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我专注于衰老和长寿研究，对雷帕霉素、肽类物质、蛋白质、补剂以及生活方式对长寿的影响有深入的理解。

白藜芦醇的真相： 白藜芦醇并非有效的长寿分子，在实验室动物实验中，其平均寿命延长效果为零。这一事实不容忽视，尽管一些宣传仍在继续。

警惕不靠谱的建议： 我不建议盲目采纳布莱恩·约翰逊等缺乏专业知识人士的健康建议。 他的观点，比如关于雷帕霉素的论断，缺乏科学依据。

雷帕霉素：谨慎乐观。 雷帕霉素是否能延缓人类衰老仍未可知，缺乏充分的随机对照临床试验数据。尽管在实验室动物中效果显著，部分人类使用者也报告了其在慢性炎症和某些疾病方面的益处（例如，降低严重或中度COVID-19的几率以及长新冠症状风险），但仍需更多严谨的研究来证实其长期有效性和安全性。雷帕霉素对老年人免疫功能（尤其疫苗反应）的潜在改善值得关注。

抗氧化剂：适量为宜。 并非所有抗氧化剂都对健康有益，过量摄入甚至可能有害。 关键在于找到平衡，避免过量补充。

生活方式优先于补剂： 生活方式对长寿的影响远大于补剂。目前，我对补剂的有效性信心有限，认为其作用相较于生活方式的改变而言是微不足道的。

潜在的长寿化合物： SGLT2抑制剂和雌激素/雌二醇展现出延长寿命的潜力。SGLT2抑制剂已有临床数据支持，雌激素/雌二醇则有动物实验和人类相关数据支持。但需注意，对于代谢健康的人群，二甲双胍的益处并不显著，甚至可能抵消运动的益处。

理性看待补剂： 我倾向于对补剂持谨慎态度。过量服用多种补剂存在潜在风险，应根据自身情况谨慎选择，充分了解其生物学机制。目前市面上面向消费者的生物年龄检测，其准确性和精确性都令人担忧，结果差异巨大，难以作为可靠的健康指标。

肽类物质：有待进一步研究。 肽类物质并非均等效，其作用取决于具体类型。目前，尚无证据表明常用肽类物质能延缓衰老或延长寿命。GLP-1激动剂的潜力值得关注，其作用机制可能与热量限制无关，但需注意其对身体成分的影响，配合健康饮食和运动。

TRIM方案：胸腺再生的尝试。 TRIM方案旨在通过恢复胸腺功能来改善免疫功能，初步研究显示其具有一定效果，但仍需更多数据支持。

静脉注射NAD和治疗性血浆置换： 静脉注射NAD疗法并非完全无效，但缺乏严谨的研究数据支持其有效性。治疗性血浆置换疗法则展现出清除循环系统中随着年龄增长积累的有害物质的潜力。

IGF-1：发育阶段的重要性。 在发育过程中IGF-1水平较低与寿命延长有关，但成年后降低IGF-1的效果尚不明确，甚至可能对大脑健康产生负面影响。小型犬的衰老速度比大型犬慢，但两者患痴呆症的风险相似，这表明IGF-1对大脑衰老的影响可能不同于对身体其他部位的影响。

人工智能与衰老研究： 人工智能在加速衰老研究方面具有巨大潜力，但需要更完善、更全面的数据集来支持其应用。

蛋白质摄入：质量优先于数量。 蛋白质摄入量应适中偏高，但需注意饮食质量，避免高加工食品和过量糖分。

握力：整体健康状况的反映。 握力强弱主要反映了整体肌肉功能和质量，并非独立的健康指标。

女性生育能力：健康生活方式至关重要。 保持女性生育能力的关键在于健康的生活方式，具体方法因人而异。

狗狗服用雷帕霉素的建议： 给狗狗服用雷帕霉素的最佳时机可能在7岁以上，体重40磅以上，但需咨询兽医。

总而言之，长寿是一个复杂的问题，需要综合考虑生活方式、基因、环境等多种因素。 科学研究仍在不断发展，我们需要更多的数据和更深入的理解才能更好地应对衰老，延长健康寿命。

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00:20 白藜芦醇并非有效的长寿分子，其在实验室动物中的平均寿命延长效果为零。

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01:04 不应根据布莱恩·约翰逊的建议改变健康状况，因为他缺乏相关专业知识。

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01:28 目前尚不清楚雷帕霉素是否能延缓人类衰老，缺乏随机对照临床试验数据。

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02:21 布莱恩·约翰逊停止服用雷帕霉素的理由站不住脚，基于无效的生物年龄评估研究。

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04:11 雷帕霉素在实验室动物中能有效延长寿命，部分人类使用者报告了其在慢性炎症和某些疾病方面的益处。

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05:34 雷帕霉素可能改善老年人的免疫功能，尤其是在疫苗反应方面。

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05:59 雷帕霉素使用者患严重或中度COVID-19的几率较低，且长新冠症状风险也较低。

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07:07 并非所有抗氧化剂都对健康有益，过量摄入可能有害。

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10:04 生活方式比补充剂对长寿的影响更大，目前对补充剂的有效性信心不足。

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12:53 SGLT2抑制剂和雌激素/雌二醇在延长寿命方面具有潜力，前者有临床数据支持，后者有动物实验和人类相关数据支持。

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16:43 对于代谢健康的人群，二甲双胍的益处并不显著，甚至可能抵消运动的益处。

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18:37 白藜芦醇被证实并非有效的长寿分子。

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19:41 过量服用多种补充剂存在风险，应谨慎选择并了解其生物学机制。

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20:58 目前市面上面向消费者的生物年龄测试的准确性和精确性都存在问题。

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29:12 肽类物质并非均等效，其作用取决于具体类型，目前尚无证据表明常用肽类物质能延缓衰老或延长寿命。

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30:37 GLP-1激动剂具有延长寿命的潜力，其作用机制可能与卡路里限制无关。

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35:05 TRIM方案旨在通过恢复胸腺功能来改善免疫功能，初步研究显示其具有一定效果。

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41:14 静脉注射NAD疗法并非完全无效，但缺乏严谨的研究数据支持其有效性。

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43:56 治疗性血浆置换疗法具有潜力，可以清除循环系统中随着年龄增长积累的有害物质。

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45:39 在发育过程中IGF-1水平较低与寿命延长有关，但成年后降低IGF-1的效果尚不明确。

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50:35 小型犬的衰老速度比大型犬慢，但两者患痴呆症的风险相似，这表明IGF-1对大脑衰老的影响可能不同于对身体其他部位的影响。

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53:30 人工智能在加速衰老研究方面具有潜力，但需要更完善的数据集来支持其应用。

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58:17 蛋白质摄入量应适中偏高，但需注意饮食质量，避免高加工食品和过量糖分。

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01:01:07 握力强弱主要反映了整体肌肉功能和质量，并非独立的健康指标。

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01:02:52 保持女性生育能力的关键在于健康的生活方式，具体方法因人而异。

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01:07:19 给狗狗服用雷帕霉素的最佳时机可能在7岁以上，体重40磅以上。

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Edit:2025.04.21<markdown>

00:00

It's a fact that some people don't like that resveratrol is the most debunked longevity molecule ever. Resveratrol does not increase lifespan in laboratory animals on average. Right now, my confidence is 100% that you can improve your health span and likely your lifespan through lifestyle modifications.

00:20

The first question is, so recently Brian Johnson stopped taking a rapamycin. Yeah. What are your thoughts about that? Yeah, well, I mean…

00:45

In general, my thought is that nobody should take health advice from Brian Johnson. Really? I mean, he has no expertise and he's not scientific in my view. So broadly speaking, it's a mistake to change anything about your health based on anything Brian Johnson says. Specifically,

01:04

Specifically with respect to rapamycin, I mean, I think, first of all, the honest answer is nobody knows whether rapamycin slows aging in humans or whether or not there are going to be significant benefits from rapamycin. I don't know. Brian Johnson doesn't know. Nobody knows because we don't have randomized clinical trials yet, at least for humans.

01:28

disease prevention, health promotion, right? They're all limited to organ transplant patients or cancer patients, things like that. So nobody knows. Brian Johnson's specific reasons, as I understand them, for stopping taking rapamycin. So it's his personal decision. He has every right to do whatever he wants with respect to his own health. But his rationale, as I understand it from what I've seen in the public domain, is

01:54

is nonsense, right? So he's basing it on one study that used biological age assessments that don't work. And in that same study, they found that exercise and quality diet doesn't have a positive impact on biological age. So using that as a reason to stop taking rapamycin because rapamycin also did not have a positive impact on biological ages is dumb in my view. Like it's nonsensical. Um, uh,

02:21

Now, you know, he's also said that some of his biomarkers may have been perturbed around lipids and glucose. That's possible. Those are side effects that are associated with rapamycin at high doses in organ transplant patients. They have not come out as significantly associated with rapamycin in people using the doses that he's reported to use or that have been used off-label. So I find it

02:42

unlikely because we've looked and other people have looked. I find it unlikely that rapamycin had that effect on his biomarkers, but it's possible. It's also, there's no way to know for sure because he's doing like a hundred other things. So again, the idea that you can attribute that to rapamycin is, is not rigorous and not scientific, which is one of the many reasons I say that he does not take a scientific approach to those kinds of things.

