Reversing Biological Age: Have we finally found the answer?? | 30 - LTW #5

Summary

هذا النص يحتوي على ملخص لسلسلة من الأحداث والاستنتاجات المتعلقة بدراسة E5، المدعومة كمستحضر لعكس الشيخوخة. يناقش المتحدث في النص تأثير E5 على عمر الجرذ والتأثير على بعض المؤشرات البيولوجية للشيخوخة. يشير إلى أنه قد ينمو عمر الجرذ بفضل E5، ولكن البيانات ليست كافية لتأكيد حجم التأثير. يشدد على أنه لا توجد دلائل قوية حتى الآن تثبت عكس الشيخوخة البيولوجية بشكل كامل. يناقش أيضًا مدى واقعية وETHICALness لاستخدام E5 على نطاق أوسع إذا كان التأثير حقيقي، مشيرًا إلى الضرورة لالمزيد من الشفافية ونشر الأبحاث في الصحف العلمية بدلاً من النشر على الإنترنت.

Takeaways

• 🧬 E5是从年轻小猪血液中提取的外泌体（exosome）的一部分，这些外泌体是细胞释放的膜结构，携带多种细胞成分。
• 📉 E5在实验中显示出对某些生物衰老指标有积极影响，包括炎症标志物、DNA甲基化模式和认知功能。
• 🚀 E5治疗的实验规模较小，且实验方法可能未达到科学界所期望的标准。
• 🐀 有一只名为SEMA的大鼠在接受E5治疗后，据称寿命最长，但该数据未经过同行评审，并且SEMA可能是一个统计上的异常值。
• 🌐 E5的研究结果和方法在YouTube和博客上发布，这在科学界并不被认为是严肃的科学交流方式。
• 📚 尽管E5可能对寿命有积极影响，但目前的证据不足以支持其能够逆转生物衰老。
• 🆚 与历史上的其他延长寿命的实验相比，如60%的热量限制，E5的效果并不突出。
• 🤔 E5治疗的实用性和伦理性尚未明确，因为它需要大量的动物血液来治疗相对较小的生物。
• ⏱️ E5的研究历史和方法论在科学文献中的发表不够透明，这阻碍了科学界对其进行评估和复制。
• 🔬 尽管E5可能对健康有益，但目前的研究结果不足以证明其可以作为一种可行的治疗策略。
• ❗️ 需要更多的高质量数据和更透明的研究方法，以便科学界可以准确评估E5的效果和潜力。

Q & A

E5是什么，它是如何被提出的？

E5是从年轻小猪血液中提取的外泌体（exosome）的一部分。外泌体是细胞释放的膜结构囊泡，携带有多种细胞成分，如小RNA、蛋白质、代谢物，甚至DNA。E5的概念源于异时共生（heterochronic parabiosis）的研究，这是一种将不同年龄的动物通过手术连接其循环系统的方法，用以研究循环因子如何影响老化。

异时共生（heterochronic parabiosis）是什么，它如何与E5相关？

异时共生是一种实验方法，通过手术将不同年龄的动物的循环系统连接起来，观察年轻动物的血液对老年动物健康和寿命的影响。E5的研究受到了这种方法的启发，因为它试图从年轻动物血液中提取可能有益的因子，以改善老年动物的健康状况。

E5在实验中对生物老化有哪些影响？

根据实验报告，E5对某些生物老化的指标有积极影响，包括减少炎症标志物、改善肌肉功能、改变DNA甲基化模式（表观遗传时钟），以及改善认知功能等。然而，这些结果并没有证明E5可以完全逆转生物老化。

实验中提到的SEMA大鼠是什么，它与E5有何关联？

SEMA是一只被声称在接受E5治疗后寿命显著延长的大鼠，据称是迄今为止活得最久的大鼠。然而，视频中提到SEMA可能是一个统计上的异常值，并且没有足够的数据来支持这一说法，因此其寿命延长的效果还需要进一步的科学验证。

E5的研究结果是否经过了同行评审和科学界的评估？

E5的研究结果已经在《老年科学杂志》（Journal of Geroscience）上发表，意味着它经过了同行评审。但是，由于实验方法的透明度不高，以及实验数据的发布方式（如通过YouTube等非传统科学渠道），科学界对这些结果的评估受到了限制。

E5治疗的实用性如何，是否有足够的信息来复制这项研究？

E5治疗的实用性尚未明确。视频中提到，由于缺乏关于E5纯化过程的详细信息，独立研究小组难以复制这项研究。此外，实验中使用的样本量小，且实验方法可能未达到科学界通常的标准，这增加了评估其实用性的难度。

