#359 ‒ 代谢与免疫系统功能障碍如何驱动衰老过程，NAD的作用，有前景的干预措施，衰老时钟等 | Eric Verdin, M.D.

我觉得这让我在社交上很孤立。

I found it socially isolating.

我们实际上已经着手解决这个问题，可以稍后在新型生酮饮食中讨论。

We've worked actually to remedy this on, we can talk about this later on novel keto.

像酮酯之类的吗？

Like a ketone ester or?

酮酯。

Ketone ester.

对。

Yeah.

没错。

Exactly.

β-羟基丁酸。

Beta hydroxybutyrate.

那么回到胰岛素的作用，有很多记录表明其强度的影响。

So going back to the role of insulin, there is a lot happening that's been documented that the intensity.

首先，你的平均血糖水平起着重要作用。

First, your average glucose plays a role.

平均血糖值，这是通过糖化血红蛋白A1c测量的，涉及一系列并发症，如心血管疾病，这你是知道的。

Average blood glucose, this is measured by hemoglobin A1c, in a whole series of complication, cardiovascular, as you know.

但或许更重要的是你的血糖峰值强度。

But perhaps more important is the intensity of your peaks.

我认为胰岛素峰值强度反映了你的葡萄糖摄入量，即快速吸收的葡萄糖。

And I think the intensity of the peaks of insulin is a reflection of your glucose intake, fast absorbing glucose.

这就是为什么我们主张——我主张人们使用连续血糖监测仪（CGM），真正了解什么会引发他们的血糖飙升。

And that's the reason why we advocate, I advocate people to go on a CGM, continuous glucose monitor, and to really learn to understand what spikes them.

整个理念就是要减轻这些胰岛素分泌的峰值。

The whole idea is to mitigate these peaks of insulin secretion.

我要把这个放给所有患者看。

I'm just gonna play this for all of our patients.

我们和每位患者都会进行这样的讨论，所以直接播放这段视频让你来讲解会很方便。

We have this discussion with every one of our patients, so it'll be nice to just play this video and let you do the talking.

核心理念还是在于缓解这些峰值，无论是通过饮食调整，还是例如GLP-1激动剂都在发挥作用

The whole idea there is to, again, mitigate these peaks and either dietary or, for example, the GLP-one agonist are playing a role

关于这点，是的，我们得好好讨论下，因为至少对我来说这个观点存在很多困惑

in this Yeah, well let's talk about this because there is at least for me a great deal of confusion around this point.

如今我们已了解肠道在代谢中的作用，并且知道大部分是通过GLP-1进行信号传导的

Now, we understand today the role that the gut plays in metabolism And we understand that a lot of it is transduced through GLP-one.

根据该领域世界权威Ralph DiFranco的说法，内源性GLP-1的生成驱动着80%与胰岛素相关的β细胞活动

So endogenous production of GLP-one, according to Ralph DiFranco, the world's authority on this, is what's driving 80% of beta cell activity with respect to insulin.

因此当出现胰岛素抵抗时，我们自身产生的GLP-1不足以生成管理血糖所需的胰岛素量

And therefore, when we have insulin resistance, the GLP-one we're making is insufficient to generate the insulin that's required to manage the glucose.

如果这个逻辑成立，那么补充外源性GLP-1——比如注射替尔泽肽或司美格鲁肽——就能增加系统中的GLP-1含量，克服β细胞抵抗，产生更多胰岛素，从而改善血糖控制，实现双赢

Makes sense if that's the case that giving exogenous GLP-one, you take a shot of tirzepatide or semaglutide, you're going to put more GLP-one in the system, you're going to overcome the resistance at the beta cell, you make more insulin, you now have better glucose control, everybody wins.

目前尚不清楚这个机制与减重方面有何关联

Now, it's not clear that that has anything to do with the weight side of it.

这是另一个独立议题，我特别想探讨这点，因为关于这些药物为何导致体重下降存在两个非常有趣的理论

That's a separate issue and I want to actually talk about that because there are two very interesting theories as to why these things cause weight loss.

但关键在于，你会不会预期使用GLP-1受体激动剂的人体内胰岛素水平会更高，从而实现更好的血糖控制？

But, point here is, wouldn't you expect to see higher levels of insulin in someone taking a GLP-one agonist to achieve that better glycemic control?

是的。

Yes.

但实际情况并非如此。

And that's not what you see.

对此我也无法解释。

And I don't have an answer for this.

我也观察到同样现象。

I've seen the same thing.

包括我个人一直在试验替尔泽肽。

Including personally, I've been experimenting with tirzepatide.

我的胰岛素值现在是5，这已经是能达到的最低值了。

My insulin is five now, which is lowest that you can possibly get it.

我内心其实很担心这会推翻我自己提出的整个理论

There was a part of me that was worried that I was going to go against my own whole theory about

你检查过餐后情况吗？

Have you checked postprandially?

你做过口服葡萄糖耐量测试吗？

Have you done an oral glucose tolerance test?

因为这可能是观察餐后胰岛素和餐后葡萄糖变化的方法，当然结果会更准确。

Because that might be something to do to see what is happening to postprandial insulin along with postprandial glucose, which of course will be better.

不，我还没做过。

No, I haven't.

这将是一个有趣的测试。

That would be an interesting test to do.

是啊。

Yeah.

我戴过连续血糖监测仪。

I've worn a CGM.

我的糖化血红蛋白从5.4、5.5降到了5.0。

My A1C has gone from 5.4, 5.5 to five point zero.

我的胰岛素水平也降到了5.0。

And my insulin is down to five point zero as well.

那你体重有减轻吗？

And did you lose any weight?

我体重减轻了一点，但不多，大概六七磅，这本来就不是我的初衷目标。

I lost a little bit of weight, not a huge amount, six or seven pounds, which was never the goal to start with.

而且肌肉量完全没有流失——这其实是人们最害怕发生的糟糕情况。

And no loss of muscle mass, which actually is the big booger boo that people will have you fear.

只要坚持锻炼，就不会出现肌肉流失。

No loss of muscle mass if you are exercising.

所以对我来说这是一次实验。

So for me, it's an experiment.

我还没决定是否要继续用药，但我就是想亲自尝试看看，这药到底有什么效果？

I haven't decided this is something I'm gonna continue, but I just wanted to really experiment for myself to try to see, okay, what is this drug really doing?

不得不说效果非常显著，从某些方面来看。

And it's been nothing short of remarkable, I think, some way.

最让我惊讶的之一就是这种饱腹感。

One of the most surprising has been for me this feeling of satiety.

你听说过饱腹感。

You hear about satiety.

我这辈子从来不是那种会感到饱的人。

I was never in my whole life the type of person that felt full.

我总是能吃得更多。

I could always eat more.

但突然之间，服用这个药大约两周后，我看着盘子说：我饱了。

And all of a sudden, after about two weeks on this, I just looked at my plate and says, I'm full.

我听到自己这么说时，感觉这真的完全不同了。

And I heard myself saying this and I just felt like, well, this is really completely different.

对我来说，你知道我为什么对这些药物感到兴奋——顺便说一句，这不是推荐。

And for me, you know, the reason why I'm excited about these drugs is and by the way, this is not an endorsement.

这是需要自己决定的事。

This is something to decide.

