积累到一定程度时，你就再也无法对发生的事件进行补偿了。

And it's in little ways here and there and here and there, and the network compensates for that and does okay, but when enough damage happens, you just can't compensate anymore for events that are happening.

所以当你生病时，比如感染了病毒，或者80岁时摔倒摔断了髋骨，你体内已经没有足够的稳态通路来帮助你恢复和应对这些事件。

So when you get sick, you get some viral infection or you fall down when you're 80 and break your hip, you just don't have that homeostasis pathways in place to allow you to recover and compensate for that.

我的意思是，这目前就是我能给你的最好答案了。

I mean, that's sort of the best answer I can give you right now.

所以如果你要猜测的话，我希望听众们能跟上我们的思路，因为这种损伤呈线性、单调递增的观点，正是如果我们想在人类寿命上实现跃升式进步就必须解决的问题。

So if you had to guess, and I'm hopeful that the listeners are with us because this idea of the linear and monotonic increasing in damage is the thing that has to be addressed if we're going to make a step function change in human longevity.

我喜欢你对它的描述。

I like how you described it.

我们其实只是在边缘上打转。

We're really tinkering around the edges.

我们所做的一切，都只是在边缘上打转。

Everything we do is tinkering around the edges.

但如果我们真正希望改变人类的最大寿命并从根本上延长健康寿命，就必须改变这条曲线的斜率。

But if we fundamentally want to get to a point where maximal human lifespan is changed and health span is fundamentally altered, we have to bend the slope of that line.

所以我的第一个问题是，根据你在动物模型中观察到的结果，你认为雷帕霉素有怎样的概率能做到这一点？

So my first question for you is, what is the probability in your mind that rapamycin is doing that based on what you've seen in animal models?

首先，如果

First of all, if

你看看像线虫这样的生物，那里的模型是完全不同的。

you look at something like a worm, think the modeling is very different there.

线虫本来就处于一种失效状态。

Worms are just already in a failure state.

它们的设计寿命只有两周左右。

They're like designed to last for two weeks.

它们没有人类那样的稳态机制，因此你可以获得巨大的

They don't have that homeostasis that humans have, and so you can get huge You can get

被干预措施所误导

fooled by interventions

是的，就在那里。

Yeah, there.

在蠕虫或其他生物中，这条通路可能适用于人类，但在人类中的效果会小得多。

In worms or other organisms that the pathway may translate to humans, but the effect size in humans is going to be much smaller.

我怀疑雷帕霉素就是这种情况，如果你正确服用，它能让你拥有更健康的一段时期。

I suspect that's where rapamycin is, that it's going to give you a healthier period if you take it the right way.

我不认为任何干预措施都能影响每个人，但大多数人可能会从中受益。

Don't I think any intervention is gonna affect everybody okay, but a majority of people may benefit from that.

但我认为它的效果是适度的，而不是改变

But I think it's in the modest effect in size, not in the change the

斜率。

hill.

不是改变趋势。

Not in change slope.

好的。

Okay.

我想回来再深入聊聊雷帕霉素和mTOR，因为你是少数几位，和马特、大卫等人一样，能真正深入探讨这个话题的人。

I wanna come back and talk more about RAPA and MTOR because you're, again, one of the few people along with Matt, David, people who can really talk in-depth about it.

但我们现在先停留在推测的层面。

But let's now stay in the world of speculation.

如果你必须想象一种能改变曲线斜率的东西，我。

If you had to even imagine something that can change the slope of the line, I.

E。

E.

我想我们把最大寿命定义为寿命的第九十百分位数。

I guess we define maximal lifespan as the ninetieth percentile of lifespan.

所以我们就随便编个数字吧，比如今天人类的最大寿命是，我不知道。

So let's just make a number up and say maximal human lifespan today is, I don't know.

105岁，

105,

也许吧。

maybe Yeah.

差不多就是这样。

Something like that.

好的。

Okay.

一百二十岁是

Hundred twenty is

99.9999百分位，没错。

the the 99.9999 Yeah, exactly.

我们要把人类的第九十百分位寿命提高二十五年。

So we're gonna take ninetieth percentile human lifespan up by twenty five years.

如果我告诉你，布莱恩，你可能活不到亲眼见到那一天，我也一样，但我有水晶球，到2100年，90%的人类将活到130岁。

If I told you, Brian, you might not be alive to see it nor will I, but I have a crystal ball and in the year 2100, ninety percent of humans will live to be 130.

现在我要你猜猜，是什么导致了这一变化？

And now I say, give me your best guess as to what did this.

你的猜测会是小分子药物、基因工程，还是表观遗传工程？

Is your guess going to be small molecules, genetic engineering, epigenetic engineering?

就像沿着这条路径走，或者多模态，必须同时涉及十种不同的方法。

Like just go down the pathway or multimodal, it's gonna have to be 10 different things.

这就像一个有趣的科幻游戏。

Like this is just kind of like the fun sci fi game.

但可怕的是，这种线性累积看起来就像熵，而逆转热力学第二定律是

Well, think the scary thing is that that linear accumulation, it does look like entropy, which reversing the second law of thermodynamics is

我们不需要逆转它。

We don't have to reverse it.

我们只需要减缓它。

We just have slow it.

减缓它。

Slow it.

即使只是减缓它，也是一个挑战。

Even slowing it is a challenge.

如果你从物理学的角度来想，而我正越来越深地陷入一个我不该涉足的领域，我现在只是告诉你实话。

And if you think about it from a physics standpoint, which I'm getting further and further and deeper in a pool I shouldn't be in, I'm just telling you that right now.

但如果你我

But if you I'm

给你救生圈。

giving you a life jacket.

只要继续踩水就行。

Just just keep treading water.

顺便说一下，我做咨询时的座右铭是：我知道自己不知道什么。

My motto, by the way, with the consulting I do is that I know what I don't know.

这并不是一个好咨询座右铭，我已经明白了。

It's not a good motto for consulting, and I've learned.