03:07

So again, I'm not suggesting anybody take rapamycin, but I also, if you are taking rapamycin and you feel like it's benefiting you, I would not pay any attention to Brian Johnson would be my advice. Yeah. I guess it's like, you know, experimental therapy for life extension. Like we don't know if it's going to work in humans. Obviously it has been shown to work in animals, which we're

03:29

would be, in my opinion, like a greater degree of certainty that it would have effects in humans than the biological age clock in that which is… Especially when the things we know work in humans didn't come out with a positive effect in that same study, right? So again, you know…

03:44

Obviously, I'm a little bit frustrated with the fact that this gets headlines and it's just not helpful for anyone in my view. But having said that, you're right. We have no idea whether rapamycin increases lifespan in people. It does in laboratory animals and quite robustly. I think what we have learned is that at least some people see a reduction in chronic inflammation and at least anecdotally report benefits like rapamycin.

04:11

reversal of hypertrophic cardiomyopathy, reversal of autoimmune disease. In my own case, reversal of inflammation of the shoulder capsule, commonly known as frozen shoulder. So it hasn't risen to the level of randomized double-blind placebo-controlled clinical trials. It's more like a series of case reports. I do believe some people get benefits. I do believe some people experience side effects. The only side effect that seems…

04:38

again, statistically significant is canker sores. About 15% of people using rapamycin off-label get canker sores. There may be a slight increase in risk of bacterial infection, although that hasn't risen to the level of statistical significance at this point. Yeah. Like one of the fears I've had in the past about rapamycin is that it's oppresses your immune system and makes you lose muscle. But over the last few years, that has been not

05:02

Turned out not to be the case, actually. Certainly in laboratory animals, it's the opposite, right? You can actually boost an age-related immune function and maintain muscle mass and prevent sarcopenia in rodents in the laboratory. And in people, again, it's anecdotal. We don't have the solid evidence

05:19

data yet. I should say there were two fairly large clinical trials that Joan Manick did with Everolimus, which is a derivative of rapamycin. It works exactly the same way. And in both of those, they did see an improvement in vaccine response in older people. So

05:34

probably rapamycin improves immune function, at least as measured by vaccine response in older people. We actually found in our study of three hundred and thirty three people using rapamycin off label, lower incidence of severe or moderate outcomes from covid-19 and a lower risk of symptoms associated with long covid. No difference in risk of

05:59

getting infected by COVID, but better outcomes in people using rapamycin. So I think that boost in at least antiviral immune effects is probably real. And there's a clinical trial that I believe the data has been collected. I haven't seen it yet for muscle function in elderly people that Brad Stanfield has gotten funded and has been running out of New Zealand. So, you know, we'll see. The PERL trial from AgelessRx,

06:27

Showed a hint of improved body composition in women at very, very low doses. So I would say if anything, the needle right now is leaning towards better outcomes in terms of, of body composition and, and, um, lean mass in people. And certainly that's what's seen in the rodents. Yeah. Well, that's super interesting. Um, next question.

06:50

Are more antioxidants always bitter? Like there's research that antioxidant supplements can actually be harmful. Yeah. So, I mean, the answer is obviously no, right? Nothing is always in biology or very little. It's useful to appreciate the term antioxidant is, is.

07:07

sort of misused, right? So it's all relative to other molecules, right? One molecule can oxidize or reduce another molecule depending on their relative oxidation status. But most of the time when people are thinking of antioxidants, they're thinking about, you know, supplements that you can take that are generally going to reduce or remove oxidation from other biological molecules. And the idea is that antioxidants

07:35

as part of a byproduct of metabolism, we produce things like reactive oxygen species, which we know can cause damage. In fact, one of the early theories of aging was the oxidative theory of aging, that aging was really driven by oxidative damage. And then that was modified to the idea that the oxidative damage primarily comes from mitochondria, right? From metabolism. So based on that, it is certainly…

08:00

plausible that if you could prevent that oxidative damage, that would be beneficial. And there's evidence to support that in experimental studies. The challenge is that oxidative signaling is also important for health, right? So we know that oxidation status can be used as a way to signal the

08:23

Throughout the body and within the cells, important functions. And so if you block that, that's actually detrimental. I think the challenge with antioxidant supplements, aside from the fact that, that, you know, we don't know exactly where the antioxidants are going to go and how effective they're going to be is how to target the bad reactive oxygen species and not target the good.

08:45

reactive oxygen species. And we just don't understand that biology enough. So, so the answer is, you know, too much antioxidants is going to be bad. And I don't personally, and I don't think anybody really has a good feel for at the population or individual level, what is the optimal amount right now? I guess like mega doses is probably not. I wouldn't do it. Yeah. Yeah.

09:09

And timing probably matters as well. And particularly where you target. There's some interesting data around what people would call mitochondrial targeted antioxidants or mitochondrially targeted peptides that reduce oxidative stress. It's intriguing. It is not yet to the level where I would suggest people should go out and start taking these things necessarily. But the idea that you could specifically target the antioxidant

09:33

antioxidants to the cellular compartment that is most problematic makes a lot of sense. And so I think there are opportunities there. We just don't have those tools yet. Yeah. All right. Next question. What percentage do supplements versus lifestyle play a role in longevity? So how much percentage?

09:51

Um, well, I mean, I, I would definitely say that lifestyle is far more important than supplements, at least in terms of what we know is going to work. I think the challenge with supplements is we don't know what's

10:04

what the right supplements are or how effective they could be. So right now my confidence is a hundred percent that you can improve your health span and likely your lifespan through lifestyle modifications. And my confidence is less than 10% that you can do that through supplements. And even if you could, I think it would be incremental compared to lifestyle. So lifestyle is by far the best

10:28

opportunity to improve health span and probably lifespan for the vast majority of, of people. Um, what would be like the ratios? Like do supplements give you 5%? I mean, again, I don't know is the answer I'm put, I'm a, I'm a scientist, so I have to say, I don't know. My guess is, you know, it depends on the person. So I would, and I would put supplements in a couple of categories. I think there are supplements where we can measure deficiencies or where we know most people are deficient, um,

10:58

And if you're deficient, supplements can have a relatively large impact on at least mortality risk and risk of certain diseases, right? So, you know, things like vitamin D or omega-3s where there's pretty good evidence that if you're deficient, there's a higher risk of a variety of different health, negative health outcomes. But then there, and so there, I would say if for people who are deficient, supplements could have a

11:25

Maybe it's 80% lifestyle, 20% supplements or something like that. But when we start getting into the more questionable stuff, NAD precursors, Bermudine, Urolithin A, alpha-ketoglutarate, I'm just picking those out of air. And I'm not saying there's no value to those. They're speculative.

11:45

Um, and the nature of speculation is I have to guess what the likelihood is that they're going to work. I would say it's like 95% lifestyle, 5% something that's maybe even more towards lifestyle, but that more comes from confidence that lifestyle is going to have a big effect. Yeah. Yeah. I agree. Like,

12:00

Even if there are like some supplements that have some effects, you know, they're not going to replace exercise and good sleep and diet. They may supplement those things, right? Like creatine is a good example, right? I mean, I think for a lot of people, creatine can have some benefits. I don't know if it's a big benefit or a small benefit. My guess is it's still relatively small compared to lifestyle. But I think especially if you're practicing a healthy lifestyle, having creatine,

12:25

supplement like that can give you added value, uh, in the context of practicing a healthy lifestyle. Yeah. Okay. Next question. Um, other than rapamycin, which compound is most likely to extend lifespan? That's a good question. So, um, I I'm pretty bullish on SGLT2 inhibitors. So these are things like canagliflozin and pagliflozin. They have come out of the mouse intervention testing program at

12:53

increasing lifespan in mice. There's human correlative data from UK Biobank that people taking these drugs have a lower risk of all-cause mortality compared to health-matched people who are not taking those drugs. They're anti-diabetes drugs. Basically, my understanding is they work by causing you to pee out more glucose from your circulatory system. So they seem pretty promising. I

13:19

I think estrogens and estradiols are really interesting. They also fit

13:24

coming out of the interventions testing program in mice as increasing lifespan in males. Um, and again, UK biobank data seemed to be associated with lower all cause mortality in females. That would probably mostly be in the context of, um, hormone replacement therapy in women, uh, because not a lot of men have been put on estrogens or estradiol, um, but also maybe birth control. So I'm not suggesting that women, you know, who, who, who are not

13:51

perimenopausal or menopausal go out and start taking

13:55

hormone replacement therapy. I don't think we're there yet, but it's the biology is intriguing. The thing is with the, the estrogens and estradiol is we don't understand the mechanism yet. So it's hard to know. I'm certainly not suggesting men run out and start taking these things, but I'm, I'm interested to see. So those are two classes that I would, I would say have, um, both preclinical and human data suggestive of, of lower all cause mortality. And, and, and certainly I would put

14:23

again i don't know about lifespan but i would put hormone therapy particularly in women although i also think in many men as a major healthspan booster so um we don't have longevity data yet but but in terms of impact on healthspan outside of lifestyle right i would probably say hormone therapy is the maybe the next biggest thing that a lot of people can benefit from but i

14:48

What about some of the carbos? Yeah. A carbos is interesting. That also comes out of the, um, the interventions testing program is one of the first things after rapamycin to show a robust effect also only in males or mostly in males. And we don't really understand the sex differences there. Um,