是啊。

Yeah.

没错。

Yeah.

这是自我实验

This is self experimentation

实验，这是我们领域长期以来的传统。

experimentation, which is a long part of the tradition of our field.

整个理念其实是，长寿医学最大的进步之一就是认识到范围值毫无意义。

The whole idea is really, the thinking was one of the biggest advance in longevity medicine is this idea that a range is meaningless.

作为一名执业医生，你很清楚这一点。

And as a practicing physician, you know this.

我上医学院时，他们告诉我们血压必须控制在130/90，那仍被认为是正常范围。

I went to medical school and we were told that your blood pressure has to be 130 over 90, and that was still a normal range.

所以即使你的血压是128/88，仍然被视为正常。

So you could be 128 over 88 and you were still considered normal.

同样的情况，我去看我的私人医生并告诉他，我的血糖每年都在缓慢上升。

The same thing I went to see my personal physician and told him, my blood sugar is creeping up every year that I'm doing it.

现在空腹血糖是96。

Now it's 96 fasting blood sugar.

我很担心，因为很快我就会变得相当...而他

I'm worried because soon I'm going to be pretty And he

说低于100就没事。

said it's below 100, it's okay.

他告诉我你很正常，别...而我告诉他，我说，什么叫正常？

He told me you're normal, don't And I told him, I said, what is normal?

我认为这正是长寿医学将产生重要影响的领域，就是重新审视这些标准。

And I think this really is where I think longevity medicine is going to make an important impact, is really sort of revisiting.

我数不清和多少人争论过血糖这个问题。

I can't tell you how many times I've had this argument with people about glucose.

这里有件有趣的事，我们有文献依据。

And here's the funny thing, we have the literature.

换句话说，我们拥有非糖尿病患者的文献数据。

In other words, we have literature in non diabetics.

你的糖化血红蛋白。

Your A1C.

那个

That

研究表明糖化血红蛋白越低，全因死亡率就越低。

says the lower the A1C, the lower the all cause mortality.

这是一种没有下限的单调递减关系。

It's a monotonic reduction that knows no lower limit.

我赞同你的观点。

I'm with you.

所以我们说5.6以下是正常的，如果你在5.6就没事。

So we say that up to 5.6 is normal and if you're at 5.6, you're fine.

但5.5比5.6好，5.4比5.5好，5.0比5.4好，4.8又比5.0好...

But 5.5 is better than five point six and five point four is better than five point five and five is better than five point four and four point eight is better than five point I'm

还没到那一步。

not there yet.

是啊，是啊。

Yeah, yeah.

但我想说的是，我也觉得——我不知道该用什么词——也许是可悲。

But my point is I also find it I don't know what the word is, maybe sad.

我觉得可悲的是，为了便于沟通我们简化了这个问题，却丢失了'更低是否总是更好'的本质。

I find it sad that we've simplified this problem in an effort to communicate but have lost the essence of where is lower better?

因为在生物学中并非总是如此。

Because it's not always true in biology.

比如你看TSH（促甲状腺激素），看甲状腺激素时，我们会说存在一个更窄的最优区间。

When you look at TSH, for example, when you look at thyroid hormone, much more narrow band in which we would say there's optimal.

如果太低或太高都会有问题。

If it's too low or too high, it's problematic.

但事实证明，对于非1型糖尿病患者或未使用胰岛素的人，在自然生理状态下，平均血糖水平确实是越低越好。

But it turns out that when it comes to average blood glucose in a non type one diabetic or someone who's taking insulin, under natural physiologic circumstances, it's just better to be lower.

随着年龄增长，这个数值会不断攀升。

And as you age, it just keeps creeping up.

血压也是同样的道理。

Same thing for blood pressure.

是的。

Yes.

他们每五年就会重新审视这个数值，试图进一步降低标准。

They're revisiting the number every five years in terms of making it lower.

我认为如果你的血压是100/65，那会比100/150/70更好

I think if your blood pressure is at 100 fivesixty five, you're better off than if you're 100 fifteenseventy

没错

That's right.

只要没有症状，数值低总是更好

Provided you're not symptomatic, lower is always better.

你知道，我虽然感到沮丧，但同时也为这正成为新常态而兴奋——整个新一代医生更清楚什么是真正的健康，体重问题也是如此

You know, I'm frustrated, but I'm also excited by the fact that this is now becoming the norm in a whole new field of physicians who are more aware of actually what is health and the same for your weight.

我们知道，在整个衰老研究领域最有趣的就是这个观点：所有事物都呈现J型曲线关系。

We know that that's the thing that is really interesting in the whole aging field is this idea that everything is a J curve.

所以存在一个你希望达到的最佳区间。

So there is a sweet spot where you want to be.

通常这个区间足够宽泛，你可以通过调整来优化人们的健康状态。

Quite often it's broad enough that you can maneuver this in a way to optimize people's health.

你认为体重——虽然这个指标很粗糙——或者我们可以通过脂肪含量、体脂率与长寿的关系来讨论，在调整代谢健康因素后？

What do you think is the relationship between, I mean, body weight is so crude, but maybe we can even talk about it through adiposity, body fat and longevity once correcting for metabolic health.

很明显，我们观察到的体脂与健康不良之间的关联，实际上只是对更难测量的代谢健康状况的一种替代指标。

So it's obvious that so much of the relationship we see between body fat and poor health is really just a proxy for something that's harder to measure, which is metabolic health.

测量体脂非常简单，我们通常用BMI来估算体脂。

It's very easy to measure body fat and we estimate body fat from BMI.

这就是为什么我们有这么多基于BMI的群体数据。

And so that's why we have all these population data from BMI.

但如果你有幸直接接触真实患者，我甚至说不出我接诊的任何一个人的BMI数值。

But if you have the luxury of working with actual patients, I couldn't tell you the BMI of one person I take care of.

但我清楚每个人的体脂率、内脏脂肪含量和口服葡萄糖耐量测试结果。

But I know everybody's body fat, everybody's visceral fat and everybody's oral glucose tolerance test.

我们了解我们所知道的，也明白什么才是关键。

We know what we know and we know what matters.

你是否认为肥胖本身就有问题？

Are you convinced that adiposity per se is problematic?

还是说你相信一个人可能体脂超标但代谢健康，并且能获得与代谢健康的瘦人相同的长寿益处？

Or do you believe that a person can have excess body fat but be metabolically healthy and confer the same longevity benefit as a metabolically healthy lean person?

我们知道有些被归类为超重的人代谢却很健康。

We know there are people who are considered overweight who are metabolically healthy.

是的。

Yes.

根据我的经验，这个比例轻松达到20%。

Easily twenty percent in my experience.

没错。

Yes.

这些都是事实。

And these are facts.

无人能否认这些事实。

No one can dispute them.

你可以体重超标但代谢健康。

You can be overweight and metabolically healthy.

我担心的是长期影响。

What I worry about is the long term effect.

你是指从骨科角度考虑，还是超重带来的其他并发症？

Do you mean from an orthopedic perspective with the other complications that come from excess weight?

或者你是说他们基本上在增加最终滑向代谢异常的概率？

Or are you saying that they're basically increasing their probability of eventually going off the metabolic slide?

两者都有。

Both.

