#333 ‒ 长寿圆桌讨论：衰老的科学、抗衰老分子、生活方式干预、研究挑战等 | 史蒂文·奥斯塔德、马特·凯伯莱恩、理查德·米勒

我感到很尴尬。

I'm embarrassed.

我不知道答案，因为我在那里工作了两年多。

I don't know the answer because I spent more than two years working there.

美国国立卫生研究院的使命是什么？

What's the mission statement of the NIH?

是保持和提升人类健康。

It's to preserve and enhance human health.

我的意思是，这基本上就是我们该做的工作。

I mean, it's basically the same thing that we do that we're supposed to be doing.

是的。

Yeah.

我其实还没来得及跟你说我的观点，但我一开始想说的是，关于NIA的预算，如果你看看主要的死亡和致残原因，我们之前也讨论过，很难定义医疗支出。

And I didn't actually get to give you my spiel here, but what I started to say about the NIA budget is if you look at the major causes of death and disability, and again we talked about how it's hard to define health spend.

如果我们只看死亡原因，看看美国十大死因，其中九个的最大风险因素都是生物衰老。

If we just look at causes of death, if you look at the top 10 causes of death in The United States, nine of them have biological aging as their greatest risk factor.

而且差距还远不止如此。

And it's not even close.

然而，本应致力于改善人类健康的研究预算中，仅有百分之零点五用于研究这一风险因素。

Yet, half of 1% of the research budget that's supposed to be focused on improving human health goes to study that risk factor.

我的意思是，我们所有人坐在这里都对此感到极其沮丧，但也有理由乐观地认为，这种情况在不久的将来可能会改变。

I mean, I think it is extremely frustrating to all of us sitting at this table that that hasn't changed, but there's reason to be optimistic that maybe it will change in the near future.

让我们再重复一遍，因为这一点至关重要。

Let's state that again because it is so profound.

我想确保在座的每一个人没有错过这个观点。

I want to make sure not a single person missed that statement.

美国十大死因已被明确列出，且极具可预测性，它们随着每个十年的推移，以每年3%到8%的比例单调上升，毫无例外。

The top 10 causes of death in The United States are well enumerated and incredibly predictable, and they increase by category, by decade, three to eight percent monotonically with no exception.

也就是说，百分之九十以上——经调整后甚至超过百分之九十——导致死亡的因素都随年龄增长而上升。

Point being, ninety percent of and more than ninety percent on an adjusted basis of what causes death goes up with age.

然而，联邦研发经费中仅有极小一部分用于应对这一问题。

And yet, a few basis points of federal R and D goes to addressing that.

让我举个例子，说明马修和你所强调的这一点。

Let me give you an example of what the sort of point that Matthew and you have been making.

大约每五年，我会受邀在密歇根大学癌症中心做一次演讲，我会指出，我们现在已有针对衰老的药物，在小鼠身上能延长其寿命，主要是通过推迟癌症发生，因为大多数小鼠都死于癌症。

About once every five years, I give a talk, an invited talk at the University of Michigan Cancer Center and I point out that we have drugs now, anti aging drugs, in mice and they extend mouse lifespan and they do it mostly by postponing cancer because most of our mice die of cancer.

如果你查看经年龄调整后的癌症发病率，我们的药物能将其降低十倍。

And if you look at age adjusted cancer incidence rates, our drugs reduce these by a factor of 10.

作为癌症科学家，他们难道不想知道，为什么我们现在有一批能推迟癌症的药物吗？

Wouldn't they like to know why, as cancer scientists, we now have a batch of drugs that postpone cancer.

他们难道不想研究这些药物吗？

Wouldn't they like to study them?

每次我都会收到一通回电，有人会说：‘这很有趣，也许我们可以聊聊这个。’

Invariably, I get one callback from somebody who says, That's interesting, maybe we should talk about that.

但之后就没了下文，五年后我又被邀请去做同样的演讲或相关演讲。

And then it dies and then five years later I'm asked to give the same talk or a related talk.

他们知道如何做癌症研究，他们是癌症科学家，这正是他们擅长癌症研究的原因。

So they know how to do cancer research, they are cancer scientists, that's how they know how to do cancer research.

你当然不会通过转移实验室对衰老的研究注意力来做到这一点。

And you certainly don't do it by diverting your lab's attention to aging.

这太疯狂了，但这种疯狂正是医学研究的组织方式。

That's insane, but that insanity is how medical research is organized.

要摆脱你从小熟悉的那种模型，因为更好的理念并非易事。

And breaking that addiction to the kinds of models you grew up on because they're a better idea, not an easy thing.

这甚至可能根本做不到。

It may not even be a possible thing to do.

这会带来巨大的麻烦。

That's a major hassle.

我认为这是因为我们对健康的理解完全错了。

I think this is because we think about health all wrong.

我们总是想着：等你得了癌症再说能做些什么。

We think, let's wait till you get cancer and see what we can do about it.

这就是癌症生物学家的做法。

That's what cancer biologists do.

你得了癌症。

You have cancer.

好的。

Okay.

我们如何能更好地治疗它？

How can we better treat that?

或者我们能否更早地诊断出它？

Or could we have diagnosed it earlier?

里奇所说的是，根据我们在多种模式生物中的研究，可以预防癌症的发生，或将它推迟相当长的时间。

What Rich is saying and what we can know how to do in lots of model organ, it prevents you from getting cancer, delay it for a considerable amount of time.

如果你是一名癌症生物学家，这会比较难研究，因为你必须先看到癌症才能研究它。

That's a little bit harder to study if you're a cancer biologist because you wanna see the cancer before you can study it.

我认为这就是为什么我们需要衰老生物学家，而不是只关注特定疾病的专家，来尝试运用我们的方法。

I think that's why we need aging biologists rather than people focused on certain disease to come and try to use what we do.

你知道，如果我们预防了癌症，他们就没工作了。

You know, if we prevented the cancers, they'd be out of the job.

我保证这些人或小鼠最终会得癌症。

I guarantee these people or mice will get cancer.

如果他们是人，就能多活十年；如果是小鼠，就能多活十个月。

They'll just have ten extra years of life if they're a person or ten extra months of life.

他们还是会得癌症。

They'll get cancer.

他们会需要专科医生。

They'll need specialists.

一切都会好起来的。

It'll be all right.

是的。

Yeah.

我认为这很重要。

I think that's important.

我的意思是，应对疾病的传统医疗模式依然会存在。

I mean, I the reactive disease care component is still going to be there.

即使我们在延缓衰老方面取得了惊人的成功，人们仍然会生病。

Even if we're insanely successful at slowing aging, people are still going to get sick.

但我认为史蒂夫的观点非常重要。

But I think Steve's point is really important.

彼得，你一直走在引领人们认识到医疗方式需要从被动转向主动的前列。

Peter, you've been a leader in helping people recognize the need to shift the medical approach from reactive to proactive.

我认为很多人没有意识到，这种思维模式早已根植于制药研究、生物医学研究和基础科学之中。

I think what a lot of people don't realize is that mentality goes all the way back to pharmaceutical research, biomedical research, basic science.

这种思维贯穿始终。

That is ingrained all the way through.

我认为，获得衰老研究资金的一个挑战在于基础科学界这种根深蒂固的思维模式。

And I think one of the challenges with getting funding for aging research is that mentality on the basic science world and how deeply ingrained it is.

这非常有趣，因为你分不清哪个是尾巴，哪个是狗。

It's very interesting because you don't know which is the tail and which is the dog.

我一直认为，引领变革的是临床方面。

I've always assumed that the one leading the charge is the clinical side of things.