15:05

The human data on a carbose, we don't have like it, it, we don't have the sort of UK biobank level. And, um, at least this is my understanding in the context of a Western diet, a carbose is not really well tolerated because of gastrointestinal upset, flatulence, things, things like that. So, um, so I don't, I don't, I'm, I'm a little bit, I mean, it's interesting. I'm a little bit less bullish on the

15:29

translational application of a carbose than sglt2 inhibitors probably working through a similar mechanism a carbose so again a carbose is also an anti-diabetes drug i mentioned the sglt2 inhibitors cause you to to basically pee out more glucose a carbose probably works by causing you to take up less glucose or other sugars that get converted into glucose because it

15:53

it's an inhibitor of an intestinal enzyme involved in breaking down complex carbohydrates. So as a class, I think anti-diabetes drugs

16:03

tend to promote longevity in laboratory animals. And certainly in Western populations, metabolic dysfunction is a hallmark of aging that probably drives a lot of age-related processes. So anti-diabetes drugs, you know, metformin being the classic example, are often thought about in the case of longevity. Maybe it's worth

16:24

talking about metformin as well in this context. I'm not particularly bullish on metformin in metabolically healthy people. I think, again, in people who are diabetic or pre-diabetic, metformin is a really good diabetes drug. Unlike ACARBOS and STLT2 inhibitors, metformin does not

16:43

appear to increase lifespan, or at least if it does in mice, it's a very small effect. It did not come out as positive in their intervention testing program. And the early data that, that

16:55

people taking metformin were at lower risk of dying has not, um, not been replicable. So if you're diabetic and you're taking metformin, you're at lower risk of dying than if you're diabetic and you don't take anything. Right. But, but in people who are not diabetic, that doesn't seem to have replicated that there's any real benefit in terms of mortality. And we're learning that metformin may blunt some of the positive benefits of exercise. So if you're not diabetic and you have a healthy lifestyle, I think metformin is probably a net, net

17:24

net negative there. Yeah. Next question. What's your most unpopular opinions on lifestyle and supplements like controversial takes? Yeah.

17:34

Oh, I don't know if it's unpopular. So around lifestyle, I don't know that I have any unpopular opinions. I mean, I sort of align with what I think is the consensus view around, you know, eating a generally whole foods diet plant based, I think is is a good idea. I like meat. I eat meat.

17:55

But I think largely plant based, I tend to align towards moderate to higher protein consumption, limit alcohol, avoid added sugars, right? That I think most people who are informed are going to land there.

18:10

Uh, exercise mix of cardio and resistance training, you know, sleep quality relationships, the pillars of health. So I don't think there's anything. I don't think there's anything controversial there in supplement world. Again, I tend to be pretty skeptical. I don't, again, I don't think it's controversial. It's, it's a fact that some people don't like that resveratrol is the most debunked longevity molecule ever. Resveratrol does not increase lifespan in laboratory animals.

18:37

on average, right? There's been a meta-analysis. It's not even my data of like 50 or 60 studies, then the average effect is zero. I'm sorry. That's a fact. If people don't like it, two

18:47

too bad so you know it's just reality um and yet you still hear you know certain influencers out there peddle the nonsense that resveratrol isn't is a longevity drug or an anti-aging drug other than that i don't have super strong opinions on most supplements other than i tend to be maybe more skeptical or less enthusiastic than than other people out there yeah just more

19:10

Waiting for more data. Yeah. And I tend to also, you know, my view is that, um,

19:17

I tend to maybe be a little bit more conservative when it comes to adding a supplement to my personal protocol, because I, I take the view that the human body is a really, really complicated piece of machinery, or at least that's a good anecdotal way to think about it. And if you consider any complicated piece of machinery and you go in there and you start taking screws out or pulling wires out,

19:41

at random, the chances you're going to make it work better are less than the chances you're going to break it. And I kind of think that's what a lot of people are doing when they start stacking 10, 20, 30 supplements. Right. They're just throwing a lot of stuff at it and they assume that there's no risk, but the reality is there is a risk. It's probably small in individual supplements, but when you start to stack a lot of stuff…

20:04

Again, my view is unless you have a very, very good rationale and hopefully a good understanding of the biology that you're perturbing, the likelihood you're going to get a better outcome is less than the likelihood you're going to get a worse outcome. Yeah, I guess you need to know if it's working or not either. Well, and that's where I think having good biomarkers is really important. I think we've got reasonable biomarkers for general health, right? What we don't have are good biomarkers of

20:31

aging longevity right yet and we can talk about biological age clocks but at least the ones that are available to consumers now um in my view are not sufficient of sufficient quality that we can use them to guide interventions you got very conflicting results from yeah so i did my own maybe that i mean this isn't a supplement related but that is maybe a controversial opinion again i

20:58

I sort of, I get that it's controversial. I don't see the controversy because I'm just, I'm just pointing out data. Like, you know, you can choose to be data driven or not. I choose to be data driven. And so I did an experiment where I tested, um, four different biological age testers.

21:14

tests from four different companies. These are all consumer facing. Anybody can go on the internet and buy these things. Right. And I did them in duplicate. I wish I'd done, I wish I'd done triplicate or four of each ones, but you know, as you know, these tests are anywhere from 300 to $600 a pop. Right. So even doing eight is fairly expensive. So, uh, so I did four tests from four different companies in duplicate, same biological samples taken on the same day.

21:41

I was 53 and three quarters years old at the day that I did this. The results I got back ranged from low forties to mid sixties. Right. Now, if I took the average of all eight, it was almost spot on my chronological age, but the variance was huge. And so, you know, and, and, and to be fair, again, I only had duplicates. Most of the companies, the two duplicates for the same test were

22:07

We're within three to five years. That's still a pretty big range, but, you know, relatively close. One of the companies was 20 years apart. But I think the bigger point is that we have no idea, first of all, what my true biological age is. So we can't know what the accuracy of these tests is, but we can know the precision is shit.

22:28

Right. The noise is bigger than the signal. And I think that's the problem is none of these tests have been validated by any regulatory body, any independent consumer watchdog organization. It's just these companies saying our tests measure biological age. I don't know why people would trust them, but they don't.

22:51

Or if they do, we don't know which ones do. And so I don't think we can use these consumer facing biological age tests for anything right now, other than enriching the people who are at these companies. They're really useful as research tools. And so I don't want to blast the idea that we can measure biologically.

23:11

by a lot, some aspect of biological age. Again, I've even been, I try not to, but I've even been using that term sloppily, you know, just, just in the last few minutes, we can measure aspects of biological age in the laboratory setting. My concern is the rush to market and selling these to people when they aren't ready for prime time. Do you use like the different clocks in the laboratories? That's right. Okay. Yeah. And so maybe it's worth just briefly talking about what, what's actually being measured in most of these. So first of all, people should appreciate, um,

23:39

You can measure biological age a bunch of different ways. And everybody will call it biological age, but none of them are measuring biological age as a true thing. What they're measuring is usually a correlation to mortality risk, right? And so we can do that with things like

23:57

LDL, HDL, insulin, glucose, right? We can come up with a set of those markers that everybody gets on their blood test and predict your risk of dying in the next 10 years. Now, it may or may not be a good prediction, but we can predict it. That's what people are calling biological age clocks. It's a correlation to mortality risk. So in most of the consumer facing biological age clocks, they're not using those blood-based

24:23

those blood-based biomarkers, they're using something called DNA methylation. So these are

24:29

chemical modifications on our DNA. And there are hundreds of thousands of them in our genome and they change over time. And importantly, they determine which genes in our genome get turned up or turned down in terms of expression. So it's a connection to biology that's really important to aging. People have found that the patterns of these methylation marks change with age. And you can look at, you know, depending on the clock, anywhere between a few dozen to 150-ish of these

24:56

specific methylation marks at specific locations in the genome. And you can identify a correlation with chronological age within a year or two in the laboratory. In principle, these companies can do exactly that same test and get a correlation to chronological age if you send them your blood. But we don't know if they're doing exactly the same test or whether it's done well. Um,

25:19

And then those are the first generation clocks. The second generation clocks, which people may have heard of, are instead of being based on chronological age, trained on chronological age, it's a different set of marks that are correlated with three-year, five-year, 10-year mortality, your risk of dying, or your risk of developing specific age-related diseases. Same principle, though. It's a correlation to those things. And those things, mortality risk, is correlated to biological age.

25:48

It's not a perfect correlation, though. It's not the same as biological age. So really what these tests are measuring is a correlation to a correlation, but they're calling it biological. That's part of, I think, the…

26:01

lack of clarity about what we actually mean. So again, I think the take-home message, though, is these can be very powerful in the research world. And I think we'll get to a point where they can be useful, say, in clinical trials, in predicting whether or not a new drug, a new intervention is going to lower risk of mortality. And

26:26

When used responsibly, if we can convince regulators that this is actually a really good prediction of your risk of dying, you could do a clinical trial and get a drug approved. It would be what's called a conditional approval, potentially, based only on the test. But we have to convince the regulators these things actually work. And this is another potential problem to the companies rushing these things to market, because

26:50

It, when the regulators realize they don't work because the ones that are being rushed to market don't work, it's going to be harder for responsible people to convince them. Oh yeah, they actually do work because we're doing it right. You know? Yeah. Maybe the last thing that's worth commenting on, because I know you've talked about this as well.