但无论如何，当你深入研究其物理本质时，其实讲的是温度。

But, anyway, as you get into the physics of it, it's really about temperature.

我说的不是房间里的温度。

And I don't mean temperature in terms of the temperature in the room.

我说的是驱动变化或损害的系统能量。

I mean the energy in the system that's driving the changes or damage.

那么问题来了，你该如何降低它呢？

And the question is how do you lower that?

因此，当你在寻找延长寿命的干预手段时，也许不该关注蠕虫能活多久，因为蠕虫的死亡原因可能完全不同。

And so maybe what you need to do when you're looking for longevity interventions is not looking for how long a worm lives because the worm is dying for a different reason.

它已经处于失效模式了。

It's already in the failure mode.

关键在于如何降低系统中的噪声，而降低系统噪声可能是改变这一趋势的一种方式。

It's about how to lower the noise in the system, and lowering the noise in the system might be a way of changing that slope.

这种噪声可能是转录噪声，也可能是任何随时间变化、可测量的噪声，你都可能希望设法降低它。

So that could be transcriptional noise, it could be anything you can measure as noise that happens over time, you might want to try to lower that noise.

这是一个有趣的概念。

That's an interesting concept.

但这也可能带来人们不希望出现的次级效应。

Now that may also come with secondary effects that people don't want.

对。

Right.

生命早期的生长和发育可能会被延缓，这可能是那种你不想在前三十年里去干预的斜率。

There might be a retardation of growth and development early in life and it might be one of those things where you don't want to touch this slope for the first thirty years of life.

没错。

Yeah.

你希望在哪个时间点进行干预？

Where's the point at which you want to intervene?

我认为这个时间因素非常重要。

And I think that temporal component is really important.

这把我们带入了一个不同的概念——拮抗多效性。

It's taking us into a different concept, antagonistic pleiotropy.

确实，如果你观察所有能延长寿命的酵母突变体，大多数在自然环境中都不会是健康的酵母。

And it is true that if you look at all the yeast mutants that extend lifespan, most of them would not make happy yeast in the wild.

它们会减缓生长，或影响交配等其他特性，而这些特性会使酵母在自然选择中难以生存。

They slow growth or they do something else, affect some property like mating that is not gonna make for a yeast that survives through natural selection.

但如果你把它们放在实验室里，它们就能分裂更多次。

But if you put them in a lab, they can divide more times.

因此，许多长寿突变体都伴随着适应性代价。

So a lot of long lived mutants have fitness costs.

所以问题在于，如果你针对系统中的这种噪声——这是一种完全不同的干预思路——这种干预的适应性代价会是什么？

And so the question would be that if you target this noise in the system, which is completely different way of thinking about interventions, what will the fitness cost be with that?

你说得对，也许你可以通过时间上的调控来规避这个问题。

And you're right, maybe you can get around it by temporal things.

比如mTOR通路，你可能不希望在儿童时期就对其进行影响，但在成年后，它在生命早期的重要性要高于后期。

Like the MTOR pathway, you probably don't want to impact as a child, but as an adult, it's more important early in life than it is later in life.

它只在某些特定时期才重要。

It's only important at certain times.

因此，如果你以正确的方式干预，就可以获得益处而避免代价，也许这些干预措施就能实现这一点。

So if you impact it the right way, you can get the benefits without the cost, and maybe that's possible at these interventions.

但我们还处于非常早期的阶段，我甚至无法有信心告诉你哪些干预措施会产生这样的影响。

But we're so early, I can't even, with any confidence, tell you what kinds of interventions would have that impact.

我还想说另一点，我认为重编程可能是减轻这种熵增变化的一种潜在方式，因为如果你能用新细胞替换旧细胞，这些新细胞虽然可能携带一些来自旧细胞的损伤，但它们也很可能清除大量损伤。

I will say one other thing is that I think reprogramming is potentially a way to mitigate some of this entropic change, because if you can replace the cells with new cells, those new cells may have some of the damage because they come from the old cells, but they will probably get rid of a lot of the damage too.

因此，这可能是改变斜率的一种方式。

And so that may be a way of changing the slope.

所以，像重编程这样的方法，我认为仍处于非常早期的阶段，这可能是一种可行的策略。

So, like, reprogramming, which I think is still very early stage, that may be feasible strategy.

所以，作为一个思想实验，如果我现在就能克隆你，或者你有一个双胞胎，我们就假设你有一个双胞胎。

So as a thought experiment, if I could clone you right now, or you had a twin, let's just say you've got a twin.

世界上有一个我就够了。

One of me is enough in the world.

嗯。

Yeah.

但你身在新加坡，所以我们会有北美版的你，也会有新加坡版的你。

But you're in Singapore, so we're gonna have a North American version, we're gonna have the Singaporean version.

所以我们有两个你，其中一个将作为对照组。

So we have two of you and in one of you we're just going to act as the control.

我们会给你注射一些安慰剂。

We're going to give you some vehicle.

在第二个版本中，假设我能够利用CRISPR的精确性，将你身体每个细胞的表观基因组恢复到你20岁时的状态。

In the second one, let's just assume I can use the fidelity of CRISPR to revert your entire epigenome in every cell of your body to what it looked like when you were 20.

一旦它出现偏差，我就立刻把它打回20岁的布莱恩状态。

And any time it gets out of whack, I smack it right back to 20 year old Brian.

只改表观基因组。

Epigenome only.

不改基因组，也不改蛋白质组。

Not genome, not proteome.

我只改变表观基因组。

I don't change anything but epigenome.

但事情肯定会发生变化。

Well, things are gonna change.

没错。

Exactly.

这些变化会影响其他所有方面。

They're gonna affect everything else.

你认为这两个版本的你，在寿命和健康寿命上会有什么差异？

What is your guess as to the difference in lifespan and healthspan of those two versions of you?

这是个有趣的问题。

That's an interesting question.

我肯定认为会有一些差异。

I think there would be a difference for sure.

我不确定这种差异会很大。

I'm not sure it would be a huge difference.