换句话说，医学2.0的引擎和机器是围绕医疗服务的提供而构建的。

In other words, the engine, the machine of Medicine two point zero is built around the delivery of care.

正如你所说，史蒂夫，医疗服务的提供是围绕着‘我等着’这一模式建立的。

The delivery of care, as you said Steve, is built around, I'm going to wait.

我会坐在这里，等着。

I'm going to sit here and hang.

我们会等着。

We're going to wait.

当你生病了，我们才准备好。

When you get the disease, we're ready.

你心脏病发作了，太好了。

You had the heart attack, fantastic.

你有胸痛，心电图ST段抬高，我们有支架给你。

You've got chest pain, ST elevations, we got a stent for you.

现在你得了癌症，我们全力以赴。

Now you have cancer, we're all in.

而研究正是源于这种思维模式。

And then the research flows from that mindset.

当然，我不知道，这其实并不重要，但也许情况恰恰相反，对吧？

Of course, I don't know, not that it really matters but it might be that it's flipped, right?

临床体系之所以如此运作，可能是因为金字塔的基础就是这么构建的。

It might be that the clinical engine behaves in that way because that's how the base of the pyramid has been built.

同样，这不一定重要，但如果你能当上卫生总管并修复其中一个问题，你或许应该从研究端入手。

Again, not that it necessarily matters, but if you could be health czar and fix one of them, you might actually start with the research side of things.

我会这么做。

I would.

事实上，研究的流向取决于资金的去向。

And I mean, the reality is the research flows from where the dollars are going.

这种现象在国立卫生研究院（NIH）一再出现。

This has been seen over and over and over at NIH.

当你将资源分配转向某个领域时，科学家们就会随之而来，并申请那些资助额度最高的项目。

You shift resource allocation to a certain area and the scientists will follow, and they will submit grants to get grants in the place where the funding line is the highest.

所以，如果有人跑来说，我们要把NIH预算的0.5%提高到50%用于衰老生物学研究，你根本不用担心没人参与。

So, if somebody came along and said, We're gonna go from 0.5% to 50% of NIH budget is gonna go to biology of aging, you'd have no shortage of people.

我的意思是，一开始可能会有点混乱，但绝对会有大量人申请资助，成为衰老生物学领域的专家。

I mean, it'd be kind of messy at first, but you'd have no shortage of people applying for grants and becoming experts in the biology of aging.

整个系统就会运转起来。

And the system would work.

最优秀、最聪明的人才会涌入这个领域，投身其中。

You'd get the best and the brightest that would go into that and do that.

这引出了另一个老生常谈的问题，但我此刻实在忍不住要问。

So, this then begs another question that is a tired question, but I can't help but ask it at this point.

衰老是一种疾病吗？

Is aging a disease?

这个问题还重要吗？

Is that even a relevant Call

叫我。

Call Call me.

我是Call me。

I am Call the me.

重要的是要恰当地使用词语，区分原因与结果。

It's important to use words optimally and to distinguish causes from effects.

衰老的一个不利之处在于，它是许多疾病的危险因素。

One of the bad things about aging is it's a risk factor for many diseases.

有些其他因素也是疾病的危险因素。

Some things other risk factors for diseases.

衰老是疾病的一个危险因素。

Aging is a risk factor for disease.

因此，说衰老是一种疾病会混淆这一讨论。

And so saying that aging is a disease confuses that discussion.

这使得我们无法看清这种关系。

It makes it impossible to see that relationship.

所以，把衰老称为一种疾病是一个根本性的错误。

So calling aging a disease is a fundamental error.

这个问题本身是我想

The question itself is I

我完全同意。

agree completely.

我认为这是个错误的问题。

I think it's the wrong question.

我同意。

I agree.

但我认为我们提出这个观点是为了营销，而不是出于科学目的。

But I think we have that idea for marketing purposes, not for scientific purposes.

而这个观点是，钱都流向了疾病。

And the idea is, well, the money goes to diseases.

那就把衰老称为一种疾病吧。

Let's call aging a disease.

因为我认为我们真正想做的是把衰老当作一种疾病来治疗。

Because I think what we're trying to do is we're trying to treat aging as if it were a disease.

尽管我同意你们两位的看法，但我并不认为衰老是一种疾病。

Even though I would agree with both of you, I don't think it's a disease.

如果我们把衰老也归为疾病，那就破坏了‘疾病’这个词的含义。

I think that destroys the word disease if we include aging in it.

但我认为，突然出现这种说法是有原因的，因为你们觉得，哦，这样或许能引起国会的关注。

But I think there was a reason that suddenly this came because you thought, oh, maybe this will get congress to pay attention to it.

你说得对。

You're right.

这是一种营销手段。

It's a marketing ploy.

如果你以为只要掐着手指说‘嗯，这算是一种疾病吧’，就能让人意识到衰老研究的重要性，

And if you think you can convince people of the importance of aging research only by crossing your fingers and saying, oh, well, it's kind of a disease, isn't it?

你觉得你能骗得了他们吗？

You think you can fool them?

是的。

Yes.

这就是营销的本质，而且在这方面可能确实有效。

That's what marketing is and it's probably good for that.

我只是不喜欢欺骗人们。

I just don't like lying to people.

这也会让一些人对这个领域产生负面情绪。

It also creates a negative feeling about the field in some people as well.

所以我认为这一点应该被考虑。

So I think that should be considered.

不过，人们经常提出的另一个观点是，我们必须把衰老称为一种疾病，FDA才会批准针对衰老的药物，但我认为这是对FDA运作方式的根本误解，但这也是支持衰老是一种疾病这一观点的人经常听到的另一种论点。

The other point that people often raise though is we have to call aging a disease in order for FDA to approve a drug for aging, which I think is a fundamental misunderstanding of how FDA operates, but that is the other argument you will often hear among proponents of the idea that aging is a disease.

非常有趣。

Very interesting.

那么，现在让我们更深入地探讨一下这一点。

Well, so now let's go one step deeper on that.

你怎么看待生物学年龄和 chronological 年龄的区别？

How do you think about biologic versus chronologic age?

在概念上和实践中？

In concept and in practice?

来这儿的路上，里奇和我聊了这个。

On the ride over here, Rich and I were talking about that.

我不认为存在所谓的生物年龄这回事。

I don't believe there is one thing as biological age.

我认为你的心脏可能有一个年龄，肝脏有一个年龄，肺有一个年龄，大脑也有一个年龄。

I think there is potentially an age of your heart, an age of your liver, an age of your lungs, an age of your brain.

但我看不出我们为什么不直接称之为健康状况。

But I don't see why we wouldn't simply call it health.

换句话说，我之前做过一次表观遗传年龄检测，但我知道该怎么看待它。

In other words, I got one of these epigenetic age clocks done on me a while ago, but I know what to make out of it.

我想，这不过是恭维话，还是它真的告诉我了什么？

I thought, is this just flattery, or did it really tell me something?

你一定得到了一个不错的结果。

You must have got a good result.

我得到了

I got a

一个好结果。

good result.

他13岁。

He's 13.

13岁。

13 years old.

这可能是整个事情的关键。

That may be the point of the whole thing.

对吧？

Right?

所以，我对某个与我自身健康状况不符的数字持怀疑态度。

So I'm dubious about some number that is different than I know I'm in good health.

以我的年龄来说，我的健康状况非常好。

For my age, I'm in very good health.

我早就知道这一点了。

So I knew that already.

现在我有了一个具体的数字。

Now I have a number for it.