E5治疗对人类可能有哪些伦理和实践上的考虑？

E5治疗如果要应用于人类，将面临伦理和实践上的多重挑战。例如，从小猪中提取E5的过程可能需要牺牲大量的动物，这引发了伦理问题。此外，治疗的规模化和可行性也是一个问题，因为目前还不清楚实现这一过程所需的资源和成本。

E5治疗的效果与其他已知的延长寿命的干预措施相比如何？

E5治疗的效果与其他已知的延长寿命的干预措施相比，如节食限制，似乎较小。尽管E5在一些老化指标上显示出积极效果，但它并没有显示出能够像节食限制那样显著延长动物的中位和最大寿命。

E5治疗的长期效果和安全性如何，是否进行了足够的研究？

E5治疗的长期效果和安全性尚未充分研究。视频中提到，目前的研究主要集中在短期内对生物老化指标的影响，而对长期健康影响和潜在副作用的了解仍然有限。

E5治疗是否能够逆转生物老化，还是仅仅改善了一些老化相关的标志物？

根据视频内容，E5治疗虽然改善了一些老化相关的标志物，但并没有足够的证据表明它可以逆转生物老化。视频中强调，改善一些老化相关的标志物并不等同于逆转生物老化。

E5治疗的研究结果是否已经在科学界得到了广泛的接受和认可？

E5治疗的研究结果尚未在科学界得到广泛的接受和认可。部分原因是由于研究的透明度不高，以及实验结果的发布方式不符合科学研究的传统标准。此外，实验的样本量小，且缺乏独立重复实验的验证。

Outlines

00:00

🚀 E5注射剂与逆转生物年龄的探索

Matt在Optisan频道上讨论了一种名为E5的注射剂，该注射剂据称能够逆转生物年龄。E5源自年轻猪血的外泌体，外泌体是细胞释放的膜结构，携带多种细胞成分。研究报道，将这些外泌体注射到大鼠体内，可以在一定程度上影响生物衰老的某些指标，甚至可能影响寿命。Matt对E5的效果持怀疑态度，认为目前没有证据表明E5或任何其他方法能够逆转衰老。他还提到了与E5研究相关的科学家Dr. Catcher，并邀请他就E5进行讨论。

05:03

🌟 异时共生法与E5的科学背景

异时共生法是一种将不同年龄动物的循环系统相连的手术方法，该方法表明年轻动物的循环因素能够对老年动物产生积极的健康效益。E5的研究背景部分源自这种方法。历史上，通过将年轻动物的血浆注入老年动物，观察到包括神经生成、肌肉功能、心脏功能和组织再生在内的多种健康效益。然而，也发现了年轻动物的负面效应，如神经生成和肌肉功能的减少。目前，科学界仍在努力寻找导致这些效应的具体循环因子。

10:04

📉 E5对大鼠寿命影响的数据审视

Matt审视了E5对大鼠寿命影响的数据，指出了其中存在的问题和局限性。他提到了一只名为SEMA的大鼠，据称是经过E5处理后活得最久的大鼠。然而，SEMA的寿命数据在统计上是一个异常值，这引发了对数据可靠性的疑问。Matt还比较了E5处理的大鼠与1970年代异时共生法实验中大鼠的寿命，指出E5的效果并不像一些人声称的那样显著。

15:06

🧬 E5的科学评估与未来方向

Matt讨论了E5的科学评估问题，强调了在科学界评估新发现时透明度和同行评审的重要性。他批评了E5研究中缺乏透明度和科学严谨性，特别是对于未经同行评审的YouTube发布的内容持怀疑态度。Matt认为，为了推动研究进展，需要更多的高质量数据和科学研究方法。他还提出了关于E5实用性的问题，包括如何从猪血中提取足够的E5以及这种方法的伦理和可行性。

20:08

🔬 E5对生物年龄逆转的证据评估

Matt评估了E5对生物年龄逆转的证据，指出尽管E5可能对大鼠的寿命有积极影响，但目前的证据并不足以证明生物年龄的逆转。他讨论了E5在减少某些与年龄相关的生物标志物方面的潜力，但同时强调这并不等同于逆转生物衰老。Matt还比较了E5的效果与其他已知的抗衰老干预措施，如热量限制和雷帕霉素（Rapamycin），并指出E5的效果并不如这些措施显著。