你

You

觉得不会很大吗？

don't think it would be huge?

嗯，我对表观遗传学的主导地位没那么确信。

That's Well, I'm not as sold on the primacy of the epigenetics.

那么，会出什么问题呢？

So what would go wrong?

我不知道答案，当然。

I don't know the answer, of course.

我只是在思考我见过的一些数据。

I'm just kind of thinking through data that I've seen.

所以，如果你看一下两个不同肝细胞的表观遗传代码，一个来自20岁的人，一个来自50岁的人。

So if you look at epigenetic code for two different hepatocytes, liver cells, one from a 20 year old, one from a 50 year old.

然后我告诉你哪个是20岁的，哪个是50岁的。

And I tell you which one's 20, which one's 50.

接着我再给你看其他一大堆样本。

And then I show you a bunch of others.

你总能分辨出哪个是年长的，哪个是年轻的。

You can always tell which one's the older one, which one's the younger one.

可能从线粒体或其他很多方面也能看出来。

Probably tell that from mitochondria or a lot of other things too.

是的。

Yes.

所以问题在于，你的信念体系是：即使你将表观基因组恢复到20岁时的状态，它也不会足以改变基因表达来产生显著影响吗？

So the question is, is your belief system that just because you revert the epigenome back to what it looked like when it's 20, it's not going to change gene expression enough to move the needle?

我认为这肯定会改变基因表达，但同时也发生了DNA损伤，还有

I think it'll definitely influence gene expression, but there's also DNA damage that's happened, there

线粒体发生了变化。

are mitochondrial changes.

我们提出的问题是，如果你将其恢复，我们能修复和恢复多少其他方面？

The question we're asking is, if you revert that, how many of these other things can we fix and restore?

而这个问题的答案尚不明确。

And that's the unknown answer.

我怀疑你对这些方面会产生显著影响，但无法完全恢复。

I suspect you would have a significant impact on those things but not fully restore them.

我认为表观基因组是否具有主导地位，这是一个悬而未决的问题。

I think the question of the primacy of the epigenome is an open question.

没有人知道这个问题的答案。

Nobody knows the answer to this.

这个假设有多容易检验？

How testable is the hypothesis?

你会如何设计实验来检验它？

How would you design the experiment to test that?

我认为这很困难，因为如果你想以非常直接的方式进行，就必须修改控制表观遗传调控的因素，但有很多因素在起作用。

I think that's difficult, because if you want to do it in a very direct way, you really need to modify the factors that are controlling the epigenetic regulation, but there are a lot of factors doing that.

不仅仅是DNA甲基化，还有组蛋白修饰。

It's not just DNA methylation, it's histone modification.

还有核包装和核纤层，它们也与衰老有关，而且并不仅仅有一条通路可以改变。

There's nuclear packaging and nuclear lamins, which are linked to aging as well, and there's not just one pathway to change.

所以从现实角度来看，很难想象如何有效地做到这一点。

So I think from a real life standpoint, it's hard to think about how you would do that effectively.

我认为人们已经对此非常热衷了，也许当我提到衰老时钟时，人们之所以如此热衷于表观基因组是衰老驱动者的观点，是因为你可以通过测量全基因组的DNA甲基化变化来获得生物年龄。

I think people have really jumped on it, and maybe when I'm talking about aging clocks at some point, people have really jumped on this idea of epigenome being the driver of aging because you can get a biologic age by measuring the DNA methylation changes across the genome.

嗯，我

Well, I

我的意思是，他们断言就是这样。

mean, they're asserting that that's the case.

我没有看到任何证据表明情况如此。

I don't see any evidence that that's the case.

我们可以稍后再谈这个。

We can come to that.

是的。

Yeah.

我们 definitely wanna into You

We definitely wanna into You

你可以通过测量蛋白质组的变化、微生物组的变化，或者观察面部结构的变化来达到同样的目的。

can get to that same point by measuring the proteomic changes, by measuring the microbiome changes, by looking at facial structural changes.

杰基·韩在中国有这方面的出色数据。

Jackie Han's got great data on that in China.

因此，只要在人类身上拥有足够深入、足够丰富的数据集，并且涵盖足够宽泛的年龄范围，你就能构建一个预测其年龄的时钟。

So anything in a human where you have a deep enough data set that's enriched enough and you have samples across a wide enough age range, you can make a clock that predicts their age.

面部时钟的准确度与甲基化时钟相当。

And the facial clock is about as accurate as the methylation clock.

所以我认为，很多人已经跟风加入了甲基化或表观遗传的潮流，但他们把相关性当成了因果性，做出了巨大的跳跃。

So I think that a lot of people have jumped on this methylation or epigenetic bandwagon, but they're taking association and causality, and they're making a big leap there.

我们现在知道，你可以改变表观遗传因素，从而延长酵母、蠕虫和果蝇的寿命，甚至可能延长小鼠的寿命。

Now, we know that you can modify epigenetic factors and extend the lifespan of yeast and worms and flies, maybe even mice.

所以它确实有作用，但你也可以通过清除衰老细胞因子、营养调节剂、热量限制或其他许多方法做到这一点。

So it does have a role, but you can do that with senolytic factors or nutritional regulators or calorie restriction or a lot of other things.

对我来说，这并不比针对其他干预措施所获得的效果更显著。

It's not clear to me that that's a bigger effect than you're going to get from targeting these other interventions.

公平地说，这些方法也没有完全逆转衰老过程，因此它们并没有回答你的问题。

To be fair, none of them are completely reversing things either, so they're not addressing your question.

是的。

Yep.

你再想想，我们又回到了哲学层面。

Do you believe again, we're in the philosophical.

我今天会回到现实。

I'll bring it back to reality at some point today.

你认为永生是不可能的吗？除非我们通过AI复制你的大脑来定义它。

Do you think that immortality is impossible Unless we define it through AI copying your brain.

我是指生理上的永生。

I mean physical immortality.

你相信这是不可能的吗？

Do you believe that that is impossible?