我不太相信那个数字，

I don't put much credence Let in

我同意史蒂夫的观点，只是用稍微不同的说法表达一下。

me agree with Steve, but just put it in slightly different terminology.

这是将一个非常丰富复杂的數據集压缩成一个数字的问题。

It's a matter of taking a very rich complex dataset and trying to collapse it to a number.

所以，如果有人想知道我有多健康，他或她需要更多信息。

So if someone wants to know how healthy I am, he or she would need information.

我的视力如何？

How good is my eyesight?

我的听力如何？

How good is my hearing?

各种认知活动的能力如何？

How good is various kinds of cognitive activities?

我的有氧耐力、关节状况，这些都与我的健康状况以及未来的健康预测密切相关。

My aerobic endurance, my joints, all of that is pertinent to how my health is and also about projected future health.

一旦你获得了这些丰富信息，就没有必要再声称：啊，有一个数字，一个单一的数字，一个数轴上的点，能够以任何有意义的方式浓缩这些信息。

Then there's no need, once you've got that information, is very rich, to say, Ah, there's a number, a single number, a real number, a point on the number line that condenses that in any useful way.

四十年前，人们曾认为生物年龄不同于 chronological age，当时这个概念有一定用处。

A notion forty, fifty years ago that biological age was not the same as chronological age For a little while it was useful.

它强调了可能存在一些60岁的人像年轻人一样，也存在一些60岁的人却像70岁的人一样，我的药物、基因突变或其他手段能否区分或改变这些人？

It emphasized that there might well be 60 year old people who were unusually like youthful people and 60 year old people who were unusually like 70 year old people, would my drug or my genetic mutant or whatever help to discriminate those people or change them in some way?

我可以延缓你的生物衰老过程。

I can slow your biological aging process.

这种讨论可能在四十年前还有些意义，但现在是时候放弃这个概念了，更不用说那种荒谬的想法——认为你可以量化生物年龄，而仍有太多人认为这个数字有价值。

That's a discussion that was maybe of interest forty years ago and it's now time to drop the notion, let alone the silly notion that you can count that biological age, that number which some people, too many people still think is of value.

你可以通过测量某些东西，比如转录组或表观遗传标记，来确定它是什么。

You can figure out what it is by measuring something, transcriptions or epigenetic markers or something.

我可以做到，并告诉你个人的生物年龄。

I can do it and give you personally, your personal biological age.

这纯粹是浪费大家的时间，还会分散人们对真正重要且需要思考的问题的注意力。

That's a waste of everyone's time and it also distracts attention from things that actually are important and need to be thought about.

我得说说，因为我从根本上不同意，而且我很惊讶，但这场对话会很有趣。

I gotta talk because I think I disagree fundamentally and I'm surprised, but this will be an interesting conversation.

我同意，那种可以购买来测量生物年龄的检测套件——首先，目前市面上的东西根本无效，我们可以也应当讨论这一点。

So I agree that the idea of a kit that you can buy to measure biological age, first of all, the stuff that's out there doesn't work and we can and should talk about that.

但我也部分认同这种观点：将生物年龄简化为一个数字，虽然概念上可能可行，但在现实中会极其困难。

But also, I sort of agree with the idea that reducing it to one number, while conceptually I think it's possible, I think in reality is going to be really, really difficult to do.

但你是否相信，存在一种与日历年龄不同的生物衰老过程？

But do I believe that there is a biological aging process that is different from chronological aging?

当然。

Absolutely.

是的。

Oh, yes.

当然。

Absolutely.

好的。

Okay.

听起来你们俩都在说不。

It sounded like you guys were both saying no.

你以为

You didn't think

那不是真实存在的。

it was a real thing.

我完全同意这一点。

I agree with that completely.

你可以同意这一点，但仍然不喜欢用一个数字来代表你的生物年龄这个想法。

You can agree with that and not like the idea of a number that constitutes your biological Okay.

有两件事让我对这个观点相当有信心。

There's two things that kind of make me feel pretty confident in this idea.

第一点是，我经常在公众中用这个例子，看看狗和人的对比。

One is, and this is the example I use a lot among the general public, just look at dogs compared to people.

每个人都熟悉‘人类一年相当于七狗年’这个说法。

Everybody's familiar with the idea that one human year is about seven dog years.

这到底意味着什么？

What does that mean?

这意味着狗的衰老速度大约是人类的七倍。

It means that dogs age about seven times faster than people do.

但当然，狗和人所经历的绝对时间是一样的。

But, of course, chronological time is the same between dogs and people.

区别在于生物衰老过程。

It's the biological aging process.

因此，你可以纵观整个动物界看到这一点。

And so you can look across the animal kingdom and see this.

狗会患上几乎与人类相同的疾病，并在组织、器官层面，乃至全身层面出现功能衰退。

And dogs get almost all of the same diseases and functional declines that we do at the tissue and organ level, but also the whole body level.

我们现在也知道，存在一些单一基因能显著调节我所说的衰老速率。

We also know now there are single genes that significantly modulate what I would call the rate of aging.

也许我们有不同的

Maybe we have a different

不，我完全同意你所说的含义。

No, meaning to what we mean I agree entirely.

所以，这种可能性的存在。

So the fact that that's possible.

对。

Right.

DAF-2，我们之前已经讨论过几次DAF-2了。

DAF two, we talked about DAF two a couple times.

TOR基因，我们可以上调或下调这些基因，而进化谱系中各种动物似乎通过调节单一基因来改变衰老速率。

TOR, we can turn these things up, turn them down, and animals across the evolutionary spectrum seem to age at different rates by modulating single genes.

因此，我想不到其他解释，只能认为存在这样一个过程——我们称之为生物衰老——它是可以被改变的。

So, don't know of any other explanation other than that there is this process, which we call biological aging, that can be changed.

而且这个速度可以加快或减慢。

And the rate can be sped up or slowed down.

它能被逆转吗？

Can it be reversed?

这是个有趣的问题。

That's an interesting question.

也许我们稍后会谈到这一点。

Maybe we'll get to that.

但我认为这个过程是真实的。

But I think the process is real.

我觉得它真的非常复杂，目前我们可能只理解了其中的5%。

I think it's just really, really complicated and we probably only understand 5% of it at this point.

是的。

Yeah.

对我来说，挑战在于，我某种程度上认同里奇的观点，即如果一位患者问我：‘嘿，你为什么不用这个生物年龄检测仪来测我？’

I think for me the challenge is, I kind of land where Rich was, which is if a patient says to me, Hey, why aren't you doing this biologic age clock on me?

我的回答是：我知道你的最大摄氧量，知道你的二区心率，知道你的肌肉量，知道你的内脏脂肪。

My response is, Well, I know your VO2 max, I know your zone two, I know your muscle mass, I know your visceral fat.

我们为你做了非常复杂的动作评估，我了解你的平衡能力，了解你的血脂和胰岛素水平。

We did a very complicated movement assessment on you, I understand your balance, I understand your lipids, your insulin.

我知道关于你的这57个方面，我能逐一告诉你每个指标的状况。

Like I know these 57 things about you and I can tell you individually on each of them how you're doing.

但这个数字并没有给我提供任何新的信息。

That number doesn't tell me a single new piece of information.

但假如你走到我面前，你可能在心里已经做了某种综合判断，

But what if you were to come up and then you probably do this in your head, you come up with some sort of composite.

你可能不会坐下来给每一项指标赋权重然后得出一个数字，但你会基于所有这些信息形成一个关于健康的综合印象。

You probably don't sit down and weight each of those things and come to one number, but you come up with some sort of composite picture of health based on all of those things.