27:06

You can also use a different set of methylation marks that are correlated with the change in health over time. This is the pace of aging, the Dunedin pace of aging or rate of aging. So there's a different set of methylation marks across a population level study that had been shown to correlate with whether people stay healthy over time or have a decline in health over time, or maybe even their health gets better.

27:29

And so based on those marks, people developed a different clock that is supposed to measure your rate of aging, your pace of aging. Again, it's a correlation to health outcomes and a change in your health is correlated to a change in your biological age.

27:46

So it's still a correlation to a correlation, but that's really valuable if it works, because then you can do experiments and say, you know, what happens if I stop drinking alcohol? Does my rate of aging go up or go down and be informed by that? So again, that's really, really exciting. And it seems to work in the laboratory in a research setting, or maybe not. I shouldn't say laboratory in a academic controlled study could be of people, but

28:15

But we have no idea whether these companies that are telling you your pace of aging, whether that is meaningful or not. Because again, it's not, there's no quality control or external validation. Yeah. I tend to agree. Like there's a lot of noise with those tests. Yeah.

28:32

I want to take a quick break to let you know that you can now get my new book, The Longevity Leap on Amazon. It contains 24 chapters ranging from the biology of aging to all the major chronic diseases such as heart disease, kidney disease, neurodegeneration and I also cover over 70 clinically relevant biomarkers for chronic diseases and their optimal ranges. You can get the book from the link in the description.

28:53

Uh, next question, peptides for longevity. Do you have any opinion about that? So like BBC, GFBs or something? Yeah, yeah, yeah. So first thing to say is I think people lump peptides together, but, but that's kind of like lumping drugs together, right? Peptides are just bioactive molecules that have a certain type of chemical structure based on

29:12

the fact that they're a combination of amino acids. That's what peptides means. So they can have all sorts of different effects. And so it's important for people to appreciate, you know, you wouldn't necessarily put

29:24

rapamycin with aspirin with, you know, a PD five and with Viagra, right? They all can do different things. Peptides can also do lots of different things. They are biologically active. Our bodies produce many peptides. So, so you can categorize peptides based on whether they're naturally occurring or not.

29:41

new drugs that people have synthesized. Right. And I think it's plausible that naturally occurring peptides are going to be like BPC 157 are going to be less likely within a physiological range to have really negative outcomes. Whereas if you're taking a new peptide that our bodies have never seen there, they could be much more likely to have be much more potent and have negative outcomes. Of course, there's going to be

30:08

exceptions to that. Okay. So all of that is groundwork. Um, I'm not aware of any peptides yet that have been shown to slow aging or increased lifespan in laboratory. Yeah. Right. Do I believe they could? Absolutely. Do I believe peptides exist that will slow aging? Absolutely. I have just haven't seen data on any of the popular ones. Um, I think GLP one agonists are super interesting. So way go V Munjaro, things like that, that, that people have heard of for anti-obesity, um,

30:37

I think they have a really good chance of increasing lifespan in laboratory animals. Um, the thing I'm really interested with about there is, is it through, if it does increase lifespan, is it through a caloric restriction mechanism or is it through a

30:53

a mechanism independent of caloric intake. You know, when people first started talking about this, I was of the opinion that sure, they'll increase lifespan, but it's just going to be caloric restriction. As I've seen more and more data on targets of GLP-1 agonists

31:10

outside of limiting appetite or food intake, I'm becoming more intrigued by the possibility that they could actually have positive health benefits through other mechanisms. I would love to see that experiment done. I have not seen anybody, I've not heard of anybody doing that experiment yet in laboratory animals, but I'd love to see it done. And in people, I think, again, there's clear evidence that GLP-1 agonists can have impacts on a variety of age-related diseases, but

31:37

That could all be because you're reducing obesity or taking people from the obese range down to the overweight range or overweight to normal health range. But it's also possible that there are other impacts. Again, speaking about GLP-1 agonists, it's worth, I think, emphasizing that

31:57

Unfortunately, the way those things were rolled out to people, a lot of people were not given sufficient education around the importance of education.

32:08

eating a quality diet when you're taking these drugs and doing some sort of resistance training. A lot of people lost a lot of lean mass in addition to fat mass. And I think what we've learned is when that happens and people come off these drugs, they tend to gain much of the weight back, but they don't get the lean mass back. So what we may be doing with, if people are not

32:30

eating a healthy diet and practicing resistance training is increasing frailty, um, and, uh, uh, osteoporosis, um, in the elderly population. So just important for people to really understand great drugs, very powerful. They work and you need to take steps to ensure that you maintain or actually improve your body composition when you're taking, um,

32:57

I think that's gotten better. The other last thing I'll say about that is also pay attention to hormones when you're on these things, because anytime you're in a calorically restricted state, your hormones can become perturbed. Okay. That's GLP-1 agonist. The other ones I, you know, this is an area where I, I need to do a deep dive and I've been meaning to for a while to really take a close look at the common, uh, peptides that are out there. I think, uh, BPC is super interesting. The papers I've read is,

33:21

in rodents, really interesting effects, lots of anecdotal stories. Um, you know, it, will it generally work for people as a regenerative peptide or a healing peptide? I don't know. It would be great to have clinical trials. Uh, the growth, uh, growth hormone secretagogues again, really interesting, you know, there, I, I, I wonder, you know,

33:44

Is that any better than just taking growth hormone? I get you can do hand wavy sort of, uh, uh, you know, explanations for why it might be. I haven't really seen anything that makes me believe that. I also haven't seen a lot of data on how effective these things are at increasing growth hormone. And honestly, the data on growth hormone is a longevity drug is

34:03

pretty weak. This is getting a little bit in the weeds, so we don't need to go there. I will say Greg Fahey and his trim protocol, which includes growth hormone, is intriguing. This is a thymus regeneration protocol. But outside of that, I haven't seen a lot of evidence that the growth hormone per se is good for longevity. And then there's a variety of other peptides that

34:24

Potentially target mitochondria and other things. Yeah. Very early, very experimental. Um, it is interesting how many doctors in this space are comfortable prescribing these things with very, very little data. Yeah. One of the questions is actually about the trim protocol. Yeah. So we're,

34:39

You can explain what it is. Yeah. So, so I actually have an episode on the OptiSpan podcast for people who want to want to get a deep dive into this. I sat down with Greg about a month ago down in LA. So the trim protocol is based around the idea that relatively early in life. So adolescence or post puberty, early twenties, there's a pretty dramatic decrease in thymic function. And our thymus is important for,

35:05

among other things, producing T cells, which are really important for the function of our immune system. So

35:11

The idea is that because the thymus declines pretty dramatically, and then there's this slow but steady decline as we get older, this is contributing to immune dysregulation, both a decline in immune function and an increase in what's called sterile inflammation or something like autoimmunity. So Greg came up with an idea for how to restore thymic function in people who are 40s, 50s, 60s, 70s. It's called

35:40

And the protocol is basically a growth hormone DHEA, which is a precursor for testosterone and other hormones also declines with age and metformin and the rationale is.

35:59

as I understand it, is the growth hormone is really doing the action here. So the growth hormone does a couple of things to the thymus. So one of the things that happens during what's called thymic involution, this dramatic loss in function, is there's an infiltration of fat in the thymus. We see this in other tissues as well, but it happens early in the thymus. So growth hormone reverses that and at least causes the volume of the thymus to decrease.

36:24

to grow right now. Is it actually new cells, new stem cells? I don't know that we know that, but you can see it by MRI. You can see an increase in volume of the thymus.

36:34

The DHEA is sort of in there, not a great scientific rationale, but in part because DHEA goes down with age and it may have some benefit for thymic function and maintaining hormonal balance. And again, we talk about this a little bit in the episode for people who are interested. The metformin is in there because growth hormone can have a negative impact on insulin sensitivity and glucose levels.

37:00

homeostasis. So metformin, again, anti-diabetes drug, this is to sort of offset that. I asked Greg about this. There's no data. I am intrigued by the idea that maybe SGLT2 inhibitors could substitute for metformin, counteract maybe some of the bad stuff about metformin. If SGLT2 inhibitors have a longevity effect on their own, also give you that, but there's no data on that. So what Greg has shown is in a number of small but intriguing

37:29

human studies evidence that the trim protocol over several months can improve thymic volume, reduce the fat infiltration, and probably improve T cell function and immune function, although that hasn't been measured in as much depth as at least I would like to see. They also have some evidence that the epigenetic clocks that we were talking about earlier show what would be

37:58

as improvements in biological age or reduced risk of mortality. So I would say pretty intriguing data, and it certainly makes sense that improving thymic function in older people is going to be generally better.