老实说，虽然不知道数据怎么说，但我担心的是你可能40岁时代谢指标看起来健康。

Honestly, don't know what the data says, but my worry would be that you might be metabolically looking healthy when you're 40.

但如果这种情况持续二十年，内脏脂肪显然会堆积。

But if you sustain this for twenty years, clearly visceral fat.

是的。

Yep.

不同类别。

Different category.

对各方面都有很强的预测性。

Is highly predictive of everything.

另外我想说的是，BMI指数本身——我的BMI正处于超重的临界点。

The other thing I'll say also, the BMI itself is a my BMI is at the border of being overweight.

按照BMI标准，我已经超重了。

I am overweight by BMI.

我超重了四磅。

I'm four pounds.

如果我减掉四磅，BMI就能降到

If I lost four pounds, would get down to a BMI of

而我体脂率只有11%。

And 20 I have 11% body fat.

所以我不担心这个，因为我知道总的来说我代谢很健康。

So I don't worry about it because I know all in all I'm metabolically healthy.

我的各项指标都很好。

My numbers are good and all this.

所以在某种程度上

So in some way

它并不是特别有用。

It's not particularly helpful.

我是说，在群体层面上它达到了目的。

I mean, serves its purpose at the population level.

是的。

Yes.

但它完全不能用于对个体做出决策。

But it can't be used to make a decision about an individual at all.

确实如此。

Exactly.

但有时它也可能成为一个混杂变量。

But it can also sometimes become a confounding variables.

当人们进行研究时使用这些数字做出预测或得出结论，而这些结论实际上并未考虑到高BMI人群在代谢健康方面具有异质性这一事实。

When people do studies and they use these numbers and they make predictions or they draw conclusions that are really not based on the fact that high BMI fraction of the population is heterogeneous in terms of metabolic health.

所以我在巴克研究所的同事Nathan Price和Lee Hood实际上已经发表了一篇论文。

So my colleagues at the Buck, Nathan Price and Lee Hood, have actually published a paper.

等一下。

Wait a minute.

没想到他们在巴克研究所。

Didn't realize they were at the Buck.

是的，他们俩都在。

Yeah, both of them.

他们之前在西雅图，对吧？

They were up in Seattle before, weren't they?

是的

Yes.

实际上我们在过去两年里招募了他们两位

We recruited both of them actually in the last two years.

哦，恭喜

Oh, congratulations.

是啊

Yeah.

谢谢

Thank you.

我认为这对我们具有变革性意义

I think this is transformative for us.

太棒了伙计们

Fantastic guys.

真的非常令人兴奋

Really exciting.

李目前仍有一部分时间在西雅图。

Lee is still partially in Seattle.

所以他有一部分时间在巴克研究所。

So he's partially at the Buck.

我们已经与表型健康建立了合作关系。

We've established a collaboration with Phenome Health.

内森之前在索恩公司，现在仍是索恩的首席科学官，但同时也在巴克研究所担任教职。

And Nathan was at Thorne and still a CSO at Thorne, but faculty member at the Buck.

他们确实在帮助我们在这些方向上做一些非常激动人心的事情。

And they're really helping us to do something really exciting along these lines.

例如，他们发表了一篇论文，描述这种基于生物标志物的BMI（生化BMI），实质上评估的是你的代谢状态。

For example, they had a paper describing this BMI but biochemical BMI based on biological markers that essentially assess your metabolic status.

所以我认为这些工具已经可用，关键在于对医生进行教育。

So I think that those tools are available and it's a question of educating the physicians.

你知道构成这个生物BMI的具体指标是什么吗？

And do you know what makes up that biological BMI?

不知道。

No.

我会把那篇论文发给你。

I'll give you the paper.

好的。

Okay.

我们在新陈代谢上花的时间比免疫健康和整个免疫系统要多一些。

We spent a little more time on metabolism than we did immune health and the immune system overall.

其实我想回过头来再多讨论一下这个话题。

I'd actually like to go back and talk about it a little bit more.

我认为，这档播客的听众对新陈代谢相关内容已经非常熟悉了。

I think, again, the listeners of this podcast are very familiar with the metabolic stuff.

关于免疫系统的讨论我们进行得相对较少。

We haven't had as many discussions on the immune system.

之前我们详细讨论过它与癌症的关系。

Talked about it at length with respect to cancer.

我几年前曾邀请过史蒂夫·罗森伯格上节目。

I had Steve Rosenberg on a few years ago.

那场关于免疫系统在癌症中作用的讨论非常精彩，我认为我们必须在这里讨论这个话题，因为我确信癌症发病率随年龄呈指数增长的主要原因在于免疫系统衰退，而不仅仅是突变积累——尽管两者可能都起作用。

That was a fantastic discussion explaining the role of the immune system in cancer, which I think we're going to have to talk about here because I certainly feel convinced that a big part of why cancer incidence goes up exponentially with age is the declining immune system, not just the accumulation of mutations, although I imagine they both play a role.

但埃里克，我还要告诉你，我几年前写过一本关于这个领域的书，在书中我提到了所谓的'四骑士'。

But I will tell you something else, Eric, which is, you know, I wrote a book a couple of years ago about this space and in the book I talk about these things called the Four Horsemen.

我将它们描述为终将降临在每个人身上的四样东西。

And I describe them as the four things that are basically coming for us all.

如果你能侥幸活过青年时期（这并非轻视创伤等其他致命因素）。

If you manage to outlive youth, this is not to diminish the role of trauma and other things that are deadly.

但对许多经合组织国家的居民而言，最终将归结为动脉粥样硬化性心血管疾病、癌症、痴呆与神经退行性疾病以及代谢性疾病。

But for many people living in OECD nations, it's going to come down to ASCVD, cancer, dementing and neurodegenerative diseases and metabolic diseases.

人们常问我：彼得，如果时光倒流，你会在书中补充什么内容？

And people often say, Peter, is there anything you wish you'd written in the book that if you go back in time you would do?

我会说：嗯，仔细想想确实有不少想补充的内容。

And I say, yeah, there are probably many things if I thought about it.

但最让我懊悔的是，我确实应该加入第五位骑士——免疫健康。

But the first thing that jumps out is I really should have added a fifth horseman and that is immune health.

那些在老年人中肆虐的感染类型，年轻人可能根本不放在眼里。

And the types of infections that ravage people in old age that a young person would laugh at.

感谢你提出这一点。

Thank you for bringing this up.

免疫学与衰老研究长期以来都未能很好结合。

Immunology and aging have been not really mixing very well.

问题在于免疫学是个极其复杂的前沿领域，与神经科学并列为最复杂的学科之一。

One problem is that immunology is an extremely complex and advanced field, along with neuroscience, one of the most complex.

所以当你参加衰老研究会议时，几乎没人讨论免疫学。

So when you go to an aging meeting, there is no one talking about immunology.

而参加免疫学会议时，又很少有人谈及衰老问题。

You go to immunology meeting, there are very few people talking about aging.

我们试图协调，甚至连专业术语的使用都存在差异。

We try to navigate, even the nomenclature is being used differently.

免疫学领域的人谈论免疫衰老，指的是

Halena People in immunology talk about immunosenescence, meaning aging of

免疫系统的老化。

the immune system.

他们所说的衰老与我们讨论的衰老概念不同，

They don't mean senescence the way we talk about yeah, it in the aging that's so

这就导致了各种严重的沟通障碍。

So that yields all kinds of crazy communication problems.