那才是另一种生物衰老评估方式。

That's a different biological aging clock.

我认为我们有时会混淆，部分原因在于这个领域里一些不负责任的人和营销者所造成的误导，我们把表观遗传检测和生物衰老时钟混为一谈。

I think sometimes we conflate, and in part this is because of the way that irresponsible people in the field and marketers have done this, We conflate the epigenetic tests with biological aging clocks.

生物衰老时钟有各种类型，包括虚弱指数或大量功能指标的度量。

There are all sorts of flavors of biological aging clocks, including things like frailty indices or metrics of a whole bunch of functional markers.

所以，我认为这些可能是衡量生物年龄相当不错的指标。

So, I think those probably are pretty good readouts of biological age.

你再次将它们全部综合起来，得到一个对每个人都有意义的单一数值吗？

Again, you combine them all to get to one number that's meaningful for every person?

这要难得多。

That's much harder to do.

是的，跟我们说说你的经历吧，因为你做了我想做但一直太懒没去做的事。事实上，我们曾经通过邮件交流过，打算一起做这件事，各自想出不同的名称。

Yeah, tell us about your experience, because this was You did what I wanted to do, but I've been too lazy to Yeah, in fact, we exchanged emails at one point about doing this and each coming up with different names.

所以我做了四款不同的直接面向消费者的生物年龄检测套件，它们都是来自不同公司的表观遗传生物年龄检测，我每款都重复检测了两次，样本都是同一天采集的。

So what I did was I tested four different direct to consumer biological age kits, they were all epigenetic biological age tests for different companies And I did duplicates of each kit and it was from the same samples collected on the same day.

我真的尽力戴上科学家的帽子。

Really tried to put my scientist hat on.

我只有两次重复检测，没有三次，那是我当时能负担得起的最好条件了。

I only had two replicates, didn't have three replicates, it's about the best I could afford at that point.

而且还挺贵的。

And it was kind of expensive.

所以，我把样本寄出去后，收到了结果，对我来说非常有启发。

So anyways, sent those in, got the results back, and they were, to me, very informative.

这从根本上改变了我对这些表观遗传年龄检测的看法。

Fundamentally sort of changed my views on these epigenetic age tests.

结果从42到63不等。

So, they ranged from 42 to 63.

我做检测时的年龄是53.75岁。

I was 53.75 years at the time I did the test.

标准差我记不清了，要么是7，要么是9。

And the standard deviation, I can't remember, was either seven or nine.

我的实际年龄是均值，标准差为7或9，我看了这些数据。

So mean of my chronological age, standard deviation of seven or nine, which I look at that data.

我不是统计学家，但懂一点统计学，知道这完全没用。

I'm not a statistician but I know enough statistics to say that's completely useless.

它们的结果集中在了我的实际年龄上，但差异巨大。

They converged on my chronological age but with a huge variation.

即使是同一公司内部，不同测试之间的结果也有差异。

Even intra So that varied between the tests.

所以我认为四家公司中有三家的结果彼此相对接近，三家公司的重复测试结果也还算接近，但单个测试之间的差距却很大。

So I think three of the four were reasonably close to each other, Three of the four companies, the duplicates were reasonably close to each other, but the individual tests were far apart.

其中一家公司的重复测试结果相差了二十岁。

And one of the companies, the individual replicates was twenty years apart.

所以对我来说，有些人可能会说，也许真正的诊断测试很棒，而Elysium的测试很糟糕，或者远程医疗测试很差，而另一个很好。

So to me and some people will say, But maybe the true diagnostic test is great and the Elysium test is terrible or the telehealth test is terrible and the other one is great.

也许吧，但我们怎么知道呢？

Maybe, but how do we know?

我的结论是，直接面向消费者的生物年龄检测行业一片混乱，我不知道该相信谁，也不知道它们当中是否有任何一家提供的数据是准确的。

My take home is that the direct to consumer biological age testing industry is a complete mess, and I have no idea who to believe or if any of them are actually giving accurate data.

我认识一些公司里的人，我对谁在认真做这件事、谁是骗子有自己的看法，但整个行业来看，真的很难分辨。

I know some of the people at some of the companies, and I have my personal feelings about who's trying to do it right and who's sort of a charlatan, but across the industry it's really hard to know.

关于这一点，我最后想说的是，我认为这些工具在研究方面非常有用。

The last thing I'll say on this is where I've sort of landed is I think these are really good research tools.

我认为直接面向消费者的部分已经远远超前了，我同意你对这些检测的看法。

I think the direct to consumer component has gotten way ahead of itself, and I think I align with what you were saying about the way you think about these tests.

目前，我认为它们在临床实践中的价值有限，因为我们还不清楚其精确性或准确性，也无法基于这些检测做出可操作的建议。

I don't think there's a lot of value in clinical practice right now because we don't know precision or accuracy, and I don't think you can make actionable recommendations based on these tests.

此外，它们在我认为它们本应实现的唯一目标上失败了。

Furthermore, they fail in the one thing that I think they're attempting to do.

我通常会用这个例子来向患者解释。

And I usually use this illustration with patients.

所以，如果我有一位40岁的患者说，他真的很想做一次这种检测。

So, if I have a 40 year old patient who says, I really wanna do one of these tests.

我会说，如果检测结果说你的生物年龄是20岁，你的预期是还能再活70年吗？

I say, if the answer comes back and says you're 20, is your expectation that you will live another seventy years?

相反，如果检测结果说你的生物年龄是60岁，你的预期是还能再活30年吗？

Conversely, if the answer comes back and says 60, is it your expectation that you will live another thirty years?

换句话说，这个数字能否预测未来的寿命？

In other words, is this number predictive of future years of life?

因为目前，我们有一个叫做生理年龄的概念，它是预测未来寿命的最佳指标。

Because right now, we have this thing called chronologic age that is the single best predictor of future years of life.

那么，我们是否认为这些检测所确定的生物年龄，能更好地预测未来的寿命？

So, do we think biologic age, as determined by these tests, is better a predictor of future years of life?

顺便说一句，这一点其实很容易验证。

Which by the way, would be very testable.

有多少人联系过你，想获取ITP样本数据，以判断这些小鼠还能活多久？

How many people have contacted you to get ITP sample data to say, Can we predict how much longer these mice were going to live?

这个问题的答案显而易见，而且广为人知。

The answer to the question is obvious and very well known.

如果你有一位40岁的患者，他或她肥胖、不运动、主要吃汉堡包，

You can tell if you have your 40 year old patient and he or she is fat, doesn't exercise, eats mostly cheeseburgers.

你就知道他们的预期寿命很可能不如你下一个候诊室里那位生活习惯极健康、父母都活到百岁的40岁患者。

You know that their life expectancy is probably not as good as the 40 year old patient in your next waiting room that has extremely healthful habits and whose parents live to be 100.

而且有很多问题，但我并不需要生物年龄来判断，这就是我的意思。

And there's tons of problems But I don't need a biologic age Right, to tell That's what I'm saying.

你可以测量个体的很多指标，对于一个70岁的人，其实只需要问四五个关键问题就够了。

There are tons of things you can measure on individuals, four or five of them are all you really need to ask of a 70 year old.

是的，美世保险在这方面做得非常好。

Yeah, MetLife does this really, really, really well.

因为他们的同行也在关注这些数据。

Because their buddies are on the line there.

他们在承保人寿保险。

They're writing life insurance policies.