38:15

beneficial. So I personally am at some point going to give trim a try. I just need to figure out the logistics of the MRI. I want to make sure I measure it, right? I want to know like what actually happened. So the logistics of the MRI analysis, make sure I get that done before get, you know, at least some biomarker panel that's going to tell me about inflammation and immune function before, and then

38:38

and then do the same thing afterwards. Right. Would repamycin have any effect on the thymus? Yeah. I asked Greg that he doesn't have any data. Um, it's, I don't know the answer. I, I, I, if,

38:49

I don't know. I mean, I think it's possible that you would also see a restoration at least of thymic volume and a reduction in fat infiltration from rapamycin. And that, but it's really speculative. That's just based on some of the data on rapamycin effects on fat metabolism from laboratory animals. And then there's some intriguing data, both in rodents and in humans on, on,

39:15

rapamycin treatment, increasing volume of the hippocampus and the caudate nucleus. So it's in the brain, very different, right? But by MRI, at least in people who are APOE3-4 carriers, so APOE4 is one of the biggest genetic risk factors for dementia and heart disease. So they tend to have an accelerated decline in brain volume in those regions. And there's two studies now that have shown that

39:42

or at least strongly suggested reversal of that reduction in brain volume as well as improved cerebral blood flow.

39:50

I'm intrigued by the possibility, yes, that rapamycin could have an impact on thymine condition, but no data that I know of. Yeah. But does it like slow down immunosensitance? So the decline? So what we know from laboratory studies and then the human studies I alluded to earlier from Joan Manick is that functionally you see an improvement in vaccine response. So there's definitely a change in age-related immune response.

40:18

function decline. Um, and you see very potent reductions in chronic inflammations in mice across many different tissues and organs. And again, anecdotal data in people with, you know, autoimmune or chronic inflammation that they have an alleviation of symptoms of inflammation with off-label use of rapamycin. So I think it's reasonable to,

40:43

it's a reasonable hypothesis that rapamycin would, would have a positive impact on an immunosenescence in people. I don't think we have any data directly addressing that at this point. Gotcha. Next question is IV NAD pure hype? Um, intravenous. I mean, I would say it's a, it's a little bit better than pure hype. Again, you know, I've talked to, I've talked to docs who do it regularly. Um, you know, they say some of their patients, um,

41:14

you know, have some pretty significant improvements in, in how they feel. So I wouldn't want to say there's nothing there. Again, I'm not aware of any data, you know, from rigorous studies showing benefits in a population of people or, or across a population of people from IV NAD. Again, this, the, the, the, the hypothesis is,

41:37

behind this is that NAD levels decline with age and that by restoring NAD, that's going to be beneficial. That

41:45

hypothesis or that idea that NAD levels generally decline with age is also not strongly supported by the literature. Again, there's evidence there, but that has been sort of overstated by people who have a vested interest in promoting that model. Often they're selling NAD precursor supplements. So I think my gut feeling is some people

42:08

particularly those who have significant mitochondrial dysfunction or metabolic dysfunction do indeed have perturbed NAD homeostasis. And that can be reflected as either a decrease in NAD itself or a shift in the redox state of NAD towards NADH. Those people may benefit and feel better from NAD drips or from NAD precursors. Um,

42:34

I think maybe the last thing to say on this is there's a variety of ways that people are trying to boost NAD. So the NAD drips is one, uh, NAD precursors that are taken orally, NMN and are, are the two expensive ones. Nicotinamide niacin are the two cheap ones. All of them in theory, if you take enough can boost your NAD levels. Um,

42:56

And then there's a sort of a new sort of, uh, uh, movement towards sublingual NAD or sublingual NMN. All of those in theory should increase circulating NAD levels. And so I don't know of any reason to believe that one is necessarily better than the other from that perspective. Yeah.

43:17

I've never done NAD drips, by the way. Yeah. I'm sort of intrigued. I'm kind of like you where I like to try stuff and see, you know, do I feel anything? But I haven't tried it yet. I haven't tried either. I've heard it's like

43:27

can be uncomfortable because it's like several hours long and you can do it fast. Yeah. I mean this, I don't know if this is on your list or not, uh, sort of related just because it's, it's, uh, IV related and takes a few hours that one thing I am becoming more intrigued by is therapeutic plasma exchange, right? The idea, and this is based on the parabiosis experiments in mice, that there's bad stuff that accumulates with age in our circulatory system and good stuff in young animals. And if you connect the circulatory system of a young mouse and an old mouse,

43:56

The, I mean, this is, this is an oversimplification, but I'm going to say it anyways, because it sounds good and it more or less fits the biology. The old mouse becomes younger. The young mouse becomes older. Right. Um, so therapeutic plasma exchange is kind of doing half of that equation, right? It's, it's, it's taking some of the bad stuff out of circulation. I'm becoming more convinced there's, there's real.

44:18

potential benefit there, both in the context of aging, but also maybe in the context of things like, you know, microplastic exposure or heavy metal exposure. Right. So, so I think that's interesting. I also haven't tried that yet, but that's definitely on the short list of stuff I want to, I want to try. Yeah. Me too. Like, um, there's even like this Ebo, which is like you, uh, do like a dialysis and filter the blood and then you like shoot ozone and UV light into it as well to, to

44:47

That sounds a little more sketchy to me, but I mean, again, maybe it also comes from a little bit of lack of, of, of knowledge of what the research actually shows. Yeah. Yeah. Well, the EBO is usually used for like autoimmune conditions and those kinds of things. Yeah. Next question. Does low IJF1 increase longevity and is low IJF1 bad for the brain? Yeah. Uh, so.

45:12

low IGF-1 during development, and let's just start with non-human animals first, right? So mice, rats, and dogs. I think it's, it's pretty clear that low IGF-1 during development leads to smaller body size and increased lifespan on average. Every individual is different, but on average in a population, yes, it slows aging, seems to slow aging. Um,

45:39

In people, it's a little bit less clear, but there is data from studies of people who have mutations in, I think it was a growth hormone receptor, but that leads to lower IGF-1, that they are at lower risk for cancer, heart disease, metabolic disease, despite even having more adiposity, right? But they're smaller of stature.

46:01

They don't, they don't live longer, but it's interesting because the, the increases in cause of death come from alcoholism and accidents. So lifespan doesn't change, but risk of at least some age related diseases does change. So I think it's plausible in people that biological aging is slowed when you have lower IGF-1 levels through development as well. How low, like, uh, because what you see from some of these observational studies is that if it's

46:31

like too low or like below a hundred, then it can increase risk. So again, I think you have to be, you have to be clear. I'm talking about people who are naturally low in IGF-1 from gestation through development their whole life. So they probably have genetic variants that make them low in IGF-1. When you look at cross-sectional or even longitudinal population data in adults, that's a very different situation because those people,

46:54

presumably or may have gone through development with much higher levels. So they could still be high, large in stature or small in stature, but to have an IGF one level that doesn't match their stature, which is determined by IGF one level development. So, um,

47:12

And I think that's important because, you know, there are people who are thinking about therapeutic strategies to lower IGF-1 in adulthood with the idea that it will slow aging. As far as I know, there's only one study in mice that looked at this. It was a study that Derek Hoffman at Einstein did several years ago now. And they had a modest but statistically significant increase in lifespan. I want to say in males, but not female mice. I might be backwards on that.

47:40

but nowhere near the magnitude of effect that you get from having low IGF-1 during development. And that probably was primarily an anti-cancer mechanism. And this is a place where, I mean, in general, I think studying aging in mice and then extrapolating to humans is…

47:59

It's certainly much more reasonable than what people have done in mice with cancer or heart disease and artificially causing the disease. Mice age very much like people do. But mice in the laboratory don't tend to die from frailty, sarcopenia, fractures. They do get some of that, but it doesn't kill them. They tend to die naturally.

48:23

Well, they tend to die from euthanasia, but usually the euthanasia is downstream of cancer. And certainly all mice will die with cancer. So it's a little bit different than people. I think the IGF-1 benefits, the lower IGF-1 benefits in adult mice primarily come from anti-cancer. So then the question is, will that extrapolate to people or dogs? And there's a company called Loyal that is moving forward with a drug that will reduce IGF-1 in adult dogs. We just don't know.

48:50

One of the arguments you'll hear for a low protein diet in people is that it will lower IGF-1 and thereby lower cancer risk. The data on that is not particularly compelling. And again, there's, you know, there's a little bit of disagreement about what the on whole, what the epidemiological data actually shows. My take is that low protein diet.

49:15

And that causes low IGF-1, but is the IGF-1 causing the downstream effects on mortality? It's not known. Low protein above about age 55 is generally a bad idea.

49:28

You're at higher risk of frailty, sarcopenia, fractures, and death than eating a high protein diet. Obviously, that's a correlation and it could be due to all sorts of other factors. High protein is also not great if you're eating an unhealthy diet. So if you're overfed and eating a lot of crap and eating high protein, that does increase your risk of cancer. So my view is the best bet is to eat relatively high protein, high quality food.

49:57

diet. That's independent of IGF-1, but worth saying. So, um, so does IGF-1 work differently in the brain? This is really interesting. Again. Yeah, it does. Um, I don't know about

50:10

I don't want to make a blanket statement about aging, but data from the Dog Aging Project is really intriguing here. So in almost every age-related disease that you can think of, and also for lifespan, small dogs age slower than big dogs do. Small dogs have lower IGF-1 through development. That's why they're small. And they live longer and seem to age slower than big dogs do. You can look at a bunch of different age-related diseases and functional declines, except for dementia.

50:35

Dementia is the only one I'm aware of. There might be others. It's the only one I'm aware of that has come out of our data set so far where there doesn't seem to be any difference in dementia risk between small dogs and big dogs. So, and it's not, and it doesn't scale with biological age. In other words, a 12 year old German shepherd has roughly the same dementia risk as a 12 year old, you know, I don't know, uh, Chihuahua, right? Small dog.