我喜欢告诉别人我是永生的，因为这种心态给我带来了非常健康的心理状态。

Well, I like to tell people that I'm immortal because I think the mindset that it gives me is a very healthy mindset for me.

你在书中谈到了很多关于衰老的情感层面。

You talk a lot about the emotional aspects of aging in your book.

我非常喜欢这一章。

I love that chapter.

我们可以稍后再谈这个。

We can come to that later.

但我不真的相信这是真的。

But that's I don't really believe it's true.

我认为实现这种程度的衰老改变的概率虽不为零，但非常低。

I think the odds that you could achieve that level of change in aging is nonzero but close.

因此，我对这种可能性持怀疑态度。

So I'm skeptical that that can be done.

我认为可以说，但我不会排除这种可能性。

I think it's fair to say, but I wouldn't rule out the possibility.

当然，最终没有人能永生，因为你迟早会被车撞到。

Of course, nobody's ultimately gonna be immortal because you're gonna get hit by a bus sooner or later.

但你真正谈论的是因衰老而死亡的永生。

But what you're really talking about is being immortal in terms of dying from aging.

我想我真正想说的是，一个人是否能达到一种程度，使得身体的恢复力足够强，从而不会因疾病而死亡？

I guess what I'm really saying is can one ever get to the point where resilience is high enough that you cannot die from disease?

到目前为止，我还没有看到任何迹象表明这是可能的。

I have seen nothing so far that suggests that's possible.

但这并不意味着它不可能。

But that doesn't mean it isn't possible.

是的。

Yeah.

是的。

Yeah.

然后这甚至延伸到身体虚弱和肌肉减少症等问题，即使我们看到百岁老人和超级百岁老人，他们的虚弱程度仍然相当显著。

And then that gets even to physical frailty and sarcopenia and things like that, where even when we see centenarians and supercentenarians, their frailty is still pretty remarkable.

意思是，他们看起来仍然很虚弱、衰弱。

Meaning, they still look pretty feeble and frail.

从年龄调整的角度来看，他们很棒。

Age adjusted, they're great.

但归根结底，当他们110岁时，看起来仍然像生命最后几年的人，就像84、85岁的人一样。

But at the end of the day, when they're 110, they still look like someone who's in the final years of their life, just as someone would if they were 84, 85.

我有两位祖母都活到了将近100岁。

I mean, had two grandmothers that lived to almost 100.

一个99岁去世，另一个101岁。

One died at 99 and the other 101.

那个101岁的。

The one at 101,

我觉得她95岁还在开车。

I would say that she was driving at 95.

我想她后来不开了。

I think she quit driving.

她93岁时还打了238分的保龄球。

She bowled a two thirty eight game at 93.

那是她。

That's She

她看起来像七十岁的人。

my looked like a 70 year old.

是啊。

Yeah.

没错。

Exactly.

我的观点是，她只是经历了二十年的阶段转变，但这并没有改变衰退的必然性。

My point is she just had a phase shift of twenty years, but it didn't undo the inevitability of that decline.

我同意这一点。

No, agree with that.

我认为，让我们活到100岁是个不错的目标。

Getting us to 100 is a good goal, I think.

我完全同意。

I agree completely.

你认为我们是不是花太多时间去追求永生、摆脱衰老的临界点、探究衰老的核心机制了？也许我们更应该多花时间思考：如何在生命的最后十年里保持健康寿命。

Do you think that we're spending too much time worrying about finding immortality, escape velocity, understanding the core of aging when maybe we should be spending more time on how do we preserve health span in the last decade of life.

为什么大多数人在生命的最后十年里，身体都虚弱到无法享受生活？即使没有阿尔茨海默病，他们的认知能力也已严重退化，不够敏锐。

Why is it that most people in the final decade of their life are physically too frail to enjoy life, are cognitively just even absent Alzheimer's disease, they're just not cognitively sharp enough.

他们还承受着痛苦。

They're in pain.

他们髋部骨折了。

They're fracturing their hips.

他们不再做那些曾经给他们带来快乐的事情。

They're not doing what gave them joy through most

是的。

of Yeah.

我们应该把对衰老的研究投入提高到接近对癌症投入的水平，这样就能同时回答这两个问题。

We their should fund aging somewhere closer to the level we're funding cancer and answer both of those questions at the same time.

我认为其中一个问题是转化性问题：我们如何在当下尽可能减缓衰老，最大限度地改善人群的健康状况。

I think one of them is a translational question about how do we slow aging as much as we can right now and improve the health of the population as much as possible.

另一个问题是基础科学问题：我们能否停止衰老？能否逆转衰老？

And the other one is a basic science question: can we stop aging, can we reverse aging?

如果有人告诉你他们已经找到了答案，那他们要么在骗你，要么在骗自己。

If anybody tells you they have the answers to that, they're lying to you or they're lying to themselves.

我们还不知道。

We don't know.

这或许是生物学中最重要的问题，我们应该大力投入资金。

It's maybe the most important question in biology, and we should be throwing money at it.

我们已经看到大量资金流向私营部门，比如生物技术公司、保健品公司、长寿诊所等等。

So we've seen all this money go into the private sector side, biotech companies, supplement companies, longevity clinics, and on and on.

我认为这非常好，而且我花了很多时间与这些团体合作，因为我觉得这很重要。

And I think that's great, by the way, and I spend a lot of my time working with those groups because I think it's important.

但我们有没有看到用于衰老和长寿基础科学研究的学术资金？

But we're not seeing the academic funding that's going into the basic science of aging and longevity?

你刚刚提出的那些重大问题仍然没有答案。

And the big questions that you just raised are still not answered.

我把你的问题转变为对更多资金的呼吁，但不幸的是，支持这类研究的资金通常来自政府和基金会，而这些资金目前正面临巨大威胁。

I'm changing your question to a plea for more funding, and, unfortunately, the kind of funding that supports that is usually government funding, foundation funding, and that's under major threat right now.

我真的很担心我们无法解答这些问题。

I'm really worried that we're not gonna answer those questions.