所以，要判断一个70岁的人大概还能活多久，找出一小套测试方法根本一点都不难。

So it's not at all hard to figure out a very small set of tests to tell you how long a 70 year old is likely to live.

这跟甲基化时钟毫无关系。

It has nothing to do with methylation clocks

那是我们的金标准。

That's or big the gold standard.

当人寿保险公司开始将生物年龄作为其精算算法的核心时，我会认为我们离那一天并不远了。

When life insurance companies start using biologic clocks as the cornerstone of their actuarial algorithms, I'll start to be don't think we're that far away from that.

我可能会听起来像老生常谈，但你们一直说'生物年龄'，而你们实际指的是表观遗传年龄或表观遗传检测。

I'm going to sound like a broken record here, but you guys keep saying biological age when what you mean is epigenetic age or epigenetic test.

不一定。

Not necessarily.

我们应该向人们解释这两者之间的区别。

And we should explain to people that there is a difference.

有些这些时钟仅使用表观遗传测量。

So some of these clocks use solely epigenetic measurements.

并非全部都是。

Not all.

大多数直接面向消费者的检测都是表观遗传类型的。

Most of the direct to consumer ones are epigenetic.

但有些检测则使用了包括表观遗传在内的多种生物标志物。

But some of these tests use a litany of biomarkers inclusive of epigenetics.

是的。

Yes.

所以他们会说，我们检测了你的甲基化模式，但也查看了你的维生素D水平、葡萄糖水平、胆固醇水平以及一大堆其他指标，并将所有这些数据压缩成一个数值。

So, they'll say, We've sampled your methylation pattern, but we also looked at your vitamin D level, your glucose level, your cholesterol level, and a whole bunch of other things, and we compressed all of that into a number as well.

所以，让我把这个当作一个问题来问你。

So I guess, let me frame it as a question to you.

那么，我们先把表观遗传部分去掉。

So let's take the epigenetic piece out.

我认为，随着技术的发展和消费者端质量控制的提升，这些检测最终会比单纯的 chronological age 更准确。

Again, I do think we will get to a point where the technology is developed far enough and the quality control is good enough on the consumer side that these tests will be better than just chronological age.

我觉得我们能做到。

I think we can get there.

这话说得可真够大的。

That's a big statement.

我不确定我是否不同意你的观点。

I don't know that I'm disagreeing with you.

我只是想确保我的意思能从研究中清楚地体现出来。

I just want make sure I mean, that think it's understand clear from the research.

除非你认为所有关于这些表观遗传衰老时钟的研究都有问题，否则很明显，你可以创建算法来预测特定的甲基化模式。

Unless you think that all of the research that's been done on these epigenetic aging clocks is somehow flawed, it's clear that you can create algorithms that can predict specific methylation patterns

完全同意。

Agree completely.

这些模式与寿命的相关性高于 chronological age。

That are more highly correlated with life expectancy than chronological age.

但我认为关键在于，即使如此，它们也不如彼得在完成所有检测后所预测的那么准确。

But I think the big but here is that even if that's the case, they would not be as good as what Peter would predict after all the tests.

生物年龄。

Biological age.

这就是我想说的。

That's what

我想达到的就是这个。

I wanna get to.

是的。

Yes.

我认为你实际上是在利用那些具有长期临床历史的其他生物标志物，来构建一个替代指标，但这个指标主要反映的还是生物年龄。

And I think what you are actually doing is looking at other biomarkers that have a long term clinical history that you're using to come up with a surrogate, but really is reflecting largely biological age.

也许并不完全如此，这也是我想强调的另一点：我不认为生物年龄和健康状况是等同的。

Maybe not completely, and this is the other point I wanted to make is I don't think biological age and health are equal.

我认为它们高度重叠。

I think they are strongly overlapping.

当然，你可以找到许多方法在不加速生物衰老的情况下降低健康水平。

Certainly, you can identify many ways to reduce health without accelerating biological aging.

我觉得这很容易。

I think that's easy.

我们都能想到一些方法来做到这一点。

We can all think of ways to do that.

所以让我们花一点时间来想一想。

So let's take a minute and try.

是的。

Yeah.

让我们稍微思考一下这个问题。

So let's think about this for a second.

我见过一些非常令人印象深刻的数据，我们可以观察器官的组织样本，并且能够判断：我来给你展示一个肾单位的样本。

I have seen very impressive data where we can look at tissue samples of organs and we can tell Okay, I'm going show you a sample of nephrons.

仅仅根据甲基化模式，我们就能知道，如果我告诉你其中一个来自20岁的人，一个来自50岁的人，一个来自70岁的人，根据甲基化模式，非常容易判断出每个肾单位来自哪个人。

And just based on nothing but the methylation pattern, we know that if I just said to you, one of these is a 20 year old, one of these is a 50 year old and one of these is a 70 year old, it's very easy to predict based on the methylation pattern which nephron came from which person.

我完全同意这一点。

Completely agree with that.

随着年龄增长，有很多事情都会发生变化。

There are a lot of things that change with age.

文献中记载了两万五千种随年龄变化的因素。

The literature has 25,000 things that change with age.

这10个位点的平均甲基化水平，在所有这些因素中排名第11,407位。

Average amount of methylation at these 10 spots is number 11,407 of those.

太好了，你又找到了一个随年龄变化的因素。

So great, you've got another thing that changes with age.

所以这就是问题所在。

So that's the question.

但这还不够。

But that's not enough.

对。

Right.

那么，你是否相信，我们目前看到的所有关于表观遗传时钟的研究，都会成为我们综合模型中的第78个变量？我不知道。

So do you believe that all of the research we're seeing on the epigenetic clocks is going to be the seventy eighth variable that we would include in our Gestalt I don't know.

是的。

Yeah.

这是个好问题。

It's a good question.

因此，我期望表观遗传算法能够达到这样的水平：它们可以取代许多——当然不是全部——其他正在被测量的生物标志物。

So I am hopeful that epigenetic algorithms can get to the point where they can replace many, certainly not all, but many of the other biomarkers that are being measured.

我认为让我感到希望的是，我们知道表观遗传变化是生物衰老的一部分。

I think the thing that gives me hope is we know that epigenetic changes are part of biological aging.

这又是另一个问题，但如果我们观察衰老的特征，表观遗传失调是其中的十二个之一。

This again is a different question, but if we look at the hallmarks of aging, epigenetic dysregulation is one of the 12.

有些人会认为这是最重要的一个。

Some people will argue it's the most important one.

这是另一个话题，但至少它是其中一部分。

That's a different conversation, but it's at least part.

因此，这让我有了一些希望，即我们实际上正在测量某种对衰老过程具有因果作用的东西。

So, that gives me some hope that we are in fact measuring something that plays a causal role in the aging process.

我认为缺失的是，如果我们能建立特定甲基化变化与某种衰老或年龄相关疾病成因之间的机制联系，那将让我们所有人都更有信心。

And I think what's missing, think what would give all of us a lot more confidence is if we had a mechanistic connection to the specific methylation changes and some cause of aging or age related disease.

换句话说，这种甲基化变化改变了某个特定基因的表达水平，从而改变了生物衰老的速度。

In other words, this change in methylation changes this particular gene's expression level, which changes the rate of biological aging.

我认为，如果我们有了这一点，我们会更有信心。

I think if we had that, we'd feel a lot more confident.

是的，你和我在上一期播客结束时简短地聊过这个话题，我想现在趁大家都在这里，再回来深入讨论一下。

Yeah, you and I spoke about this very briefly at the end of our last podcast and I want to come back to it with all of us on this table.