是啊，因为如果你在衰老研究领域听到免疫衰老，你会联想到SASP和T细胞分泌的物质

Yeah, because if you were in the aging field and you hear immunosenescence, you think of SASPs and things It that are being secreted by T

它仅仅指免疫系统的老化。

just means aging of the immune system.

我认为这对两个领域都是可悲的失败，看看疫情期间的情况就知道了。

Now, the reason why I think this is a tragic failing for both field is what happened during COVID.

很明显，感染风险与年龄并不直接相关。

Became obvious that your risk of infection was not linked to your age.

病毒会感染所有人，但结果可能截然不同——75岁以上人群的死亡率会高出84倍，整整84倍。

The virus infected everyone across, but the outcome could be completely different with 80 four excess, eighty four fold excess mortality if you were above 75, 84 fold.

当这种情况发生时，我们可以尝试理解其原因，我开始查阅相关文献。

Now, when this happened, and we can go in terms of trying to understand why did this happen, what are the reasons for this, I went and started to look at the literature.

流感的情况完全一样。

Influenza, it's exactly the same thing.

呼吸道合胞病毒(RSV)也是如此。

RSV, same thing.

所有这些在晚年可能感染的病毒都会以相当高的致死率夺人性命。

So all of these viruses that you can contract in later years will kill you with really significant rates.

据我所知，流感每年导致约三万人死亡。

Influenza, I think thirty thousand people die every year from influenza.

就COVID而言，死亡率在老年群体或表现出加速衰老特征的群体（如肥胖人群等）中明显更高。

The mortality in terms of COVID was really highly segregated into the older part of the population or in that part of the population that showed accelerated aging, obesity, and so on.

你认为大多数死亡案例中，每当我们看到死亡率差异时——无论是年轻与年长者之间、肥胖与非肥胖者之间、糖尿病与非糖尿病患者之间——这种差异总是存在吗？

Do you think that most of the mortality, any time we saw a gap in mortality, whether it was young versus old, whether it was obese versus non obese, diabetic versus non diabetic, any time you looked at that you saw a difference in mortality.

你认为这始终是免疫功能的差异导致的吗？

Do you believe that it was always a difference in immune function?

我是说，年轻人和老年人之间的差异非常明显，但你认为这种情况也适用于

I mean with young versus old, it's very obvious, but do you think that was also true in

其他合并症吗？

the other comorbidities?

我认为是的。

I would say so.

没错。

Yeah.

这主要有两个原因。

And it comes from two reasons.

一是我们免疫系统分为两大类，即先天免疫和适应性免疫——不知道你是否需要我

One is there are two broad immune system, what we call the innate and the adaptive immune I don't know if you want me to.

我需要。

I would.

其实我正想说，我认为这件事值得全力以赴。

I actually was gonna say I think it is worth going full bore on this.

我认为现在是时候让大家卷起袖子，去理解这个可以说是人体中最有趣的系统了。

I think it is time for people to roll up their sleeves and understand arguably the most interesting system in the human body.

我承认我有偏见。

I am biased.

我曾在NCI花了两年时间研究免疫学。

I spent two years at the NCI doing immunology.

但我认为这是个非常有趣的领域。

But I think this is such an interesting field.

我们的免疫系统天生就能识别外来物质。

Our immune system is built to recognize foreign elements.

这正是它进化的原因。

That really is why it evolved.

它有两道防线来对抗微生物、细菌、病毒、真菌等所有病原体。

It has two lines of defense against microbes, bacteria, viruses, fungi, all of those.

我们时刻都在遭受它们的侵袭。

We are constantly bombarded by those.

这其实很神奇，因为证据就是如果你的免疫系统不工作，泡泡...这与...这与...所以我们体内外都寄居着细菌。

It is actually amazing because I mean the evidence of this is if your immune system doesn't function, the bubble- It's incompatible with It's incompatible with So we are colonized with bacteria in and out.

我们的皮肤无处不在。

And our skins everywhere.

因此我们不断以恰当的方式对它们作出反应。

So we constantly respond to them in an appropriate manner.

我们能挺过一切，包括屏障受损的情况。

And we survive everything including disruptions to the barriers.

完全正确。

Absolutely.

完全正确。

Absolutely.

所以我们的免疫系统有两道防线。

So we have two lines of defense in the immune system.

首先是所谓的先天免疫系统，包括巨噬细胞和树突状细胞。

First, the so called innate immune system, which is your macrophages, your dendritic cells.

但几乎每个细胞都拥有一整套非病原体特异性的防御机制。

But also pretty much every cell has a whole series of mechanism that are not pathogen specific.

它们能识别入侵者，无论是病毒、真菌还是细菌，并激活第一道防线。

Is they will recognize an intruder, be it a virus, be it a fungi, be it a bacteria, and it will activate a first line of defense.

这些防御机制是非特异性的，因此效果相对较弱。

Those line of defenses are nonspecific, and therefore they're less effective.

它们为所谓的适应性免疫系统争取时间，这是第二部分，由T细胞和B细胞组成。

And they give time to the so called adaptive immune system, which is the second part, which is made up of T cells and B cells.

这两种细胞都具有高度选择性的防御机制。

And both of those cells have highly selective defense mechanism.

B细胞产生抗体，能够识别细菌、真菌或病毒；而T细胞则可以直接杀死被感染的细胞。

The B cells make antibodies, which will go recognize a bacteria or a fungus or a virus, and the T cells, are able to actually kill the infected cell itself.

因此当细胞被外来病原体入侵时，T细胞能识别并消灭它。

So it will recognize when the cell is colonized by a foreign pathogen and will kill it.

因此这些反应的时间进程是：一旦遭遇病原体，你就会激活先天免疫反应。

So the time course of these is that once you encounter a pathogen, you will be activating your innate immune response.

典型表现可能是发烧。

Typically, it can be fever.

可能是各种症状，但都是这种防御机制的激活表现。

It can be all kinds of symptoms, but activation of this defense.

这让整个机体有两周左右的时间来针对特定识别出的病原体建立防御。

And this gives the whole organism a couple of weeks to actually build the defense for the specifically recognized organism.

我们来聊聊这个系统中的记忆功能。

Let's talk a little bit about memory within that system.

先天免疫系统并不具备真正的记忆能力。

So the innate immune system does not really have a true memory.

无论遭遇多少次，它都会以相同方式作出反应。

It will always react in the same way no matter how many times.

如果孩子从学校反复把同样的呼吸道病毒传染给你，你的先天免疫系统只会重复同样的应对方案。

If your kids are ping ponging the same respiratory virus at you from school, your innate immune system has the same playbook.

发烧。

Fever.

你会发红。

You're going to get red.

发炎。

Inflammation.

对。

Yeah.

你会感到疼痛。

You're going get sore.

是的。

Yes.

所有这些症状无论如何都会发生。

All of those things are going happen regardless.

完全正确。

Exactly.

是的。

Yeah.

这与适应性免疫系统形成对比，因为一旦通过感染或疫苗接种产生了初始反应——疫苗接种的本质就是让你接触病毒的一部分或全部，你的身体会产生反应，这将导致选择性细胞的扩增。

And that's in contrast to the adaptive immune system because once the initial response has been generated, either via an infection or a vaccination, this is what a vaccination is, presents you with a given fraction or the whole virus or a part of it, your body will mount a response and this will lead to the amplification of a subset of cells that are selective.