25:10

🤔 E5的实用性和伦理考量

Matt对E5的实用性和伦理问题进行了深入探讨。他提出了关于E5生产过程的问题，包括从猪血中提取E5的效率和所需的猪的数量。他还质疑了每年对人类进行E5治疗的可行性和伦理性，指出如果要在全球范围内实施这种治疗，可能需要牺牲大量的猪只。Matt强调了进一步研究以确定E5中起作用的具体因子的重要性，并认为这可能是开发更具体治疗方法的途径。

Keywords

💡E5

E5 هو جزء محدد من الاكسوسومات المشتقة من دم البطات ال年少، والتي يُعدها مرشحاً لتأثيرها في تحسين بعض المؤشرات المتعلقة بالعمر الحيوي وممكنة التأثير على عمر الحياة. في الفيديو، يُشير إلى أنه يُعتقد أنه يمكن أن يكون له تأثير إيجابي على عمر الحياة، ولكن لا يُعد الدليل قاطعًا بشأن التأثير الكامل على العمر الحيوي.

💡الاكسosomes

الاكسوسومات هي جذعية خارجية خلية تُطلق من الخلايا وتحمل محتويات متنوعة مثل RNA صغير والبروتينات ومواد متabolites، وبعض الأوقات حتى DNA. يُشير في الفيديو إلى أن E5 هو عبارة عن جزء محدد من هذه الاكسosomes.

💡العمر الحيوي

العمر الحيوي يشير إلى المدة الزمنية التي يعيش فيها الكائن حيوي، ولكن أيضًا إلى ال Slate الوظيفية وال_STRUCTURAL للخلية أو العضو. في الفيديو، يُناقش التأثير المحتمل لـ E5 على تحسين بعض المؤشرات المتعلقة بالعمر الحيوي.

💡التحول البيئي

التحول البيئي هو عملية تغير الكائنات المعيشية من نمط حياة إلى آخر، وهو يُشار إليه في الفيديو كتأثير ملحوظ يحدث عند الحيوانات الأكبر التي تشارك نظمها الدامية مع الحيوانات ال年少.

💡التأثيرات ال正面 والسلبية

في الفيديو، يُشير إلى أن التحول البيئي قد يسبب تأثيرات正面 مثل تحسين işaretler الخلايا في الحيوان الأكبر، وكذلك تأثيرات سلبية على الحيوان ال年少 مثل تقليل işaretler الخلايا.

💡العمر الأقصى

العمر الأقصى هو أكبر عمر يعيش فيه الكائن حيوي في المجموعة. يُشير في الفيديو إلى أن التجارب قد أظهرت زيادة في عمر الحيوان الأكبر بعد التحول البيئي، ولكن يُشير إلى أنه لا يُعد الدليل قاطعًا بشأن تأثير هذا على عمر الحياة في سياق الAGING الطبيعي.

💡الحد الأدنى للعمر

الحد الأدنى للعمر هو عمر أقل يعيش فيه الكائن حيوي في المجموعة. يُستخدم في الفيديو لمقارنة بين تأثيرات E5 وتأثيرات أخرى على عمر الحياة، مع التركيز على المتوسط والحد الأقصى للعمر.

💡الحد الأقصى للعمر

الحد الأقصى للعمر هو أكبر عمر يسجله أي عضو من فصيلة معينة. يُشير في الفيديو إلى أنه يُعد مقياساً لمدى تأثير التدخلات الطبية أو البيولوجية على عمر الحياة.

💡الحد المتوسط للعمر

الحد المتوسط للعمر هو متوسط عمر الحياة لمجموعة معينة من الكائنات الحية. يُستخدم في الفيديو لتوضيح تأثير E5 على عمر الحياة ومقارنة هذا التأثير ب其他的 تداخلات.

💡ال膳食 المحدودة

ال膳食 المحدودة هو تداخل يؤثر على عمر الحياة من خلال تقليل كمية الغذائية الم供ة للكائن الحيوي. يُشير في الفيديو إلى أنه يُعد أحد التأثيرات الأكبر على عمر الحياة، ويُقارن مع تأثير E5.

💡البيانات الغير منشورة

البيانات الغير منشورة تشير إلى المعلومات العلمية التي لم تُنشر بعد في منصات علمية رسمية. يُشير في الفيديو إلى وجود بيانات حول تأثير E5 على عمر الحياة التي لم تُنشر، مما يثير استفسارات حول جودتها العلمية.

Highlights

A study published in the Journal of Geroscience suggests that a young porcine plasma fraction, known as E5, may reverse biological age in multiple rat organs.