因为刚才你所说的内容非常丰富，马特，我会先提出一个宏观的问题，然后我们可以从不同角度来探讨。

Because there's so much in what you just said, Matt, that I'm going to lay out a broad question and then we can start attacking it in different ways.

所以，我想探讨的一个问题是：我们是否相信，在衰老的十大特征中，表观遗传变化是最关键的？

So one of the things I want to address is, do we believe that it's possible that of the hallmarks of aging, epigenetic change is the most important?

另一个我想探讨的话题是：我们是否相信，随着时间推移所观察到的、无可否认的表观遗传变化，是导致其他状态出现的因果因素？

Another topic I want to address, do we believe that the epigenetic changes that we observe over time, which are undeniable, are causal in the arrival of other states?

从衰老细胞的出现、炎症的增加，到器官功能的下降——这些才是真正构成衰老特征的表现。

Everything from the arrival of senescent cells, the increase in inflammation, the reduced function of the organs, which really is the hallmark of aging.

如果是这样，那么逆转表观遗传表型，是否就能逆转我们所关注的这些表型？

And if so, does that mean that reversing the epigenetic phenotype will undo the phenotype of interest?

里奇，我接下来想说的是，你和我上次聊到的地方——那关于蛋白质组呢？

And Rich, where I'm going that you and I left off was, what about the proteome?

那代谢组呢？

What about the metabolome?

你刚才说了三点。

So you made three statements there.

都是宽泛、笼统的陈述。

Broad, general statements.

我认为这三点中的每一点都值得仔细修正，我们来一一讨论吧。

And I think each of the three deserves careful amendment Let's do it.

说得客气一点。

To be polite about it.

第一点涉及衰老的标志，我认为这严重拖累了整个领域的发展。

The first has to do with hallmarks of aging, which I think set the field back dramatically.

我认为，当两个人独自坐在电脑前写一篇综述文章，就正式将某物命名为衰老的标志时，

I think when you are officially branded a hallmark of aging by two people sitting alone at their computers and writing a review article, a hallmark of aging

我以为他们是在湖边散步时想到的，边走边说

I thought they were walking around a pond when they came up Walking with

在湖边散步。

around a pond.

对，好的，好的。

Right, okay, okay.

这意味着有人想说，我对衰老感兴趣，这还挺重要的，不是吗？

Means that somebody wants to say, I'm interested in aging, that's kind of important, isn't it?

咱们把它列到清单上吧。

Let's put it on our list.

你无法判断某物是否是衰老的标志，它是否随年龄增长而上升或下降，你是否能通过改变它来延长寿命，或者通过移除它来杀死小鼠或蠕虫。

You can't tell if something is a hallmark of aging, does that mean it goes up with age, it goes down with age, you can change it in a way that will extend lifespan, you can kill a mouse or a worm by removing it.

基本上，它只是某人曾经认为可能与衰老有关的东西。

Basically it's something that somebody once thought might be of interest to aging.

这样做的弊端是，一旦你被正式认定为衰老的标志，任何想为此申请资助的人都不必证明其具有根本性的因果关系，因为它已经是衰老的标志了。

And the downside of that is once you're officially branded as a hallmark of aging, anyone who wants to write a grant on that doesn't have to prove that a fundamental cause and effect model has any merit because it's a hallmark of aging.

我不必再证明它了。

I don't have to prove it anymore.

有人——我不知道是谁，也不清楚基于什么理由——已经决定它很重要。

Someone, I don't know who or on what grounds, has decided it's important.

我的审稿人知道它很重要，因为他们读过《衰老特征》这篇论文，所以我无需再思考它是否重要。

My reviewers know it's important because they've read the Hallmark of Aging paper so I don't have to think about whether it's important.

这一观点的负面之处在于，有很多东西并没有被列入特征清单。

The negative side of that coin is that there are lots of things that didn't make it into the hallmark list.

我真的认为，过早地关闭对其中一些问题的思考为时过早。

I really think it's premature to close thought off on some of those.

很容易列出十几项值得研究的内容，但如果你想要研究某项内容，而它又不在特征清单上，那你是在浪费什么？

It's easy to come up with a dozen things that ought to be investigated but if you want to investigate it and it's not on the hallmarks list, what are you wasting?

所以，去讨论哪个特征是最重要的‘核心特征’之类的，我觉得在讨论衰老特征时并不恰当。

So deciding which of the hallmarks is the big daddy hallmark or whatever strikes me as not the correct thing to talk about in the hallmarks arena.

所以在我们逐一讨论这些之前，也许我们应该先谈谈这一点。

So maybe we should talk about that before we go through all of these.

因为我觉得其他那些内容也大有可谈之处，老兄。

Because I think there's a lot to unpack the other ones too, man.

是的。

Yeah.

你们完全可以给我一张纸和一支笔

You guys could afford to give me a little piece of paper and a pen

这样我就能

so I'd

把想法写下来

be able to write down

我认为标志列表是一个相当随意的清单。

the I think the hallmarks is a list, a kind of arbitrary list.

并不是完全随意的，因为他们列出这些确实有某些理由。

Not completely arbitrary because they had some reasons for being there.

我想我们都不会否认这12个因素与衰老有关。

I don't think any of us would say that those 12 things are not involved in aging.

但这只是很小的一部分，你们中有谁想

But that's a very little Do any of

把它们一一列出来吗？毕竟我是唯一一个面前放着清单的人

us wanna rattle them off being that I'm the only one that's got the list sitting in front

是我？

of me?

我们可以玩个游戏，每人说一个，看看谁

We could do a game where we each name one and see who

说不出来，看我们能不能

can't See if we get

把12个都说全。

to all 12.

是的。

Yeah.

是的。

Yeah.

但在这份清单中，如果真有这种关键标志的话，我不会把表观遗传学视为关键标志。

But certainly in that list, I would not consider epigenetics as the key hallmark, assuming there are such things.

我认为这是一份有趣的清单。

I consider it to be an interesting list.

它几乎立刻变得像圣经般不可侵犯，我始终不明白为什么。

It became biblically sacrosanct almost immediately, and I've never understood why.

但不知为何，它确实如此。

But for some reason, it did.

所以我会同意

So I'd agree with

里奇，真美。

Rich that beautiful.

我的意思是，我完全同意里奇的观点，他也知道这一点，因为我们以前就讨论过。

I mean, so I agree completely with Rich, and he knows I do because we've talked about this before.

我认为另一方面是，这些特征对这个领域起到了极大的作用。

I think the flip side is, I think the hallmarks have been immensely useful to the field.

它们是传达生物衰老这一概念的非常简便方式，有助于说服那些原本认为这全是胡言乱语和骗术的科学界人士，让他们意识到确实存在一些机制性研究。

They are a very easy way to communicate this idea of biological aging, and it helps convince some of the scientific community that thought it was all just hocus pocus and snake oil that there is some mechanistic research happening.

我们可以指出一些具体的衰老现象。

We can point to specific things that are aging.

我认为，这些特征的一部分实际上非常有价值，推动了长寿领域的普及，至少在长寿科学被普及的程度上，它起到了促进作用。

I think that part of the hallmarks has been actually really valuable and has contributed to the popularization of longevity, and at least to the extent the science of longevity has been popularized has contributed to that.

但它对这个领域造成了极大的损害。

And it has been extremely detrimental to the field.

我认为这是因为导致该领域过早地变得狭隘。

And the way I think about it is it just caused the field to narrow prematurely.

这让我回想起我之前提到过的内容。

And this goes back to what I alluded to before.