是的。

Yeah.

这是一次在长寿圆桌会议上提出的讨论。

This was a discussion that came up on a longevity roundtable.

我认为，包括我在内的大多数人，听到资金分配差异如此之大时都感到非常惊讶，如果你能将10%的特定疾病资金重新分配到衰老研究领域，可能会产生巨大的影响。

I think most people, myself included, were really surprised to hear how disparate the funding differences are and how if you could put, I don't know, if you could reallocate 10% of funding from the disease specific pools to the age pools, it could have an enormous difference.

‘巨大’这个词都太保守了。

Enormous is an understatement.

是的，当你想到那些主要的慢性病时，比如心血管疾病、癌症、神经退行性疾病和代谢性疾病，这些是四大主要疾病。

Yeah, So when you think about the big chronic diseases, cardiovascular disease, cancer, dementing diseases and metabolic diseases, those would be the big four.

我经常认为，其中最不必然的，恰恰是今天最致命的疾病——衰老。

I've often maintained that the least inevitable of them is ironically the one that is the most deadly today, which is disease.

动脉粥样硬化性疾病，即脑部和心血管疾病，讽刺的是，它们是最可预防的。

Atherosclerotic diseases, so cerebral and cardiovascular, ironically the most preventable.

这既因为我们对它们的病因有最深入的理解，也因为我们拥有最丰富的预防工具，比如控制高血压、血脂异常等手段。

Both because we have the best understanding of what causes them and we couple that with the most tools to prevent them, whether it be tools to combat hypertension, dyslipidemia, etcetera.

而且它们对生活方式的调整反应良好。

And they're responsive to lifestyle modification.

在其他三种主要疾病——痴呆、癌症和代谢性疾病中，你认为哪一种对我们的物种来说是最不可避免的？

Which of those major diseases of the other three, dementing, cancer, metabolic, do you believe is the most inevitable to our species?

我不太确定是否该把代谢性疾病算进去。

I wouldn't put metabolic for in sure.

因为我把它看作更像心血管疾病。

Because I see that more like cardiovascular.

我同意。

I agree.

那么在剩下的两种——癌症和痴呆或神经退行性疾病中，哪一种看起来是不可避免的？

So of the other two, cancer and dementing or neurodegenerative diseases, which one is just seemingly inevitable?

医生。

Doctor.

我们对痴呆的了解还不够，无法给出答案，但我认为癌症和其他疾病有点不同。

We don't know enough about dementia to answer, but I will say that cancer is a little bit different than these other diseases, I think.

它可能不太容易通过长寿干预来改变。

And it may be less modifiable by longevity interventions.

痴呆症，我们真的不知道。

Dementia, we just don't know.

我猜测它也很容易被干预，但目前缺乏足够的数据来确认这一点，而代谢性和心血管疾病则有更多证据。

My guess is it's highly modifiable too, but there's not enough data to be sure of that like there is for metabolic and cardiovascular disease.

但癌症是突变的累积，因此这是一个更明确发生的事件。

But cancer is an accumulation of mutations, so it's a more defined event that's happening.

它对免疫系统的影响也与正常衰老略有不同。

It's also an impact on the immune system that's different a little bit than normal aging.

因此，从长寿的角度来看，它可能更难干预。

So it may be less approachable from a longevity viewpoint.

有趣的是，这正是我的观点，癌症是这些疾病中最不可避免的。

It's funny, that's exactly my view that cancer is the most inevitable of these diseases.

你认为这种不可避免性或与年龄相关的因素更多是源于突变的积累，还是免疫系统的衰退？

Do you think that the inevitability or the age related component stems more from the accumulation of mutations or the weakening of the immune system?

可能是两者都有。

It's probably both.

没有发生正确的突变，你是不会得癌症的。

You don't get to cancer without the right mutations happening.

但我认为我们正越来越多地了解到免疫系统在其中扮演着重要角色。

But I think we're learning more and more that the immune system is playing a major role in it.

我们可以从那些改善免疫功能的干预措施中清楚地看到这一点，它们在某些类型的肿瘤中发挥了重要作用。

We can see that very clearly from the interventions that improve immune function, and they're having a big role in certain types of tumors.

但我认为这将会

But I think that's going to

对阿尔茨海默病和痴呆症也是如此。

be true for Alzheimer's and dementia as well.

我们完全低估了炎症和免疫系统在这些疾病中的作用，它们可能是主要的驱动因素。

We've completely underestimated the role of inflammation in the immune system and those diseases as well, and they may be the primary drivers.

我对这些领域中的一些做法感到非常沮丧。

I'm very frustrated by some of these fields.

其中之一就是阿尔茨海默病。

One of them is Alzheimer's.

我总觉得那些阿尔茨海默病研究者，有些人活到九十岁去世时，墓碑上写的最大成就居然是彻底清除了大脑中的斑块，但自己还是在94岁死于阿尔茨海默病。

I kind of feel like one of these Alzheimer's researchers, they're gonna die at some point of 90, and on their tombstone, it's gonna be like major accomplishment was to completely remove plaques from the brain died of Alzheimer's at 94.

我们过于聚焦于一两种疾病机制，以至于三十年来都没去研究其他可能更重要的机制。

There's been so much focus on one or two mechanisms of disease that we spent thirty years not studying the others, which may be more important.

你为什么这么认为？我的书里也写过这个。

Why do you think that I mean, I write about it in the book.

我真的很想知道，你认为为什么会发生这种情况。

I'm really curious as to why you think that's happened.

不幸的是，这在科学界并不是孤立的事件。

Unfortunately, that's not an isolated incident in science.

那么，在一个结果普遍如此惨淡的领域里，你认为为什么会这样呢？

So why do you think it's happening in a field where the results are otherwise so dismal?

有句话说，科学进步是一场葬礼接着一场葬礼才实现的。

What's the saying that scientific progress happens one funeral One funeral at a time.

是的。

Yeah.

我认为这是其中一部分原因。

I think that's part of it.