The E5 formulation, derived from the blood of young piglets, is claimed to extend the lifespan of rats, with one rat named SEMA reportedly living up to 1460 days.

Dr. Catcher, associated with the E5 research, argues that the formulation reverses biological age, a claim that has been met with skepticism by some in the scientific community.

The concept of heterochronic parabiosis, where the circulatory systems of animals of different ages are connected, influenced the development of E5.

Exosomes, extracellular vesicles that carry various cellular components, are a key component of E5, which is the exosome fraction of young piglet blood.

The study's author, Dr. Catcher, has been invited to the Optisan podcast to discuss the E5 formulation and its potential effects on aging.

Improvements in health or age-related phenotypes are not necessarily equivalent to reversing aging, according to the podcast host, Matt Cauble.

The longest-lived rat, SEMA, treated with E5, is considered an outlier in the study, raising questions about the statistical significance of the findings.

The E5 study's results have not been replicated independently, which is a critical step in the scientific process to validate findings.

The potential application of E5 in humans raises ethical and practical concerns, including the number of piglets required per treatment course.

Caloric restriction has been shown to have a more significant effect on lifespan extension in rodents compared to the reported effects of E5.

The paper on E5 includes the creation of epigenetic clocks in rats, aligning them with existing clocks in other species, which is mostly a methodological tool.

The E5 treatment's effect on a subset of healthspan metrics in rats is intriguing but does not demonstrate a reversal of biological age.

The study's small cohort sizes and lack of transparency in methodology make it difficult to assess the true impact and reproducibility of E5.

Matt Cauble suggests that the field of aging research may have stagnated due to a lack of new, effective interventions compared to classic experiments like caloric restriction.

The podcast emphasizes the need for more transparency in scientific findings and a focus on publishing in peer-reviewed journals rather than on the internet.