想想你的T细胞或B细胞，它们每一个都是独一无二的。

So think about your T cells or your B cells, none of them are the same.

我们有一个生成所谓多样性的过程，能产生数十亿种不同形式的抗体或T细胞受体，原则上可以识别微生物的任何化学结构和蛋白质。

We have a process by which we generate so called diversity, which is billions of different forms of antibodies or T cell receptors that are recognizing in principle every chemical structure, every protein from a microorganism.

在初次遭遇（无论是疫苗接种还是感染）时，那些具有能识别病原体受体的B细胞或T细胞将会扩增。

Now what happens during the initial encounter, either be it a vaccination or an infection, is those B cells or those T cells that have a receptor that is able to recognize the pathogen will become amplified.

它们会大量产生抗体或T细胞克隆。

And they will churn out large amount of the antibody or the T cell clones.

任务完成后，它们会收缩，但不会回缩到原有水平。

Once the job has been done, they will contract, but they will not contract back down the same level.

它们会变成我们所说的记忆T细胞或记忆B细胞。

They will become what we call memory T cells or memory B cells.

这样当你未来再次遇到相同抗原时，激活过程会缩短，成熟速度会加快。

So that if you encounter the same antigen in the future, the reactivation process is shortened, the maturation happens faster.

所以疫苗的核心理念就是让你提前准备好一批记忆T细胞克隆或B细胞克隆，当真正的病毒来袭时，你就能在几天至一周内迅速产生免疫应答。

So eventually the whole idea of the vaccination is to sort of get yourself ready with a subset of memory T cell clones or B cell clones that once the true virus will come, you will be able to mount a response within a few days or up to a week.

这就是疫苗的工作原理。

And so that's how vaccination works.

而衰老过程中有趣的是——这一点人们往往没有意识到。

Now what's interesting during aging is and people are not aware of this.

如果你年过70，大多数疫苗都不起作用。

If you're above 70, most vaccinations do not work.

所以人们会问，实际上你的免疫系统已经老化，疫苗接种效果确实会大幅下降。

So people then will ask, they actually your immune system has aged and your vaccination rate really decreases very strongly.

根据我的记忆，不同人群可能有所不同，但70岁以上人群的疫苗接种成功率接近30%。

From what I remember, might be different in different populations, but vaccination rate success is close to thirty percent if you're above 70.

在新冠疫情期间，75岁已接种疫苗者与未接种者的感染率差异是多少？

During COVID, what was reduction for a person 75 who was vaccinated versus not vaccinated?

哦，就保护效果而言几乎完全逆转了。

Oh, it was almost complete reversal of the effect in terms of the protection.

意思是疫苗的保护效果非常非常强？

Meaning it was highly, highly protective?

是的。

Yeah.

确实有保护作用。

It was protective.

那我们该如何调和这两个事实呢？

So how do we reconcile those two facts?

确实如此。

That's true.

老实说，我不知道这方面是怎么研究的。

To be honest, I don't know how this has been studied.

我很乐意阅读相关研究资料。

I would be happy to read about this.

因为新冠疫苗在老年人群体中似乎显著降低了风险。

Because the COVID vaccine seems to have had a remarkable risk reduction in very old people.

在年轻人中风险降低不明显，因为绝对风险本就极低，影响似乎不大。

Didn't seem to have an impressive risk reduction in younger people because the absolute risk was so low, it didn't seem to matter that much.

但对老年人群体而言，效果确实非常显著。

But boy, did it matter in older people.

但这影响是体现在人口层面还是个人层面？

But did it matter at the population level level or at the individual level?

这点我还不确定。

This is what I'm not sure about.

我当然不想公开表态说些什么。

I certainly don't want to go on record saying something.

我想我们能找到答案并放在节目说明里。

I think we can find the answer and put it in the show notes.

我的记忆可能不准确，但印象中年龄越大的人，接种新冠疫苗在降低死亡率方面的获益就越大。

My recollection, which could be wrong, is that the older a person got, the greater the benefit they got from COVID vaccines with respect to mortality.

那么我想问题是，我们或许可以谈谈其他疫苗。

So I guess the question is, let's maybe talk about other vaccines.

流感疫苗不是这样吗？

Is that not the case with influenza?

肺炎球菌疫苗或其他主要针对老年人的疫苗也不是这样吗？

Is that not the case with pneumococcus or any of the other vaccines that are used primarily in older adults?

一般来说——我不是疫苗专家——但观点认为随着年龄增长，针对流感、RSV等所有病毒的疫苗接种效率会急剧下降。

In general, and I'm not a vaccine specialist, but the thinking is that there is a dramatic decrease in the efficiency of vaccination against influenza, against RSV, against all of those as you age.

那么问题就变成了：这在群体层面是如何起作用的？

The thinking then is how does it work at the population level?

这就是群体免疫概念的运作方式——比如通过限制病毒在家庭中的传播，爷爷被感染的几率就会大大降低。

And this is where the whole concept of herd immunity works is that if you limit the spread of the infection in a family, for example, you're much less likely to infect grandpa.

我明白了。

I see.

所以这就是我对大多数这类病毒的理解

So that's been my understanding of how most of these viruses, these

病毒，是的。

viruses Yeah.

我在问一个不同的问题。

I'm asking a different question.

那是个重要的问题。

That's an important question.

我想我刚才问的是，显然他们可能没有进行随机对照试验。

I guess I was asking, obviously, they didn't probably do a randomized control trial.

所以这里面混杂了各种干扰因素。

So you've got all these confounders in it.

但我好奇他们是否只是简单对比了接种与未接种疫苗的住院患者。

But I wonder if they just looked at all comers to the hospital vaccinated versus non.

我们试着控制所有混杂因素。

Let's try to control for all the confounders.

如果风险比是1.2，那说明不了什么，0.8也一样。

If the hazard ratio is 1.2, it means nothing or 0.8.

但如果风险比为0.2或8，那么即使存在混杂因素，你也会认为这必然提供了某种高度的保护。

But if the hazard ratio was 0.2 or eight, well, you'd say even with the confounders, there must be some high degree of protection that came from that.

总之，我相信听众中有人知道这个问题的答案。

So anyway, I'm sure someone listening to this knows the answer to that.

我们会尝试找到答案并放在节目备注里。

We'll try to find the answer and put it in the show notes.

但让我们回到原因探讨。

But let's go back to the why.

为什么随着年龄增长，人们对疫苗的反应会减弱？

Why is it that as a person ages, they're less likely to respond to a vaccination?

是因为A：他们的免疫系统（适应性免疫系统）识别外来病原体的能力下降，无法积累足够多的T细胞和B细胞来应对？

Is it because A, their immune system, the adaptive immune system is less able to recognize the foreign pathogen and build up a high enough reserve of T cells and B cells that will respond?

还是B：他们虽然能产生这些细胞，但这些细胞保持记忆状态并被重新激活的能力受到了损害？

Or is it B, that they can do that but the ability for those cells to stay in a memory state and be reactivated is somehow impaired?