我不知道我们是否理解了80%的生物衰老，还是仅仅理解了0.005%的生物衰老。

I don't know if we understand 80% of biological aging or 0.005% of biological aging.

我猜测，实际情况更接近0.005%。

My guess is it's closer to 0.005.

一旦这些特征成为主导范式，外界对非特征研究的资金支持就基本枯竭了，人们也不再探索了。

And by and large, the funding to look outside of the hallmarks dried up once the hallmarks became the dominant paradigm, and people stopped looking.

我认为我们需要回归更多探索性科学，跳出固有思维框架。

And I think we need to go back to more discovery science and thinking outside the box.

所以我觉得这是一把双刃剑。

So I think it's been a double edged sword.

如果我们能挥动魔杖增加资金，这种情况会自动发生吗？

Would that happen automatically if we could wave that magic wand and increase funding?

这会有帮助。

It would help.

我不知道这是否足够有效，但确实会有帮助。

I don't know that it would help enough, but it would help.

我的意思是，你还得改变人们对所谓的‘探索性研究’的看法。

I mean, you also kind of have to change the mindset about what people call fishing expeditions.

在基金评审小组里，这简直就是个贬义词。

That's like a bad word in grant review panels.

‘探索性研究’意味着你并不知道会发现什么，但你必须先去探索，才能弄清楚什么是重要的。

Fishing expedition meaning you don't really know what you're gonna find, but you gotta go look before you can figure out what's important.

所以我觉得我们必须改变这种观念。

So I think we have to kind of change that mindset

我们可以用一种有效的方式将这一讨论具体化。

as One can usefully concretize this discussion.

我想，其中之一——我不读这些论文，因为它们让我难过——但我推测炎症是这些因素中的一个或多个。

I imagine that one of this I don't don't read these papers because they upset me, but I imagine inflammation is on one or more of these.

确实如此。

Sure is.

我打赌是这样。

I'll bet.

慢性炎症。

Chronic inflammation.

好的。

Okay.

很好。

Good.

慢性炎症。

Chronic inflammation.

所以，如果你说我对慢性炎症感兴趣，因此在做些有益的研究，但实际情况可能是，某些胶质细胞过度表达了这一组细胞因子，从而导致认知功能下降。

So what that does if you say, I'm interested in chronic inflammation so I'm doing good stuff, But what could be happening is this particular set of cytokines might be overexpressed by some glial cells and that leads to loss of cognitive function.

而另一组由脂肪组织中的巨噬细胞产生的、部分重叠的细胞因子，可能会让你更容易患上糖尿病或代谢综合征。

Whereas this other overlapping set of cytokines produced by the macrophages in your fat may make you more prone to diabetes or metabolic syndrome.

而这一组特定的淋巴细胞对于抵御新冠病毒至关重要，这就是你更容易感染新冠的原因。

Whereas this particular set of lymphocytes are necessary to repel COVID and that's why you are more susceptible to COVID.

因此，去了解在‘炎症’这个极其宽泛的通用概念下，究竟哪些细胞类型、在哪些人身上、在何种药物或基因变化下发生了改变，以及它们如何与其他病理方面相互作用，这才是非常了不起的研究。

So learning what changes within the extremely broad generic idea of inflammation, What changes in what cell types, in what people, under what pharmacological or genetic changes, how they are interacting with other aspects of pathology, that's marvelous to do.

但如果说‘炎症在年老时会变糟’，这实际上是在回避深入思考的艰辛，而这正是我反对这种说法的原因。

But to say, Oh, inflammation, that gets bad when you're old, is a way of avoiding the labor of thinking, and that's why I'm against it.

我认为马特提出了一点非常重要的见解，而我们科学家也难辞其咎，那就是研究评审的方式。

And I think Matt brought up a really important point, and we scientists are to blame, is the way that research gets reviewed.

对于懒惰的审稿人来说，这十二大特征确实非常有用。

For lazy reviewers, having these 12 hallmarks is really helpful.

哦，这项研究包含了一个特征。

Oh, this has got one of the hallmarks in it.

这一定是好东西。

This must be good stuff.

我认为评审人员需要对新想法和新方法更加开放。

I do think reviewers need to be more open to new ideas and new approaches.

我的意思是，大家都清楚，NIH的资助申请如果只是渐进式的，就更容易获批。

I mean, everybody knows that NIH grants are approved if they're incremental.

如果真是突破性的，反而不会获批。

If they're really breakthrough, they don't get approved.

事实上，一位非常著名的生物学家E.

In fact, a very famous biologist, E.

O.

O.

威尔逊多年前告诉我：永远不要在资助申请中包含你最好的想法。

Wilson, told me years ago, he said, don't ever include your best ideas in a grant.

它们不会获得资助。

They won't get funded.

做些常规的事情。

Do standard stuff.

把你最好的想法留到业余项目中去实现。

Save your best ideas for projects that you do on the side.

这正是我离开学术界的原因之一。

That's one of the reasons I left academia.

简直把我逼疯了。

Drove me nuts.

几乎不可能获得

Almost impossible to get the

重要项目资金的支持。

important stuff funded.

你那个多部分问题的第二部分是，表观遗传会改变吗？

The second of your multipartite question was, does epigenetic change?

结果是什么？

What are the results of?

这是因果关系吗？

Is it causal?

它有因果效应吗？

It causal effect?

第三个问题，我们可能会谈到，那就是能否逆转它，以及这是否是好事？

And the third, which we may get to, is can you reverse it and would that be a good thing?

那么我们来谈谈这里的第二个要素：这是因果关系吗？

So let's talk about the second element here, is it causal?

问题在于它的含义是什么。

The problem is what it means.

在这组特定的40个松果体细胞中发生了一些变化，骨髓中的这些细胞也发生了其他变化，肠道绒毛细胞和隐窝细胞中的细胞也发生了变化。

There are some changes that occur in this particular set of 40 cells in the pineal and there are other changes that occur in these cells in the bone marrow and there are other cells that change in the gut and villous lining cells and the crypt cells.

所以它们在某种程度上都是表观遗传的，由某些因素引起。

So they are all epigenetic in some, they are caused by some things.

但我们并不真正知道这些变化中，是否有任何一种与衰老有关。

And we don't really know which, if any of these, count for aging.

如果有人声称要证明表观遗传变化是衰老的原因，那他们连细节都还没开始触及。

If someone says, I'm going to prove that an epigenetic change is responsible for aging, they haven't begun to come to grips with the nitty gritty.

人们总是会问，就像你暗示的那样，你的药物会改变表观遗传状态吗？

People always ask, just as you hinted, does your drug change epigenetic things?

不幸的是，他们想到这里就停止思考了。

And unfortunately that's where they stop thinking.

我们总是愿意提供经过药物处理的小鼠的组织样本。

We're always willing to give people tissues from our drug treated mice.

如果有人对影响神经元再生的表观遗传变化感兴趣，那很好。

If they are keen on epigenetic changes that affect neuron regeneration, excellent.

他们的专家会把大脑样本寄给他们，他们可以做这些研究，这很重要。

Their experts will send them the brains and they can do that stuff, it's important.

我并不是在嘲笑这一点。

I'm not making fun of it.

但普遍认为衰老仅仅是由于表观遗传变化——这种更模糊的理解，实际上并不能带来真正的进展。

But the general notion that that's aging vaguely thought of is due to epigenetic change, more vaguely thought of, doesn't really get you anywhere.

这就是我的怀疑观点。

That's my skeptical view.

你所说的部分问题是不是在追问：是什么导致了这个原因？

Is part of the issue that you're saying, well, what's causing the cause?