你会有那些成功研究项目的学者，他们的博士后会被聘到各个岗位。

You get people that have successful research programs, and their postdocs get hired in all the jobs.

因此，当一个领域从小规模发展成大规模时，每个人都能将自己的学术谱系追溯到四到五位不同的首席研究员，而这些首席研究员所专注的模型就成了他们获得奖项的途径，于是大家就只聚焦于疾病机制中的一小部分，而忽略了其他所有机制。

And so when you take a field and it grows from a small field to a bigger field, everybody can draw their lineage back to four or five different PIs, and so whatever models and those PIs get really focused on those models and they see that as their ticket to prizes and things like that, and so then you focus on a subset of the disease mechanisms at the exclusion of all others.

我不只想把阿尔茨海默病单独拎出来。

And I don't want to single Alzheimer's out.

我认为很多疾病都符合这种情况，但这很遗憾，因为我们逐渐意识到，任何疾病都受多种因素影响。

I think a lot of diseases meet that category, but it's unfortunate because what we're realizing is that there's a lot of factors that contribute to any disease.

我认为长寿可能是一个有趣的观察角度。

And I think longevity may be an interesting way of looking at it.

比如，想想更好的做法是用小鼠。

Like, think it's better take a mouse.

我们曾试图在小鼠身上建立阿尔茨海默病模型，但它们的参考价值并不大。

We've tried to make Alzheimer's models in mice, and they don't prove that informative.

为什么？

Why?

你是在创造一种小鼠基因上不会得的疾病。

You're creating a disease a mouse doesn't get genetically.

在年轻的小鼠身上制造疾病，然后与年老人类的自然疾病进行比较。

In a young mouse and comparing that to a natural disease in an old human.

我认为，如果你观察小鼠在正常衰老过程中大脑发生的神经退行性变化，会更了解阿尔茨海默病。

I think you learn more about Alzheimer's if you look at the brain neurodegenerative changes that happen in the mouse normally with aging.

下游的机制可能不同，但驱动因素可能与导致阿尔茨海默病的驱动因素非常相似，这可能比人为制造小鼠不会得的疾病更能模拟阿尔茨海默病。

The downstream things are different, but the drivers may be very similar to the ones that are driving Alzheimer's, and that may be a better model of Alzheimer's than trying to artificially create something that a mouse doesn't get.

所以我认为衰老正在帮助改变这种观点。

So I think aging is helping change that perspective.

我认为小鼠和人类的衰老驱动因素非常相似。

The drivers of aging I think are very similar between a mouse and a human.

下游事件可能不同，但我们关心的是驱动因素。

The downstream events can be different, but the drivers are what we care about.

让我们暂时回到雷帕霉素。

Let's go back to rapamycin for a moment.

你是否认为雷帕霉素的主要作用是通过间歇性抑制mTOR来减轻适应不良的炎症？

Do you believe that the primary effect of rapamycin is tamping down maladaptive inflammation through obviously the intermittent blunting of mTOR?

我认为这是其中之一

I think that's one of

毫无疑问，这是主要机制之一。

the major things, certainly.

有充分的证据表明它能增强自噬，也有充分的证据表明它影响蛋白质翻译，而这些机制与炎症变化并不互斥，但我认为我们目前有充分证据支持的就是这三点。

There's good evidence for enhancement of autophagy, there's good evidence for changes in protein translation, and those things are not mutually exclusive to inflammatory changes anyway, but I think those are the three things that we have pretty good evidence for.

我真的认为，我们所研究的所有这些干预措施都是在恢复动态范围。

I really think that all of these interventions that we're looking at are restoring dynamic range.

也许需要超生理水平的改变才能改变这条直线，但我觉得我们现在关注的并不是这个。

It may take super physiologic changes to change that linear line, but I don't think that's what we're looking at right now.

我们是在恢复年轻时原本存在的状态。

We're restoring things that happened when you were young.

鉴于我们不太可能开展针对衰老的人类临床试验来研究雷帕霉素，因为我们甚至还不知道什么是衰老的生物标志物，因此在决定将雷帕霉素用于抗衰老时，我们很大程度上只能依赖动物数据。

So given that we're not likely to have human clinical trials of rapamycin that study aging for the simple fact that we don't even know what an aging biomarker is, we're gonna largely be extrapolating from animal data if we have to make decisions about humans using rapamycin for gero protection.

我稍微提出一点不同意见。

I'll push back a little bit.

我知道我们接下来要讨论什么，但我们在新加坡正在对人类开展这样的研究。

I know where we're going with this, but we're doing a study like this in Singapore on humans.

好的。

Okay.

为期六个月的雷帕霉素干预。

Six month intervention with rapamycin.

我们正在观察多种与衰老相关的参数。

And we're looking at as many different parameters of age.

我们不是在研究疾病。

We're not doing disease.

是的，

Yeah,

你不能

you can't

这么做

do it

六个月。

six months.

没错。

Yep.

我们招募的是40到60岁的人。

We're taking people that are 40 to 60.

他们可能有某种疾病的前期症状，但并没有被定义为疾病。

They may have a precondition for a disease, but they don't have anything that would be defined as a disease.

所以可能是高血糖。

So it could be high glucose.

然后我们观察一系列不同生物标志物和衰老时钟的变化。

And then we're looking at changes in a wide range of different biomarkers, clocks.

所以给我多讲讲这个研究吧。

So tell me a little bit more about the study.

那么有多少受试者呢？

So how many subjects?

我们正在进行这些实验，我不记得确切数字了，大概在150到200之间，规模不算大。

We're doing these, I don't remember the exact numbers, it's somewhere around 150 to 200, so it's not huge.

你们是怎么给药的？

And how you're dosing it?

间歇性给药。

Intermittently.

每周一次？

Once a week?

对。

Yeah.

剂量是多少？

How much?

我认为协议中规定的是五毫克。

I think it's five milligrams is what's in the protocol.

这项研究由安德里亚·迈耶负责，她是我在新加坡的合作者之一。

It's being run by Andrea Meyer, which is one of my collaborators in Singapore.