我认为两者都有，但T细胞有个独特之处——这些细胞的多样性是由胸腺产生的，而T细胞对大多数疫苗反应至关重要。

I think it's both, as in everything in But there's one aspect which is really unique, at least in terms of T cell, which are really instrumental in terms of most vaccine response, is the fact that these T cells are generate the diversity of the T cells is generated by the thymus.

而胸腺，就是胸骨后面的那个小器官。

And the thymus, the small organ behind the sternum.

你我的胸腺现在有多大？

How big is your thymus and my thymus right now?

我68岁了，所以它可能非常非常原始，估计没剩多少了。

I'm 68, so it's probably very, very embryonic and there's probably not much left.

大多数人50岁以后，胸腺就会变得非常小。

After age 50, in most people, you find it very small.

而年轻时，实际上通过影像检查就能看到它。

Whereas when you're young, it's actually, you can see it on an imaging study.

是的。

Yes.

我猜如果我们做个胸部CT扫描，你的胸腺几乎都看不到了。

And I would imagine if you and I had a CT scan of the chest, you'd barely be able to pick it up.

完全正确。

Exactly.

实际上在大多数人随着年龄增长，胸腺会被脂肪组织取代。

And it's replaced by fat actually in most people as you age.

尽管存在一些颇具争议的证据表明，即使在老年人中，仍可能存在一些可以被重新激活的克隆细胞。

Although there is some somewhat controversial evidence that there might still be some clones that can be reactivated even in older people.

如你所知，人类生长激素是已被证实能重新诱导胸腺生成的干预手段之一。

And human growth hormone, as you know, is one of the interventions that has been shown to actually re induce thymogenesis.

那我们稍微详细讨论下这个话题。

So let's talk about that a little bit.

你是指大约七八年前Fahey那篇关于生长激素联合二甲双胍和DHEA（或类似药物）的研究论文吗？

Are you referring to that Fahey paper from about seven or eight years ago that looked at growth hormone with metformin and DHEA or something like that?

这是其中一项研究。

That's one.

但Fahey那篇论文其实受到我在Gladstone研究所时一位同事工作的启发——实际上是Mike McEwen及其团队在HIV慢性感染者身上做的研究，这些患者会大量丧失CD4 T细胞。

But that Fahey paper was actually inspired by work of a colleague of mine when I was at the Gladstone Institute who did this, actually Mike McEwen and colleagues did this in patients with HIV, who are chronically infected with HIV, where they lose a lot of their CD4 T cells.

当时对此存在研究兴趣。

And there was an interest.

感染初期会形成严重的损伤。

So there's a big lesion initially in infection.

当时曾尝试观察是否能够再生这些细胞群使其恢复正常水平。

And there was an attempt to actually try to see if you could regenerate these populations to bring them back to a normal.

尽管我们已有对抗HIV的优秀药物，但这些药物仍无法使患者完全康复。

Because even though we had great drugs against HIV, they could not bring those patients back to normal.

最初的免疫损伤仍然存在。

There was a remaining original insult.

所以他们进行了人类生长激素试验，证明这些患者能产生一定程度的胸腺再生和幼稚T细胞增加。

So they did a trial with, human growth hormone that were able to show some degree of thymogenesis and increase in naive T cells in these patients.

我相信FEHE试验实际上试图复现这一结果。

And I believe the FEHE trial actually tried to reproduce this.

我记得还有第二个FEHE试验正在进行，我还没看到结果。

I think there's a second FEHE trial that is ongoing, I haven't seen the results

是啊，第一个试验的结果我记不清了。

of Yeah, mean the first one was, I don't remember the results.

这个混合疗法有点可疑。

The cocktail was a little suspect.

我同意。

I agree.

所以如果这是你的假设，使用生长激素是合理的。

So the GH made sense if that's your hypothesis.

我相信——虽然从未和Greg交流过——但从试验报告来看，二甲双胍的剂量简直像顺势疗法一样毫无作用，我记得只用了500毫克，如果不是的话我道歉。

I believe, I've never spoken with Greg, but I believe reading the trial, the metformin, which was really given at a homeopathic useless dose, I think it was only given at five hundred, so apologies if it wasn't.

我记得只用500毫克是为了抵消生长激素对葡萄糖代谢的干扰。

I think it was only given at five hundred, was meant to offset the glucose metabolism disturbances of GH.

你还记得为什么用脱氢表雄酮吗？

Do you remember why the DHEA was given?

不记得。

No.

理论上有些理由说得通，但从生理学角度讲不通。

There was some reason for it that made sense on paper but didn't make sense physiologically.

现在，更重要的问题是，我对那次试验的看法是它只使用了单一活性剂——生长激素。

Now, the more important question is, my take on that trial was it was a single active agent which was growth hormone.

比如我认为DHEA没什么作用，五百毫克的二甲双胍也没什么效果。

Like I don't think DHEA does anything, I don't think five hundred Metformin does anything.

所以问题在于，那是个规模很小的试验，且我认为它是开放标签的。

So the question is, and it was a very small trial and I think it was open label.

我对那次试验的结论有重大异议

I have significant problem with the readout of that trial

所以这就是

So that's

我想

what I wanted

请教你的

to ask you.

问题。

About.

提醒我一下那个读数结果

Remind me of the readout.

读数结果是关于其中一个生物钟的

The readout was one of the clocks.

啊，没错

Ah, that's right.

另一位作者是Steve Horvath

This was Steve Horvath was the other author

正是如此

of Exactly.

实际上这件事推动我们开展了一个完整项目，后来发表了关于'入门时钟'的研究

That And actually this whole story sort of pushed us into a whole project that we've published on what we call entrant clock.

因为在实验中，患者体内确实观察到初始T细胞比例有所增加，这向我们表明某种干预起了作用

Because there was in the experiment, in the patients, they indeed observed some increase in the fraction of naive T cells, which tells you and me that something worked.

初始T细胞相对于记忆T细胞的比例有所上升

The fraction of naive T cells increased with respect to the memory T cells.

幼稚T细胞是在胸腺中生成的。

The naive T cells are the ones that are generated in the thymus.

它们之所以被称为幼稚，是因为它们从未遇到过同源抗原，只是在那里等待某些事情发生。

They're naive because they have never met their cognate antigen, and they sit there waiting for something to happen.

因此，使用人类生长激素治疗的整个理念是诱导胸腺生成并恢复这些幼稚T细胞池。

So the whole idea of treating with human growth hormone was to induce thymogenesis and to restore the pool of these naive T cells.

我认为在某种程度上，它在低水平上是有效的。

I think to some degree it works at low level.

然后他们在全血样本上使用了这个时钟。

Then they used the clock on the whole blood.

当我看到这篇论文时，我的担忧——这种担忧其实早已存在——就像人们使用端粒长度时一样，问题是：当你采集血液样本时（作为一名免疫学家，我知道这是一个高度动态的器官）。

And my worry when I saw the paper, which is a worry that actually existed, predated this, it was also a worry when people were using telomere length, is the idea when you sample the blood, as an immunologist, I know this is a highly dynamic organ.

把血液想象成一个器官。

Think about the blood as an organ.

以目前最先进的技术，我们已经在血液中识别出超过500种不同的细胞群。

We enumerate at this point today with the best technology more than 500 different populations of cells in the blood.