Transcripts

reversal of biological age in multiple

rat organs by Young porine plasma

fraction published in the Journal of

geroscience this miracle formula for

quote unquote reversing aging all of the

other rats die between 1150 and 1250

days or close to 1250 days and then

there's this one rat that lives looks

like 1460 days and that's SEMA this rat

had been given E5 and has been claimed

to be supposedly the longest lived rat

ever if you ask me is this interesting

I'd say hell yes this is really really

really interesting but my name is Matt

cabine and welcome to the optisan

YouTube

channel all right hey everyone welcome

to the optis span podcast so on today's

episode we're going to do a bit of a

deep dive into sort of a wild and wacky

story about anti-aging MO ules from Pig

blood and several of you have asked

about this E5

formulation um which really derives from

the work of Harold catcher and

colleagues um Dr Catcher also reached

out to me directly he was a bit

frustrated at my comments around um not

believing that uh people should be using

the phrase reversing uh aging which I

still stand strongly by um I've invited

Dr Catcher to come on the podcast at his

convenience the the invitation is open

and and if after this episode Dr Catcher

would like to come on the podcast I

would love to have a conversation um

with him so Dr catcho feel strongly that

the E5 formulation which I'll get into

in a minute reverses biological age I've

told him that I don't believe they or

anyone else has demonstrated age

reversal and in particular I would argue

strongly that improving health or a

subset of age related phenotypes is not

equivalent to reversing aging

um we've agreed to disagree which is

absolutely okay in science and um in our

last correspondence Dr Catcher left with

the uh phrase time will tell and it will

um okay so today I'm going to do like I

said a pretty deep dive into E5 discuss

how it fits into the overall picture of

the longevity field and I'll talk in

some detail about a paper from Dr

Catcher and colleagues titled reversal

of biological age in multiple rat organs

by Young porene plasma fraction um so

let's start with E5 so for a long time

we didn't really know what E5 was it was

sort of presented as this mysterious

Elixir that um Dr Catcher was working on

from pigs um that could have potentially

some rejuvenating properties uh again

kind of a different approach here it

wasn't really published in the

scientific literature it was a company

working on this kind of in stealth but

putting stuff out on YouTube or on blogs

um that couldn't really be evaluated by

the scientific community so it had this

sort of mysterious feature to it um now

we know based on this publication that

E5 is in fact the exosome fraction of

blood from Young piglets so exosomes are

um extracellular vesicles all that

really means is these are surrounded by

a membrane

uh that are given off by cells and they

carry cargos and those cargos inside

this membrane bound molecule can include

pretty much everything that you would

find in the cell but in particular uh

small rnas often what are called

non-coating rnas they can have other

functions proteins metabolites even

sometimes DNA so really anything that

you find in a Cell can be found in these

extracellular vesicles um and there as I

said they're shed by our cells

continuously they make it into

circulation so E5 is a specific fraction

of these exosomes from piglet blood and

what uh has been shown or at least

reported is that if you take this

purified fraction of exosomes from from

the blood of young pigs and you inject

that into rats and you do it in the

right way you can have some effects on

certain measures of biological aging and

we'll talk more about that and

potentially life span as well so we'll

get into the actual data in a minute but

I think it's important to first give a

little bit of background on even where

this idea comes from like who in their

right mind would think let's purify

exosomes from Pig blood and inject it

into other animals and see what happens

so this really is derived from a a long

history of research in a a methodology

called heterochronic

parabiosis um so if you kind of take

that word apart hetero means different

cron means time and parabiosis means

living beside so putting that all

together heterochronic parabiosis

different times living beside and what

this refers to is a

methodology um that was developed I

believe First in rats where you

create uh animals that have a shared

circulatory system using surgical method

so basically you using surgery connect

the circulatory systems of two different

animals and they're still different

animals they're just kind of tied

together sewed together in a way that

they share their circulatory systems um

that's parabiosis the heterochronic part

refers to when you do this and the

animals are of different ages so

different time in general we're talking

about an old animal biologically

chronologically old animal and a young

animal as the two parab that share a

circulatory system um there's actually a

really good review on the history of

heterochronic parabiosis it was written

now about 10 years ago by uh Michael uh

and Arena Convoy uh very well-known

researchers in this area who've done a

lot of important work as well as Tom

Rando who is also very well-known

researcher one of my favorite scientists

in the field I have a huge amount of

respect um for all of these authors but

particularly Tom uh just as a very very

solid uh scientist who's done a lot of

great work so anyways the boy and Tom

Rando wrote this review titled

heterochronic parabiosis historical

perspective and methodological

considerations for studies of aging and

Longevity and I'd refer people to that

review because it really takes you

through a lot of the history of

heterochronic parabiosis um so interest

in this idea that circulating factors

might influence aging seems to have

started to get traction I guess in the

1950s or so when studies showed that

parab I is with healthy donors so not

necessarily old versus young but healthy

versus unhealthy healthy donors could

predict Mice from certain types of

insults or disease models so for example

um there was some data showing that when

you did this parabiosis model where you

have a normal mouse and a muscular

distrophy Mouse model you could

alleviate some of the symptoms of

muscular distrophy suggesting there were

factors in circulation that could have a

positive health benefit in that context

likewise experiments were done with the

radiation showing that uh circulatory

factors from a

non-irradiated parab could have

beneficial effects on the irradiated

parab um and so that sort of set the

stage for this idea of heterochronic

parabiosis which again is the same type

of experiment except you're looking at a

young parab and an old parab surgically

connected together and that was actually

first reported to increase lifespan uh

in the late 1950s or early 1960s that

that if you did that in the older parab

you actually saw increase in lifespan um

compared to an experiment where you had

two old parab for example since then uh

and really I think this was probably in

the early 2000s when a lot of this work

was done we now know that this

heterochronic parabiosis model or even

things like plasma exchange where you

take plasma from a young animal put it

into an old animal can have a bunch of

Health span benefits as well so for