不是。

No.

只是表观遗传变化涵盖了数百种细胞类型下、受数百种因素影响的成千上万种变化。

It's just that the concept of epigenetic change encompasses thousands of changes in hundreds of cell types under hundreds of influences.

当然，其中一些会引发其他变化。

Of course, some of that causes other stuff.

同意表观遗传变化是导致各种与年龄相关病理的因果因素，这一点人人都能认同，但这毫无意义，真正重要的是指出：这一特定变化在该疾病中确实至关重要。

Agreeing to that, assenting to that notion that epigenetic change is causal for all sorts of age related pathologies, Everyone can agree to that but it's meaningless because what counts is to say, This specific change is really important in this disease.

这是一个表观遗传改变。

Here's an epigenetic alteration.

或者，这种在多个组织中广泛发生的特定变化会带来正面或负面的影响。

Or, This specific broad spectrum change in multiple tissues causes something good or bad.

你必须先定义它是什么，然后才能去检验它。

You have to define what it is before you can test it.

那我们用一个具体的例子吧。

So let's use a specific example.

当你观察一名1型糖尿病患者的胰腺β细胞时，它们的表观遗传特征与年龄匹配的健康人不同。

When you look at a patient with type one diabetes and you look at their beta cells in their pancreas, they look different epigenetically than the beta cells of an age matched person without type one diabetes.

而且我们也知道，这些β细胞已经失去了功能。

And we also know that their beta cells don't function.

所以它们丧失了功能。

So they've lost function.

让我们以这个具体例子来提出这个问题。

So let's ask that question as a specific example.

你认为，或者你有多大把握相信，1型糖尿病患者β细胞上的表观遗传变化确实导致了β细胞功能的丧失？

What do you believe or what confidence would you assign to the notion that the epigenetic change on the beta cells of the type one diabetic are indeed causal to the loss of function of the beta cells?

我最后一次接触1型糖尿病病因还是在医学院读书的时候，那已经是五年前的事了。

My last exposure to the causes of type one diabetes was when I was in medical school, was more than five years ago.

但如果我没记错的话，它是一种自身免疫性疾病。

But if I vaguely remember, was an autoimmune disease.

自身免疫性疾病，对吧？

Autoimmune disease, right?

如果你可怜的、无助的β细胞正被抗体、巨噬细胞等攻击，这些应激反应会导致表观遗传变化。

If your poor little helpless beta cells are being attacked by antibodies and macrophages and things, those stressors reactions are gonna cause epigenetic change.

这些表观遗传变化在多大程度上加剧了β细胞的不幸命运，是有可能的。

And whether those epigenetic changes contribute to some extent to the ill fate of the beta cells, it's possible.

如果我是糖尿病发病机制的专家，我真的很想知道这一点。

If I were an expert on diabetes pathogenesis, I'd really wanna know that.

这跟衰老没关系，但这是个有趣的问题。

Doesn't have anything to do with aging, but it's an interesting question.

但这确实是探讨因果关系的一种方式。

But it's way to address causality.

是的。

Yeah.

但你也可以同样说，不。

But you might equally say, no.

不。

No.

发生变化的是线粒体。

It's the mitochondria that have changed.

它们是糖尿病的标志。

They're a hallmark of diabetes.

是的。

Yeah.

或者是糖基化蛋白。

Or it's the glycated proteins.

这里面有很多因素。

There's a ton of things in it.

我认为，在现阶段，完全没有理由把表观遗传学置于其他任何因素之上。

There's no reason in the world at this stage, I think, to actually give epigenetics primacy over anything else.

这是一个不错的假设。

It's a nice hypothesis.

这是一个假设。

It's a hypothesis.

你可以提出这些问题，因为人们对1型糖尿病了解很多。

You can formulate these questions because a lot is known about type one diabetes.

我对衰老的生物学机制了解大约0.05%。

And I understand point 05% of the biology of age.

零零五。

Zero zero five.

是的。

Yeah.

我刚才想说的是，你

I was giving you You're

差了一个数量级。

off by an order of magnitude.

我是一只蝌蚪，我用一根木头在养你。

I'm a tadpole, I was raising you by a log.

是的。

Yeah.

我以为你差了一个数量级。

I thought you're one log off.

以史蒂夫那种方式提出问题，清楚地表明了评估表观遗传变化对1型糖尿病发病机制贡献这一概念有多么困难。

Formulating the questions in exactly the way Steve did makes it clear how difficult it is to evaluate the concept that epigenetic change contributes to pathogenesis in type one diabetes.

我们大致知道1型糖尿病中发生了什么，但对衰老过程却一无所知。

And we know more or less what is going on in type we don't know what's going on in aging.

我们甚至不知道身体的哪个部位在发生改变，或者身体的哪些部位更有可能发生改变。

We don't even know what part of the body is going on or parts more likely of the body.

我至少在内心稍微重新思考了一下，问：这个实验会是什么样的？

I at least internally reframe it a little bit and say, what would the experiment be?

你需要做些什么才能让自己相信，无论是广义上的表观遗传失调导致衰老（无论那意味着什么），还是这种与年龄增长相关的特定表观遗传变化导致了衰老？

What would you need to do to convince yourself that either broadly speaking epigenetic dysregulation causes aging, whatever that means, or this specific epigenetic change that is associated with chronological age causes aging.

因此，对我来说，这样想更容易一些，因为我觉得这整个讨论都很有趣，但除非有人真的去做实验，否则我们永远无法得到答案。

And so that's an easier way for me to think about it because I feel like it's all a fascinating conversation, but we're never going to get to the answer until somebody actually does the experiment.

或者决定它无法被表述，因为太复杂了，是的，然后放弃

Or decides that it can't be formulated because it's too complicated Yeah, and gives

没错。

that's right.

但人们正在尝试做这两件事。

But people are trying to do both of those things.

我的意思是，人们正在使用部分或暂时的表观遗传重编程，来探究这是否会对生物衰老产生影响？

I mean, are using partial or transient epigenetic reprogramming and asking, can that have effects on biological aging?

我实际上持谨慎乐观的态度，认为它可能有效。

I'm actually cautiously optimistic it can.

我不认为这会成为颠覆性的改变，但我相信你可以调控生物衰老的某些方面。

I don't think it's going to be a game changer, but I think you can modulate aspects of biological aging.

用于靶向表观遗传修饰的技术正在开发中。

The technologies are being developed for targeted epigenetic modifications.

所以，如果我们认为基因组中这个特定位置的表观遗传标记控制着衰老，我认为事情不会这么简单，但假设它确实是这样。

So, if we think this particular epigenetic mark at this particular location in the genome controls aging, and I don't think it's going be that simple, but let's say it is.

你可以介入，修改这个标记，然后观察：疾病是否减少了？

You could go in, you could modify that and then see, do you reduce disease?

寿命是否延长了？

Do you increase lifespan?

健康寿命是否改善了？

Do you improve health span?

这些正是我认为能让我们获得高度信心的实验类型。

Those are the kinds of experiments that I think would get us to where we can have a lot of confidence.

如果真的有人——比如Altos公司——三年后发表论文，称他们通过多次短暂的表观遗传重编程让小鼠多活了六年，我会成为他们最大的粉丝。

If it's the case, if somebody, let's say at Altos, publishes a paper three years from now that they have made a mouse live six years by multiple rounds of transient epigenetic reprogramming, I'll be like their biggest fan.

他们真正推动了进展。

They move the needle.

这会让我相信，这种策略确实能调控生物衰老。

That convinces me that that strategy modulates biological aging.