假设这些细胞对任何干预措施的反应各不相同，且每个细胞具有不同的表观遗传年龄，你就会产生正在逆转衰老的印象——这正是Feyi论文中声称他们实现了人类年轻化的依据。

Suppose that these cells vary in response to any intervention and that these cells individually have a different epigenetic age, you would have the impression that you are rejuvenating, which was the claim of that Feyi paper that they had rejuvenated people.

但实际上，你所做的只是改变了表象。

But in effect, what you would do is simply change.

对。

Yeah.

就像你处于一个正弦波上，波形如此起伏，而你只取了两个采样点。

It's like you're on a sine wave that goes like this and you take two sample points.

它们可能在这里，可能在这里，也可能在这里。

They could be here, they could be here, they could be here.

顺便说一句，你可能知道，Matt Cabralin著名地购买了四到五种市售衰老时钟。

And by the way, as you probably know, Matt Cabralin has famously purchased, I think, four or five of the commercially available aging clocks.

他每种买了两份，同时进行了所有检测。

He bought them in duplicate and did all of them, sampled them all simultaneously.

两份这个，两份那个，两份另一个，全部同步检测。

Two of this, two of this, two of this, two of this simultaneously.

采集10份样本后，不仅各时钟间结果相互矛盾，就连同一时钟内部也存在显著分歧。

Take 10 samples and not only do all the clocks disagree with each other but even within the same clock, there was disagreement, significant disagreement.

所以，是的，我其实想详细讨论下这些衰老时钟的问题。

So, yeah, I mean, want to actually come back and talk about clocks in some detail.

但考虑到这项研究是多年前用旧版时钟做的，我认为时钟部分根本没什么讨论价值。

But given that that study was done years ago with an older clock, I think the clock part of it is not even remotely interesting.

我觉得更有趣的问题是：是否真的存在胸腺再生？

I think the more interesting question is, was there genuine thymic regeneration?

如果存在，我们该如何解释老年科学中这个紧迫而棘手的问题——生长激素的作用？

If so, how do we reconcile a very pressing and vexing question within geroscience which is the role of growth hormone?

所以我本人从未使用过生长激素。

So, I've never taken growth hormone.

不该说从未开过处方——

Never I shouldn't say I've never prescribed it.

我曾在极少数情况下为创伤愈合开过这种处方。

I've prescribed it in very rare circumstances for injury healing.

但我从未为了延长寿命而开过这种处方。

But I've never prescribed it for longevity benefits.

但很多人确实在这么做。

But a lot of people are out there doing so.

因此，我的诊所里有许多患者正在服用或曾经服用过生长激素。

And as such, I've had lots of patients who come to my practice who have been taking or are on growth hormone.

我要说的是，每个人都无一例外地表示：'服用生长激素时感觉比不服用时好多了'。

And I will say this, to a person, every single one of them has said, I feel so much better when I take growth hormone than when I do not.

我的意思是，所有人都是这样，百分之百。

I mean, across the board, 100%.

而且我确实找不到证据告诉他们服用这个有害。

And I can't actually point to evidence that tells them it's bad to take.

我只能说，如果我们的目标是降低癌症风险和延缓衰老过程，服用它就不合理。

I can just say it doesn't make sense to take if our goal is to reduce the risk of cancer and if our goal is to slow the aging process.

那么你对这个问题怎么看？

So what is your take on that?

这只是你的直觉，还是你了解的任何数据会让人认为，或许我们可以偶尔少量使用生长激素，如果能促进胸腺再生的话。

Just your intuition or is there any data you're aware of that would lead one to think that well, maybe we could pulse a little bit of growth hormone here and there if we get some thymic regeneration.

我们不需要一直使用它。

We don't have to be on it all the time.

我是说，你会怎么考虑这个问题？

I mean how would you think about that?

我确实对此有所顾虑。

I do worry about it.

我并非生长激素方面的专家。

I'm not a specialist on growth hormone itself.

它会诱发糖尿病。

It induces diabetes.

它会导致葡萄糖耐量降低。

It induces glucose intolerance.

因此从这个角度，我确实担心长期使用的影响，尤其是对年轻人。

So from that angle, I do worry about what it would do chronically, especially in someone young.

这有点像增加蛋白质摄入量。

It's a bit like increasing your protein intake.

有明确证据表明，增加蛋白质摄入量，尤其是随着年龄增长，会变得有益，那些蛋白质摄入量较高的人在肌肉质量等方面确实表现更好。

There's clear evidence that increasing your protein intake, especially as you age, becomes beneficial, and the people who have higher protein intake actually do better in terms of muscle mass and so on.

因此，对于65至70岁、开始感受到某种肌肉减少症影响的人来说，适度增加肌肉质量可能带来益处，尤其是如果不持续进行的话。

So in someone who is 65 to 70, who is starting to feel the effect of manifest some form of sarcopenia, there might be a benefit for that person to actually increase muscular mass and all the benefits with this, especially if it's not done continuously.

但我想我不认为有什么疑问，益处是存在的， 但说到缓解肌肉减少症， 你会从睾酮或合成代谢类固醇中获得更高的效果。

But I mean, would argue there's no doubt that there's benefits, but you're going to get far more efficacy from testosterone or anabolic steroids when it comes to mitigating sarcopenia.

生长激素在增加肌肉质量方面其实并不显著。

Growth hormone actually is not remarkable at inducing muscle mass.

它远不如睾酮有效。

It's nowhere near as effective as testosterone.

它在促进脂肪减少方面更有效。

It's more effective at eliciting fat loss.

但我想知道是否还有更深层次的作用。

But I wonder if there's something that goes beyond that.

因为我觉得当人们告诉我他们在使用后感觉更好时，我想他们指的是疼痛减少了。

Because I think when people tell me they feel better on it, I think they're talking about less aches and pains.

关节感觉更舒适了。

Joints just feel better.

我不认为有人会说他们感觉更好是因为胸腺更饱满。

I don't think anybody's saying they feel better because their thymus is more plump.

但我思考的是，这对我来说可能成为考虑制定一个方案的潜在理由。

But I wonder, that to me would be a reason to potentially consider a schedule.

一种间歇性方案——如果它... 这里要回到我的宏观论点，我一直在反复强调这四个骑士，四个骑士。

An intermittent schedule of something if it's Again, going back to my macro thesis here which is I've been harping on these four horsemen, four horsemen.

那么如果我们引入第五个骑士，策略是什么？

Well, if we introduce a fifth horsemen, what is the strategy?

因为我可以详细告诉你应对心脏病、癌症等所有其他疾病的缓解策略。

Because I can give you chapter and verse, the strategy for how you will mitigate heart disease, cancer, all of these other conditions.

我们应对免疫衰退的策略又是什么？

What is our strategy for mitigating immune decline?

我会说这与延缓其他器官衰退的策略相同。

I would say the same as a strategy that would mitigate decline in every other organ.

有明确证据表明，运动对免疫系统的影响与对每个单一器官的影响相同

There's clear evidence that the effect of exercise on immunology is the same as in every single

我对这方面不太熟悉。

So I'm not familiar with it.

那给我讲讲这方面的情况吧。

So tell me a little bit about that.

我不具体了解运动如何影响免疫系统。

I don't know specifically how exercise impacts the immune system.