明白了。

Got it.

所以每周一次，每次五毫克雷帕霉素，持续六个月，然后我们逐一讨论所有的测量指标。

So five milligrams of Rapamune once a week for six months and then let's go through all the different measurements.

包括一系列时钟、炎症细胞因子面板、功能指标、脉搏波速度、双能X射线吸收法、力量测量和认知测量。

So a range of clocks, inflammatory cytokine panels, functional measures, pulse weight velocity, DEXA, strength measurements, cognitive measurements.

我仍然漏掉了一些指标。

I'm still missing a couple of them.

你期望在力量或认知等方面看到变化吗？

Do you expect to see changes in strength or cognition or things like that?

我的意思是，你担心在针对这些人的六个月研究中，这些可能并不是合适的观测指标

I mean, you worry that those are kind of the wrong outcomes to look for in a six month study of people that

是年轻人？

are young?

这又回到了我们要测量什么的问题。

This comes back to what do you measure?

我知道我们会谈到这一点。

And this is where I knew we were going with this.

我认为我们并不清楚。

I don't think we know.

我的意思是，你当然可以改变这些参数。

I mean, certainly you can change those parameters.

我认为如果你锻炼，你会改变你的状态。

I think if you exercise, you're gonna change your stream.

当然。

Absolutely.

肯定。

For sure.

如果这是六个月的运动试验，那就放手去做吧。

If this was six month exercise trial, fill your boots.

我认为六个月的运动试验也可能改变认知参数。

I think six month exercise trial might also change the cognitive parameters.

有可能。

It's possible.

没错。

Right.

是的。

Yep.

六个月的睡眠矫正试验无疑会改变认知参数。

A six month sleep correction trial would undoubtedly change cognitive parameters.

所以，我认为药物也能产生这些效果并不为过。

So I don't think it's unreasonable that a drug could do these things as well.

我认为雷帕霉素在肌肉方面很复杂，我知道这一点部分是因为我要暂时不那么科学了。

I think rapamycin is complicated when it comes to muscle and I know that partly because I'm going to be non scientific for a minute.

我已经成了自己最好的模式生物。

I've become my own best model organism.

所以我现在会对自己尝试各种不同的东西。

So I try all kinds of different things on myself now.

我知道这只是一个n=1的样本。

I know it's n equals one.

我不确定雷帕霉素对骨骼肌的影响，尤其是在不运动的情况下，我不确定它会有什么效果。

I'm not sure rapamycin and skeletal muscle, you know, without exercise, I'm not sure what it's gonna do.

我注意到的一件事是，当我服用雷帕霉素时，如果我进行一次高强度的跑步——我是个跑步者。

One of the things I notice is when I take rapamycin, if I do, like, a hard run I'm a runner.

过去三四年里，我增加了力量训练。

I've gone to more lifting the last three or four years.

我一直都是个跑步者。

I've always been a runner.

在服用雷帕霉素后的24小时内，我的跑步状态都不好，这可能是因为你需要在特定环境下激活mTOR，或者类似的原因。

I don't have good runs within twenty four hours of taking rapamycin, and it may be because you have to activate ImmTOR in a context or something

抱歉，如果你在跑步前24小时服用雷帕霉素？

like Sorry, if you take RAPA twenty four hours prior to a run?

在跑步后的24小时内。

Within twenty four hours of running.

明白了。

Got it.

那如果你在跑步后服用雷帕霉素，恢复会更好吗？

Now what about if you take RAPA after a run, Is your recovery better?

我没有这种感觉。

I don't have a sense of that.

我知道的是，在服用雷帕霉素三到四天后，我的训练效果非常好。

What I do know is three or four days after I take RAPA, have really good training.

我认为发生的情况是，在服用后的短时间内，你无法充分激活这条通路。

I think what's happening is that maybe in that short window after you take it, you can't activate the pathway enough.

但从长期来看，你是在抑制基础信号，从而获得更好的动态范围。

But in the long term, what you're doing is dampening the basal signaling and you're getting the better dynamic range.

所以如果谷值水平很低，我想那就是我。

So if the trough levels are low, I think that's me.

我会在这方面做个实验，布莱恩，因为我总是在每周的同一天服用RAPA。

I'm going to experiment with that, Brian, because I always take RAPA the same day of the week.

我每周都在同一天做同样的锻炼，我要调整一下，看看效果如何。

I do the same workouts on the same days of the I'm gonna do an adjustment on that and see.

我还没试过。

I didn't try

我也没在抗阻训练中试过，所以我不知道会有什么效果。

it with resistance either, so I don't know what it's gonna do there.

我们有什么工具可以测量人体内的自噬作用？

What tools do we have to measure autophagy in humans?

你可以抽取血液细胞。

Well, you can pull out blood cells.

我们讨论的是从人体中能获取的数据的局限性，对吧？

We're talking about the limitations of what you can get from a human, right?

血液、唾液，我认为这就是我们的方向。

Blood, saliva, that's where we're going, I think.

可以抽取血细胞，观察白细胞是否激活了自噬通路，但在我们的临床研究中我们不太愿意这样做，因为这会让招募志愿者变得困难。

Can pull out blood cells and you can look at white cells and see whether autophagy pathways are induced or We don't really like doing that in our clinical studies because it makes it harder to get volunteers.

我认为如果正确进行肌肉活检，对人们来说可能没那么痛苦，但人们有这种认知，而我们的研究需要健康的志愿者。

I think if you do muscle biopsies the right way, they're probably not that painful to people, but people have that perception, and we need healthy volunteers for our studies.

我非常希望研究肌肉。

I would love to look at muscle.

但我认为自噬也是一把双刃剑，对吧？

I think that autophagy is another one of these dual edged swords though, right?

你不希望自噬持续不断地进行。

You don't want autophagy on all the time.

你希望它在适当的时间以适当的水平被激活。

You want it on at the appropriate levels at the right time.

如果它一直持续激活，你可能会出现肌肉萎缩。

If it's on all the time, you're going get muscle atrophy probably.