51:01

So that suggests that if IGF-1 is really driving the difference in aging rate in the rest of the body, the same relationship isn't there in the brain and it's

51:11

it's not as strong, but there might even be a hint of protection in the big dogs. And there's a hint of that in people as well. So yeah, it might be the case that having higher IGF-1 is better for brain aging. I think an interesting question is, is that effect due to higher IGF-1 during development or is it due to higher IGF-1 during adulthood? I really don't know the answer to that. So the

51:33

So does the IGF-1 like help with neuron growth or what does it do? I don't think we know. Yeah, I don't think we know. Um, or at least I don't know. Maybe, maybe people who are experts in, in, uh, in the brain or in dementia would have a better feel for that. Uh, it is interesting to me that one of the therapies, you know, that has gotten some traction, uh, for, uh,

51:52

for dementia is intranasal insulin and the insulin and IGF-1 signaling pathways overlap. So again, that may have nothing to do with this relationship, but it is sort of intriguing. There may be a connection there. Yeah. I think it's with mTOR as well. Like mTOR is needed for neuroplasticity. It is. Yeah. I mean, again, you're right. The challenge with, um,

52:13

the challenge with interpreting that as, as causal for anything to do with dementia is, you know, it's really all about the levels of signaling through IGF-1 or, or mTOR. So, and, and where that comes from is if you completely inhibit mTOR, you, you take a very high dose of rapamycin. Yeah. You'll block neuroplasticity, you'll block, you

52:34

you know, new memory formation, but that's because mTOR is required for all protein synthesis and cell division. Right. So the question, and this gets back to like muscle function, which we talked about before, or, or lean mass, uh, muscle formation. If you turn down mTOR too much, you won't build new muscle.

52:52

But is it possible that turning it down a little bit from where it's at, especially in the context of aging, is actually going to be net beneficial for muscle or for cognitive function or for memory formation? I think that's why we see these benefits from rapamycin because we're only turning it down a little bit and maybe transiently turning it down as opposed to just, you know, dropping it down to the floor. Yeah.

53:11

Uh, next question. Do you use AI and language models in your work? I do. I use it a lot. Yeah. I mean, um, and it's, and it's growing, right? I mean, I think, I think I'm certainly not one of these people who subscribes to the idea that AI is going to solve all of our problems, but, um, I use it, uh, uh,

53:30

We use it at OptiSpan and we're thinking a lot about… So again, OptiSpan is really about creating tools, technologies to enable people to get on a better health trajectory, right? Writ large. So we have clinical programs, but we are…

53:44

I'm absolutely trying to think about how do we use these AI tools to integrate lots of different data types, to get that back to people, to create interactive ways for doctors and patients to interact with their data. Lots of other people are thinking about this as well. I see really, really powerful use cases in the clinical application and what I would call healthspan medicine or what Peter described.

54:06

Atiyah would call medicine 3.0. Although I actually think that's medicine 4.0 when we add AI and geroscience on top of medicine 3.0. So yes, there, there are tons of really obvious use cases that are going to happen. You and I, within the next few years, we'll have a healthspan agent on our devices that we can interact with if we want to. Right. And it will function as well as most doctors. Very confident that can happen. Yeah. We're not that far away. Um,

54:35

So that's a really obvious use case for AI. I think in the broader, you know, longevity geroscience space,

54:42

AI is going to accelerate the pace of research everywhere, including geroscience and longevity. But I think we need much better data sets than we currently have in order for AI to really be a game changer when it comes to understanding the biology of aging and being able to use that to impact lifespan and healthspan. I think our data sets right now are pretty bad. Certainly in the intervention space, our data set is

55:10

woe woefully underrepresented for all of the different genetic or environmental and I put small molecules under environmental and

55:21

things that we could test to see what impacts longevity, tiny, tiny fraction. Um, and I sort of, you know, use the analogy that, you know, garbage in garbage out, everybody gets that right. You put garbage into the best AI tool. You're going to get garbage out. You put rapamycin and metformin in a carbosin, guess what you're going to get out. Right.

55:41

Right. We need a better data set to know what are the most effective ways to impact longevity than what we've got right now. And then I would also add to that, we need larger human, what you, you know, sort of crudely describe as multi-omic longitudinal data sets in

55:58

Basically, over time in lots of people measure everything you could think to measure. Yeah, those are observational in nature, but and they're very, very complex data sets. But that's the kind of thing that the new AI tools are going to be very capable of sort of teasing out what's important. So that's what I would like to see.

56:18

the AI tools are going to keep developing. I'd like to see smart people in the longevity community actually put some thought into figuring out as these things keep developing, how do we use them most effectively to really move the needle? Yeah. Do you think like the AI will figure itself out things that isn't in the data or like,

56:39

Because I don't know, I'm less optimistic about that. Right. Um, I kind of feel like the, the, the, the sort of foundational information needs, maybe I'm wrong. I hope I'm wrong, but I sort of feel like the foundational information needs to be there. And again, you know, I, I sort of use this, this graphic sometimes in my talks where, you know, I compare the hallmarks of aging, which are just a representation of our

57:00

are how much we understand aging today, the biology of aging today. And I compare it to a map of the surface of the earth, you know, in 500 BC, right? Which I don't know if you've ever seen this map, but you know, it's got like a, uh, uh, a sort of, you know, vaguely Europe shaped thing in Asia that looks nothing like Asia and Libya is

57:19

Like a flat earth. 10 times as, as yeah. And then, and then you sail too far and you fall off the edge. So if you think about it that way, you could have the best AI tool in the world and you give it that map and say, show me the surface of the earth. It's not going to show you the surface of any earth that looks anything like what we know it looks like today. I sort of feel that is, is, it's the same idea if we give it how we understand aging today. Yeah. I'd love to be wrong, but, but that's the way I, the way I would guess it's going to go. Yeah. Next question. Um,

57:48

How much protein for longevity? How much is it? I mean, again, I don't, we honestly, we don't know the answer and it's going to be individual, right? So there's two things I would say. I would say for most people, the important thing, and it's going to depend on the quality of the diet, definitely that you're eating. So I would say the best strategy for most people to adopt is what I would consider moderate to high protein. So anywhere from, and again, I'm just throwing numbers out, but anywhere from 0.6 to one gram per pound of body weight per day is

58:17

But you got to be eating a high quality diet. If you're eating a crappy diet and you eat a lot of protein, you're going to increase your risk for cancer.

58:25

Period. So like sugar and cut out simple sugars, again, highly processed foods in general, cut out highly processed foods. We could have a debate. I mean, I had this conversation with, with Peter, uh, Peter Atiyah recently, you know, about protein bars, right? And his view is if you have really good ingredients and you can maximize sort of like the protein ratio per calorie, that that's, that's a good thing. Right. Um, so, and I think there's, that's a reasonable, uh,

58:51

That's a reasonable thing. I still wouldn't say eat 10 protein bars a day, even if they're the best protein bars in the world. But I don't want to say never eat highly processed foods, but most highly processed foods have a lot of added sugars. Read the frigging labels. I can't believe still today a lot of people don't look at labels. Cut out the simple sugars, right? Cut down the alcohol. Don't waste your calories on nonsense. So eat a high quality diet. Then I think high protein relatively and protein.

59:17

definitely resistance training should be part of your exercise routine. That to me, those three are really the strategy and you can't really talk about protein in the absence of that. Might there be a slight increased risk of cancer from doing that compared to not compared to eating a low protein diet? Yeah, there might be, but I think by eating a high quality diet and

59:37

and exercising regularly, you probably dramatically reduce that increased risk. Right. And you're going to get lots of benefits in terms of muscle mass for metabolic health, bone density for frailty, hormonal health. Like you're going to get all these other benefits that more than offset the

59:53

If there is a tiny increased risk of cancer, the increased risk of cancer. And again, I don't really like, I mean, you hear people do this all the time and it's like, you know, oh, I look at that guy and he looks 65. So his longevity protocol must not be working. I'm like, yeah, he's actually 75. It's working great. I don't like, I don't like that sort of mindset. But the honest answer is I know people who have dabbled with and still practice a very low protein diet.

01:00:15

In general, they don't look very good and they don't seem very happy. So that's a generalization. But I do think that, you know, if you look around in your own life and you see the same thing, that may be telling you something. So no protein margaritas. Yeah, I never had a protein margarita. That's for sure. I'm sure they're out there somewhere.

01:00:39

Um, and, uh, next question, what makes grip strength link to healthspan? Oh, good question. Yeah. I mean, I tend to think it's, it's mostly just a reflection of overall muscle function and muscle quality, right? I don't think there's anything special about grip strength per se. Um, I do think, you know, having a, having a, a good grip strength functionally for being able to do the stuff you want to do in your daily life is a good idea, but I wouldn't necessarily consider

01:01:07

I definitely don't train for grip strength itself. It's a byproduct. Yeah, it's a byproduct of being strong, being able to lift weight. But like I said, if your grip strength is low, that's

01:01:20

That will make it harder for you to, to do the stuff that you want to be able to do when you're 60, 70, 80 years old. Yeah. So be strong, I think is the real answer there. Yeah. Like they find that even 20, 30 years in advance, if you have low grip strength, then you're going to have hard time putting on clothes, getting off the toilet. But that usually reflects a sedentary lifestyle and, and, and not.