我无法针对具体论文发表意见。

I cannot speak to specific papers.

显然有证据表明，经常锻炼的人对感染反应更佳，对疫苗接种反应也更好。

Clearly there's evidence that people who exercise actually respond to infection better, respond to vaccination better.

这些都有据可查。

So that's all been documented.

我明白了。

I see.

我无法具体谈论某些研究。

I cannot speak to specific studies.

你有

Do you have a

从机制上理解为什么会这样的概念吗？

sense of mechanistically why that's the case?

这太复杂了，我想说。

It is so complex, I would say.

我无法告诉你。

I would not be able to tell you.

但话虽如此，我认为诱导胸腺再生的整个研究路线是一个重要领域，特别是如果我们考虑进一步延长目前所做工作的寿命。

But that being said, I think the whole line of investigation to induce thymic rejuvenation, I think, is an important one area, especially if we're thinking about increasing lifespan further for what we are doing now.

在未来，这将成为限制因素之一。

That in the future, it will become one of these rate limiting steps.

这与卵巢的情况有些相似，我们把卵巢和胸腺比作煤矿中的金丝雀。

It's a bit the same situation as the ovary, where the ovary and the endothymus, we call them the canary in the coal mine.

我是说，确实存在某些器官比其他组织更早表现出加速衰老的特征。

I mean, there really are specific organs that show accelerated aging way earlier than other tissues.

现在的问题是，为什么胸腺会这么早退化？

Now the question is, why is the thymic involuting so early?

我认为这可能是因为从进化角度讲，我们本就不该活这么老。

I think it's probably because evolutionary, we were never meant to live this old.

这确实是当前的一种主流观点。

And so that really is one of the thinking that goes on.

长远来看，这将是我们必须面对的问题之一。

That's going to be in the long term one of the problems that we have to face.

我们正在积极研究这个课题，实验室刚完成一项研究，旨在寻找预测疫苗接种反应的新型生物标志物。

And this is something we're actively studying, and the lab is trying to we just completed a study where we are looking for novel biomarkers that are predictive of whether you will respond to a vaccination or not.

这项研究是与斯坦福大学的马克·戴维斯合作完成的，利用了他们的'千种免疫组计划'——这是最大规模的人类免疫系统衰老研究项目。

And it's something done in collaboration with Mark Davis at Stanford using their 1,000 Immunome Project, which is one of the largest studies studying aging in the immune system only in humans.

因此我们得以通过研究人群，识别出与疫苗反应不良相关的某些代谢物。

So we've been able to studying people to identify some metabolites that are associated with poor response to vaccine.

这些不仅是生物标志物，还可能成为我们作为佐剂或预处理疗法纳入的工具。

And so those are not only markers, but they could also become tools that we include in as adjuvant or as a pretreatment theory.

我相信您对琼·曼尼奇的工作很熟悉。

I'm sure you're familiar with the work of Joan Mannich.

当然。

Of course.

是的，我正想请教您关于曼尼奇和Before Clixene的事，不过在此之前，我想回到这个重点——生物标志物在心血管疾病中的重要性。

Yeah, I was going to ask you about Mannich and Before Clixene a we do, I want to go back to this point here which is biomarkers are so important when I think about cardiovascular disease.

尽管它是头号致死病因，但我告诉患者，只要你愿意主动管理，这反而是最无需恐惧的疾病。

And even though it's the leading cause of death, why I tell my patients it's the one you need to be least afraid of if you're willing to be proactive in management.

这归根于我们对疾病机制有清晰认知，并拥有卓越的生物标志物。

And it comes down to the fact that we just have such a clear understanding of how the disease works and we have exceptional biomarkers.

因此我们能够测量导致疾病的各项指标。

So we can measure the things that are causing the disease.

我们可以测量炎症水平

We can measure inflammation.

我们可以测量载脂蛋白B

We can measure ApoB.

我们可以测量极低密度脂蛋白胆固醇和脂蛋白

We can measure VLDL cholesterol, LP.

我们可以测量血压

We can measure blood pressure.

我们可以测量代谢健康状况，并且知道如何改善这些问题

We can measure metabolic health and we know how to address those things.

而且我们知道，当我们处理这些问题时，可以检测干预措施是否有效

And we know that when we address those things, we can measure whether what we're doing is working.

好的

Okay.

所以基本上问题就解决了

So, problem solved, basically.

说到免疫系统，我们稍后会谈到曼尼奇和克里克斯坦。

When it comes to the immune system, we're going to talk about Mannich and Klickstein in a moment.

但从他们十年前发表的论文中我们看到，他们给60多岁的人群服用雷帕霉素类似物后接种疫苗，结果发现免疫反应显著增强。

But as we saw from their paper ten years ago, they gave arapamycin analog to people, people who were in their 60s, vaccinated them and demonstrated that oh boy, you got a much better immune response.

好的。

Okay.

他们通过实验室技术成功证明了这一点。

They were able to demonstrate that using laboratory techniques.

我确信他们使用了流式细胞术之类的方法进行测量。

I'm sure they used flow cytometry or something like that to measure it.

我们距离商业化应用这类技术还有多远？

How close are we to being able to do that sort of thing commercially?

我说的商业化是指可以在药店直接购买。

By commercially, I mean over the counter.

不接近。

Not close.

我认为在那项研究中，他们实际上测量了抗体效价。

I think in that study, they actually measured antibody titers.

所以比流式细胞术还要复杂。

So even more complicated than flow cytometry.

是的。

Yes.

好的。

Okay.

在那种情况下，他们确实展示了已知Giroprotector的增强效果。

In that case, they definitely showed an enhancing effect with a known Giroprotector.

这是一个疑似Giroprotector，

This was a A suspected Giroprotector,

至少在人类中是这样。

at least in humans.

没错。

Exactly.

雷帕霉素类似物

Rapalog.

他们不仅显示抗体滴度增加，还显示出保护效果增强

And they showed not only increased titers, but also protection, increased protection.

最终临床试验因一系列其他原因失败，部分原因在于FDA强制要求的试验设计方式

Eventually, the clinical trial failed for a whole series of other reasons, which were in part due to the way that the FDA imposed the trial to be generated.

我认为这只会让整个情况更加复杂

I think it just complicated the whole picture.

是的

Yeah.

顺便说一下，对于听我们讨论感到困惑的听众，我和Matt Cabralin专门讨论过，因为这不是2014年的试验

By the way, for folks listening to us who were confused by that, Matt Cabralin and I had a specific discussion because it wasn't the 2014 trial.

那是后来的一个试验

It was a later trial.

不是RAD001试验

It wasn't the RAD001 trial.

是另一个试验失败了，我其实不记得具体原因了。

It was the other trial that failed And I actually don't remember the reason.

但马特解释过这件事。

But Matt explained it.

很明显这是一场官僚主义的悲剧。

It was very clear that it was a tragedy of bureaucracy.

确实如此。

It is.

这不应该被视为那个分子的污点。

And it shouldn't be viewed as a black eye on that molecule.

嗯。

Yeah.

马特在雷帕霉素领域更专业，我会参考他的说法。

Matt is more of a specialist in the whole rapamycin, so I will defer to what he said.

我们会在节目说明中附上我和马特讨论的链接。

We'll link in the show notes to where Matt and I had that discussion.