所以这关乎动态范围。

So it's about dynamic range.

在这项研究中，你需要看到什么才能认为雷帕霉素具有抗衰老作用？

What would you need to see in this study to feel that rapamycin is gero protective?

因为我的担忧是，你可能在DEXA上看不到差异，在身体功能上看不到差异，在认知功能上也看不到差异。

Because my concern I suppose would be you're not gonna see a difference in DEXA, you're not gonna see a difference in physical performance, you're not gonna see a difference in cognitive function.

你可能会看到某些细胞因子的减少，但并非所有细胞因子都会减少。

You might see a reduction in certain cytokines but not all cytokines.

我忘了你之前提到的其他标志物是什么。

I forget what the other markers that you said were.

但我想我的担忧是，既然我们无法衡量衰老，就看不到足够的信号。

But I guess my concern is since we can't measure aging, we're not going to see enough of a signal.

哦，你提到了表观遗传时钟。

Oh, you mentioned epigenetic clocks.

在理想情况下，这将是衡量衰老的完美工具，除了Cabralin实验之外。

In an ideal world, that would be the perfect tool to measure them except for the Cabralin experiment.

我现在去所有会议都带着Matt，因为我用这张幻灯片。

I bring Matt to all my conferences now because I use that slide.

他一次性做了八个。

Where he did like eight of them at once.

但这里存在多个问题。

But there are multiple issues here.

一个问题就是，消费级检测公司是否有足够标准化的协议来保证可靠性？

One issue is are the consumer testing companies, do they have a standardized enough protocol that it's reliable?

我认为我对这一点持怀疑态度。

And I think I'm skeptical that that's the case.

你是在内部进行测量。

You're doing in house measurement.

我们所有事情都是内部做的。

We're doing everything in house.

我们可以控制一切。

We can control everything.

所以我们避开了很多这些问题。

So we get around a lot of those problems.

为了让听众理解我们在说什么。

Just for the listeners so they understand what we're talking about.

马特·卡布拉林购买了四种顶级商业检测产品，并同时进行了双份检测。

Matt Cabralin bought four of the top commercial tests, did them in duplicate simultaneously.

因此他在同一时刻进行了八项检测，并且有一张有趣的图表展示了这些检测结果有多糟糕。

So it took eight tests at the same moment in time and he has a funny graph that shows how pathetic they are.

不仅这些检测结果彼此之间不一致，相同的检测也很少彼此一致。

Not only do none of the tests agree with each other, the identical tests rarely agree with each other.

是的。

Yeah.

所以，如果你正在听这个，并且想去做一项商业检测来告诉你你的生物年龄，那就重新考虑一下吧。

So just if you're listening to this and you wanna go out and get a commercial test that tells you how old you are biologically, reconsider it.

我想告诉你，我们有潜力开发出更好的生物钟。

I want to tell you we have the potential for a better clock.

想聊聊这个，是吧。

Wanna talk about that, yeah.

是的，从消费者角度来看，我认为存在一些担忧。

Yeah, so consumer wise I think there's concerns.

当你谈到炎症和表观遗传变化可能是你在这里发现的仅有的两个信号时，你用什么作为对照？

What are you using as a control when you talk about given how inflammation and epigenetic change might be the only two signals that you find here?

再说一遍，这只是我这个悲观的保姆在说话。

And again, this is just me being pessimistic nanny.

这只是我的预测。

This is just my prediction.

我不认为在其他任何那些测量中会有发现，但如果你能测量炎症和表观基因组，你或许有机会。

I do not think there will be a finding in any of those other measurements, but you might have a chance with inflammation and epigenome if you Maybe measure

脉搏波也测一下。

pulse wave too.

布赖恩，我对脉搏波有个问题。

Here's my problem with pulse wave, Brian.

这完全取决于操作的技术人员，我们临床上根本不用它。

It is so user dependent in terms of the technician who is doing, like we don't use it clinically at all.

是的。

Yeah.

因为我们觉得这是个无用的检查。

Because we think it's a useless test.

我觉得颈动脉内膜增厚检查也是无用的，而这个检查其实更容易做，除非你有个技术员几乎拥有血管影像学的博士学位，并且每天每分钟都在做这项操作。

I think the carotid intimal thickening is a useless test and that's an easier test to do because unless you have a tech who basically has a PhD in how to do vascular imaging and they're the only one that does it every minute of every day.

如果我的病人带着CIMT报告来，我会打开鸟笼，拿出粪便纸，把他们的CIMT报告放进去，然后关上鸟笼。

If my patients come in with a CIMT, I open a birdcage, I take out the poopy bottom paper, I put their CIMT in there, I close the birdcage.

这就是它有多无用。

That's how useless it is.

所以我只是担心所有这些检查都只会是噪音，没有信号。

So I just worry that all of those tests, they're just going to be noise, no signal.

但另外这两项可能有信号。

But these other two might have signal.

你对加速衰老或其他因素的对照组是什么？

What's your control for accelerated aging or something else?

换句话说，如果你进行一项为期六个月的平行禁食试验，让受试者处于热量限制状态，让他们执行一种极其严格的60%热量饮食持续六个月，你认为这会显著降低炎症和自噬。

In other words, would be really interesting if you did a six month parallel fasting trial where if you took people and you rendered them hypocaloric, you put them on some draconian 60% calorie diet for six months, where you really think you would tamp down inflammation and autophagy.

如果有什么能在六个月内重编程表观基因组，你认为这会是它吗？

If anything's going to reprogram the epigenome in six months, you think that would be it?

即使受试者数量只有一小部分，这也是一个非常有趣的对照组。

That would be a very interesting control, even if you had a fraction of the number of subjects.

是的，我们的第一项研究是与PDL健康公司合作，使用了AKG的缓释版本。

Yeah, I mean we're doing multiple the first study we did was with the time release version of AKG with PDL health.

α-酮戊二酸？

Alpha ketoglutarate?

对。

Yeah.

好的。

Okay.