01:01:43

being not having sufficient muscle mass throughout your entire body. Like I think there are probably very few people who have sufficient muscle mass everywhere else and their grip strength is low.

01:01:53

Yeah. I guess it's like, yeah, like, uh, if you're otherwise with decent muscle and strength and, uh, in good health, you should have like, at least like above normal grip strength. You don't have to train specifically for the grip strength. I've never been one of those guys that, you know, has that gripper thing and, and does that. Right. Right. Although, I mean, I've used it. It's, it's a very good exercise for the grip. Like, yeah, yeah. It's good for pull-ups, good for pull-ups, good for former carries. And yeah. Yeah. Good for arm wrestling. If someone is interested. Yeah.

01:02:24

Next question, preserving women's fertility and AMH with H. I guess that's like a marker of fertility or A quality. Yeah. So I'm definitely not an expert in female reproductive health. There are really, really smart people out there who are looking into this. I'll just preface it by that. So again, I would, I would, my immediate, you know, answer to that is that like almost any other, again, it's going to be dependent on your genetics and, and, and whether you're at, um,

01:02:52

high risk for premature infertility or menopause or other ovarian syndromes. But in general,

01:03:01

the same lifestyle factors that are going to have a positive impact on other aspects of age-related functional decline in other tissues and organs are also going to have a positive impact on reproductive health. So I know that's not a profound answer, but I think it's important to appreciate that's almost always going to be the place to start if you are concerned about a particular age-related functional decline or disease. And then you have to get into the

01:03:31

the more, you know, either genetic risk factors or specific lifestyle risk factors that could have an impact. So I'm going to leave it there because again, that's outside my area of expertise. It is in tree. It is, it is interesting to me. And, um, I view it as a positive development that the field as a whole is starting to pay much more attention to ovarian aging and female reproductive aging as both an early indicator of age related, um,

01:03:59

processes and potentially a causal factor in differences in risk for specific age-related diseases in women so i think there's a lot that's being done and a lot of work to be done there yeah kind of follow-up question like what do you think of the children having children like there's like data that having children later in life is like associated with greater longevity in women

01:04:23

Oh, okay. Yes. So there's two things to say there. So, so I thought you were going to ask about whether that has any negative consequences on the, on the children. Right. Um, so yeah, I think my guess is the, the, the correlation between fertility between childbirth later in life and, um, longevity in women is mostly because women who are able to have children later in life have, uh,

01:04:47

later cessation of reproduction. In other words, their ovarian aging is delayed for some reason. And so aging in the rest of the body is

01:04:55

also probably proportionally delayed. That's the most likely explanation. Although, you know, pregnancy itself does have an impact on a whole bunch of physiological functions and using these DNA methylation clocks that we talked about before, you can see changes in the DNA methylation clocks during pregnancy and after pregnancy that look like

01:05:17

an increase in epigenetic age followed by, in most women, a decrease in epigenetic age. So is it possible that the hormonal and other changes that happen during pregnancy are impacting biological aging itself? Yeah, I think that's pretty plausible. And in some women, it may actually reset

01:05:36

Some aspects of biological aging to a lower baseline value than before pregnancy. So it's total speculation, but that could also be a real thing. Yeah. So there's like, it increases during pregnancy, the biological age. The DNA methylation. Yeah. Patterns associated with biological age. Yep.

01:05:52

But then then would you predict that the more children you have, the faster you would age, right? Well, again, the, the data that I've seen in most women, it goes up, but then after pregnancy, it comes back down. Okay. And in some women, it actually goes down, down below the baseline where they started. So yeah, if it only went up or if it only went up and partially came back down, you would expect an acceleration of age. Right. Gotcha. But I mean, obviously having kids can have all sorts of other impacts on your, uh, your stress levels and aging and, and so it's complicated. Yeah.

01:06:20

Yeah, I think that is, you know, having generally more children is associated with slightly longer longevity to a certain point. Sure. And I mean, again, that could be for all sorts of reasons. It could be biological effects of pregnancy. It could be later, you know, the fact that when these women can just have children later in life, their ovarian aging is delayed, their aging is delayed in their whole body could also be due to the social component, right? And

01:06:43

you know, having children who hopefully are going to be around when you're an adult and maybe even care for you. Right. So there's all sorts of factors that could weigh into that. Yeah. Last question is,

01:06:53

is um when should we start giving rapamycin to our dog so that's for my wife i have a puppy yeah who is i'm not a veterinarian i do not make veterinary recommendations but hypothetically speaking if you were going to give rapamycin to your dog um the the idea would be you're doing that because you believe that it might increase lifespan and improve healthspan in dogs um so

01:07:19

I mean, again, no way to know. Uh, so what I can say is from our studies in the dog aging project, they have all been in dogs that are over seven years old and at least 40 pounds. So that's, you know, what, about 18 kilograms, right? Um,

01:07:35

And that's because big dogs age faster than small dogs. So it has nothing to do with the idea that rapamycin is going to work better in a big dog than in a smaller dog. It's just because for clinical trial purposes, you need a rapidly aging population. So that's a reasonable thing to think about, right? That roughly biological age. So if you're a 40 pound dog, seven or greater, if you're a smaller dog, might be a year or two later. But that's just a guess.

01:08:02

What we can say for mice is that, you know, rapamycin treatment starting around that same biological age. So a 60 to 65 year old person, maybe 55 year old person,

01:08:15

to a seven, eight-year-old dog increases lifespan pretty robustly and improves a whole bunch of healthspan metrics. So that would be my sort of gut reaction for, this is all really based on, I think maybe it's worth saying explicitly, what's the underlying sort of

01:08:33

calculation here, right? It's always a risk reward. So what's the reward from starting when the dog's a puppy or the kid's a teenager versus the reward of starting when the dog's older or you're 50, 60, right? The difference in reward, the way we understand it now from mice is pretty small. You get pretty much the same benefits starting later in life that you do if you start the mice very young. So then what's the difference in risk? Well,

01:09:02

Certainly, if this is before puberty, obviously, there's lots of risks that would go along with that. And I think the idea is the longer you're taking any intervention, any drug, the more likelihood that side effects could happen and compound. So, again, with rapamycin, given that we don't completely understand the risk profile, I think we've learned a lot more. We still don't completely understand it.

01:09:26

The risk is lower if you start later. So that's kind of where I land both for off-label use and people, and if you're going to do it in dogs. Yeah. Yeah. Our dog is a 1.5 years old and he's like 10 pounds or something, like four kilos. Yeah. So pretty young. Yeah. So he has a long time to go. Yeah. Which, you know, that you're going to, you're going to most likely have that dog for 15, 16, 17 years. Right. So. Yeah. Yeah.

01:09:52

One interesting thing, so he got car sickness, so we were giving him some of this nausea medication, which is like some antihistamine, and the ingredient was meclizine. Actually, I found that there was one of the ITP ingredients. That's interesting. Yeah, I actually, I mean, I knew about it from the ITP study. But yeah, it's a common anti-nausea medication as well that may have geroprotective effects. So he's already on the protocol. Yeah, yeah.

01:10:21

Uh, I assume that meclizine was only for a short period of time. Yeah. It was a small dose. It was very small. But I mean, that's another intriguing one where from the ITP, you know, the, the, the, the mechanism that was at least how that was proposed and selected, uh, was, was based on the potential that it also is an mTOR inhibitor. So same idea as rapamycin, but could be lots of other mechanisms by which meclizine is,

01:10:46

working to have an impact on longevity in mice. And intriguing to think about the possibility it could have similar effects in people and dogs. Yeah. Well, it was a great conversation. And where can people learn more about you? Where can they find your channel? Yeah. So, at MK Berline on LinkedIn, X,

01:11:09

Instagram, and then the OptiSpan podcast is you can find all sorts of content. So if you enjoyed this and maybe got to get a little bit more edgy, you can check out the OptiSpan podcast. Yeah, we'll put the link in the show notes. And yeah, thanks for coming. Thank you. All right, that's it for this episode. Make sure you check out my new book, The Longevity Leap on Amazon. I'd also appreciate if you share this episode with a friend or family member. Other than that, my name is Seem. Stay tuned for the next episode. Stay empowered.

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白藜芦醇作为长寿分子的争议，

白藜芦醇被认为是“最被戳穿”的长寿分子。研究表明，白藜芦醇并未显著延长实验室动物的平均寿命。尽管如此，通过生活方式的调整可以改善健康寿命（healthspan），并可能延长寿命（lifespan）。

关于布莱恩·约翰逊（Brian Johnson）停止服用雷帕霉素（rapamycin）的决定。

不应以他的做法为健康建议的依据，因他缺乏专业背景和科学严谨性。关于雷帕霉素，目前尚无随机临床试验明确证明其在人类中能延缓衰老或带来显著益处。现有的研究主要集中在器官移植或癌症患者中，针对健康人群的抗衰效果未知。约翰逊停止服用的理由基于一项生物年龄评估研究，但该研究存在问题，因其同样显示运动和优质饮食对生物年龄无积极影响，这显然不合理。约翰逊将血脂和血糖的生物标记物变化归因于雷帕霉素缺乏依据，因为高剂量雷帕霉素在移植患者中可能引发此类副作用，但在低剂量下（如约翰逊使用的剂量）未见显著关联。此外，约翰逊同时进行多种干预，难以将变化归因于单一因素。若有人因雷帕霉素感觉良好，不应受约翰逊的影响而停止，但也不推荐盲目使用雷帕霉素。

进一步讨论了雷帕霉素在动物实验中的表现，指出其在实验室动物中可显著延长寿命，可能通过降低慢性炎症、逆转肥厚性心肌病或自身免疫疾病等带来益处。他自己因雷帕霉素缓解了肩关节炎症（冻结肩）。然而，临床证据仍限于病例报告，尚未达到随机双盲试验水平。副作用方面，约15%的人会出现口腔溃疡，细菌感染风险可能略增，但未达统计显著性。关于免疫抑制和肌肉流失的担忧，实验室动物研究显示雷帕霉素反而可增强老年动物的免疫功能、维持肌肉量并预防肌少症。人类研究中，Joan Manick的两项大型临床试验表明，依维莫司（everolimus，雷帕霉素衍生物）可改善老年人的疫苗反应，暗示免疫功能增强。一项针对333名非处方使用雷帕霉素者的研究发现，其COVID-19严重后果和长新冠症状风险较低，提示抗病毒免疫效果的提升。正在进行的PEARL试验和Brad Stanfield在新西兰资助的试验可能进一步揭示雷帕霉素对体成分和肌肉功能的益处。

抗氧化剂是否越多越好，以及补充抗氧化剂是否可能有害。

“抗氧化剂”这一术语常被误用。抗氧化剂的作用是相对的，取决于分子间的氧化还原状态。人们通常认为抗氧化剂可清除代谢产生的活性氧（ROS），ROS被认为是衰老的驱动因素之一（氧化衰老理论）。然而，氧化信号对健康至关重要，如细胞内和全身的信号传导。若盲目阻断氧化信号，可能反而有害。抗氧化剂补充的挑战在于难以区分“有害”和“有益”的活性氧，且目前对这一生物学机制的理解不足。因此，过量抗氧化剂可能有害，个体化剂量和靶向问题尚无明确答案。线粒体靶向抗氧化剂或肽类（如SS-31）具有潜力，但证据不足以推荐广泛使用。

关于补剂与生活方式在长寿作用中的比例，

强调生活方式远比补充剂重要。他对生活方式改善健康寿命和寿命的信心为100%，而对补剂的信心低于10%，且补剂的效果相较生活方式是增量性的。对于明确缺乏的营养素（如维生素D、omega-3），补剂可显著降低疾病和死亡风险，占比可能达20%（生活方式80%）。但对于推测性补剂（如NAD前体、伯伯因、尿石素A、α-酮戊二酸），效果未知，占比可能仅5%或更低。以肌酸为例，指出其在健康生活方式下可提供额外价值，但效果仍较小。

除雷帕霉素外最有可能延长寿命的化合物，

看好SGLT2抑制剂（如卡格列净、恩格列净），其在小鼠干预测试计划（ITP）中延长寿命，英国生物银行数据也显示其降低全因死亡风险。这些抗糖尿病药物通过增加尿液葡萄糖排泄发挥作用。雌激素和雌二醇也具潜力，ITP显示其延长雄性小鼠寿命，英国生物银行数据提示女性激素替代疗法降低全因死亡风险，但机制尚不清楚，男性使用需谨慎。阿卡波糖在ITP中延长雄性小鼠寿命，但因胃肠道副作用（如胀气），在西方饮食中的耐受性较差，其应用前景低于SGLT2抑制剂。关于二甲双胍，在代谢健康人群中无显著长寿益处，且可能削弱运动益处，仅适合糖尿病或糖前患者。

关于生活方式和补剂的“非主流”观点，白藜芦醇的长寿效应已被元分析否定（50-60项研究显示平均效应为零），这是事实，尽管一些网红仍在推广其“抗衰”作用。他对补剂持谨慎态度，认为人体是复杂系统，盲目堆叠多种补剂（如10-30种）可能弊大于利，除非有明确生物学依据和监测生物标记物。他对现行生物年龄检测的可靠性表示怀疑，分享了自己测试四家公司的八次生物年龄检测（53.75岁时），结果从40多岁到60多岁不等，显示出巨大变异性和低精确度。这些检测未获监管机构或独立机构验证，仅适用于研究而非临床决策。

关于长寿相关肽类，指出肽类种类繁多，作用各异。天然肽类（如BPC-157）在生理剂量下副作用较小，而合成肽类可能更强效但风险较高。目前无肽类被证明能延缓衰老或延长寿命，但GLP-1激动剂（如奥格利司他、替西帕肽）具潜力，可能通过热量限制或其他机制（如改善代谢疾病）延长寿命。GLP-1激动剂使用者需注重优质饮食和抗阻训练，以避免肌肉流失和停药后体重反弹导致的脆弱性增加。BPC-157在小鼠中显示再生和愈合效果，但缺乏临床试验数据。生长激素促分泌素的作用尚无充分证据，生长激素本身作为长寿药物的证据也较弱。对Greg Fahey的TRIM（胸腺再生）协议表示兴趣，该协议通过生长激素、DHEA和二甲双胍恢复胸腺功能，初步研究显示其可增加胸腺体积、减少脂肪浸润并改善免疫功能，但需更多数据验证。

关于静脉注射NAD（IV NAD），效果略优于“纯炒作”，一些医生报告患者感觉改善，但缺乏严谨研究支持。NAD随年龄下降的观点证据不足，且常被商业利益夸大。特定人群（如线粒体或代谢功能障碍者）可能受益，但NAD滴注与口服前体（如NMN、烟酰胺、烟酸）效果相当，舌下给药也具潜力，尚无证据显示某一方式优于其他。对治疗性血浆置换表示兴趣，认为其可清除循环中的“有害物质”，在衰老和环境毒素（如微塑料、重金属）暴露方面具潜力。

关于IGF-1（胰岛素样生长因子-1），讨论了其与长寿和大脑健康的关系。在动物（小鼠、大鼠、狗）中，发育期低IGF-1导致体型较小、寿命延长。人类中，生长激素受体突变导致低IGF-1者癌症、心脏病和代谢疾病风险较低，尽管体脂较高，但寿命未延长（死因多为酗酒和事故）。成人期降低IGF-1的干预（如低蛋白饮食）长寿效应有限，主要通过抗癌机制起作用，且数据不充分。提到Dog Aging Project数据，显示小型犬（低IGF-1）除痴呆外，衰老相关疾病风险低于大型犬，暗示高IGF-1可能对大脑衰老有保护作用，但具体机制（如神经元生长）尚不清楚。鼻内胰岛素疗法（与IGF-1信号通路重叠）在痴呆治疗中的潜力也值得关注。

在AI和语言模型的应用上，在工作中广泛使用，尤其在OptiSpan项目中，用于整合多类型数据、开发健康管理工具和促进医患互动。他预测未来几年内，AI健康助手将媲美医生水平，加速老年科学研究。然而，当前数据集质量较差（尤其在干预和多组学纵向数据方面），限制了AI的潜力，“垃圾进，垃圾出”，呼吁长寿领域开发更高质量的数据集，以充分发挥AI作用。

关于蛋白质摄入，嘉宾建议适中至高蛋白（每磅体重0.6-1克/天），但需搭配优质饮食（减少简单糖、加工食品和酒精）。高蛋白饮食结合抗阻训练可改善肌肉量、骨密度和代谢健康，降低脆弱性和骨折风险。尽管高蛋白可能略增癌症风险，优质饮食和运动可显著抵消此风险。低蛋白饮食（尤其55岁以上）可能增加脆弱性，不利长寿。

握力与健康寿命的关联，认为其反映整体肌肉功能和质量，而非握力本身特别重要。低握力通常提示久坐生活方式和全身肌肉量不足，预示未来功能下降（如穿衣、如厕困难）。健康人群若肌肉和力量充足，握力通常高于平均水平，无需专门训练。

关于女性生育力和抗缪勒氏管激素（AMH），他坦言非女性生殖健康专家，但强调生活方式对生殖健康的积极影响与对其他衰老相关功能下降的益处一致。遗传和特定风险因素需进一步考虑。近年卵巢衰老研究增加，作为衰老早期指标和女性特有疾病风险的潜在原因，受到更多关注。

讨论晚育与长寿的关系，晚育女性长寿可能因卵巢衰老延迟，全身衰老也相应减缓。妊娠期间DNA甲基化模式变化显示生物年龄暂时增加，但产后多回落，甚至低于基线，提示妊娠可能重置某些衰老标志物。多次生育与略长寿命相关，可能因生物、社会（如子女陪伴）或延迟衰老的综合效应。

最后，关于给狗使用雷帕霉素，非兽医，仅提供假设性建议。Dog Aging Project研究针对7岁以上、40磅以上的狗，因大型犬衰老更快。雷帕霉素在小鼠中（相当于人类55-65岁）延长寿命并改善健康指标。鉴于幼犬（1.5岁、10磅）寿命较长（15-17年），及长期用药风险，建议推迟使用，以平衡风险与回报。提到抗恶心药物美克洛嗪（meclizine）在ITP中显示潜在抗衰老效应，可能通过mTOR抑制发挥作用，值得进一步研究。

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Edit:2025.04.21

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