example you can see in the old parab

improvements in neurogenesis

improvements in muscle function

improvements in heart function olfactory

perception tissue regeneration so really

a wide range of potential health

benefits across different organs and

tissues I think the thinking is that

this is at least largely mediated

through um restoration of stem cell

function although probably not

exclusively mediated through stem cells

I think the other interesting piece here

though is that in addition to increasing

lifespan of the older parab and

improving at least a subset of

healthspan metrics you see corresponding

negative effects in the young parab so

things like decreased neurogenesis

decreased muscle function decreased

tissue regeneration so taken together

that really supports the idea that there

are both positive factors potentially in

the Young parab that are having an

impact on the old parab as well as

negative factors in the old parab that

are having a detrimental effect on the

Young parab and there's been a whole

bunch of work multiple different Labs

trying to find what are these factors

and I think that's still is an area of

active research the real answer is we

don't completely know what the molecules

are that are in circulation that are

having these positive and and negative

effects that are seen in the

heterochronic parabiosis experiments

okay so I mentioned

lifespan and this I think was first

convincingly shown by lwig and elashoff

in 1972 and it's worth taking a look at

the data you know I always recommend

going back and actually looking at the

primary data um whenever possible and so

in this case it's worth looking at the

absolute numbers in these experiments as

well as the effects of the parabiosis so

in this particular experiment they

looked at both males and females they

had uh single animals not connected

surgically to share circulatory system

so those are the negative controls in a

sense uh they had control parab so this

is another control group where they were

what they called homo chronic right

meaning they were the same age um and

then they had the heterochronic parab

and the interesting comparison here

there's really two things to take away

from this one is if you look at the life

uh expectancy the average lifespan and

you look at just the effect of this

surgery right the connecting of the the

circulatory systems that has a negative

effect on lifespan so the control parab

compared to the singlet controls are

shorter lived that's not shocking but

it's important to know because you can

really only interpret the heterochronic

parab effect if you know that the

surgery itself has a negative effect on

lifespan and it does so then what

happens if you look at the heterochronic

parab and look at the older parab in

particular and compare them to the

control parab you can see there's a

significant increase in lifespan um

suggesting that there is a lifespan

benefit from heterochronic parabiosis

now it is worth noting in the males at

least the heterochronic parab aren't

really longer lived than the singlet

controls and the reason I point this out

is it's just useful to recognize we've

done something artificial to shorten the

lifespan of the animals that's this

surgery and when you see that you are in

increasing the lifespan of those animals

um you can't really tell the difference

between whether this is having an effect

on lifespan per se in the context of

normal aging or if you're just

suppressing whatever the negative effect

of the experimental procedure is in this

case the surgical procedure that's hard

to know and so it's just worth noting

that um you can't really resolve that in

this case now what we can see is that in

the female animals the heterochronic

parabs even outlive the singlet control

so that adds support to the idea that

the heterochronic parabiosis itself is

doing something fundamental to longevity

even in the context of a normally aging

animal and it's not just suppressing the

detrimental effects of the surgical

procedure so this I think was really the

first convincing evidence that lifespan

could be extended by heterochronic

parabiosis the other thing I want to

note about this survival experiment is

the maximum lifespan and I'm just going

to point out that in this particular

study they had about 30 animals per

group the longest lived animals made it

out close to 1300 days so between 1,50

and 1300 days the reason why I'm

specifically mentioning numbers here is

I'm going to come back throughout the

rest of this video and talk about

absolute lifespan effects because this

is really important when you want to try

to understand how does a particular

intervention in this case E5 stack up

against what's in the literature so just

remember that number maximum life Span

in the ballpark of in this particular

experiment 1,50 to 1300 days okay now

let's talk a little bit about how we get

to to E5 so if I look at the literature

at least I can see that Harold catcher

really started getting interested in

this space in 2013 when he wrote a

review titled studies that shed new

light on Aging this was published in the

Russian Journal biochemistry and so in

this review article he dismisses the the

quote unquote wear and tear model of

Aging the idea that biological aging is

really driven by accumulated damage wear

and tear that is the result of probably

a bunch of stuff but you know at least

largely internal metabolic reactions uh

Associated sort of with the rate of

living Theory also environmental factors

that cause damage to accumulate and

instead he favors the idea that it's

really extrinsic circulating factors

that regulate aging and points to the

body of literature that I just alluded

to as well as others that there are

factors in circulation that can

rejuvenate at least stem cells um and

again that view is largely inspired by

the heterochronic parabiosis literature

um also by studies which I haven't gone

into that had been published at the time

on heterochronic plasma exchange so

heterochronic plasma exchange

conceptually is pretty similar to

heterochronic parabiosis it just does

doesn't require surgical connection of

the circulatory system it involves

taking plasma from Young animals and

exchanging that in Old animals so

removing some of the old plasma putting

in young plasma conceptually though I

think they're they're it's pretty

reasonable to think that you're doing

essentially the same thing in those two

paradigms um and so at this time in 2013

Dr Catcher proposed that effort should

be made to identify the factors in young

plasma that have rejuvenating potential

and he's absolutely right and in fact at

that time people were doing that I mean

the the work of Amy Wagers and Tom Rando

and the conboys and others you know had

really gone down that path of trying to

figure out what are the key factors that

were mediating these potential

rejuvenating effects I think the thing

that resonated with me the most about um

this review article or perspective

article from Dr Catcher was when he said

that really we don't need to wait

necessarily to figure out what those

factors are and understand the mechanis

Ms in order to have a therapeutic effect

so in other words if heterochronic

plasma exchange is sufficient to

rejuvenate stem cells functional

measures in Old animals and perhaps

people we don't really have to

understand the mechanisms to actually

have an impact therapeutically and I

agree 100% I think it is often the case

especially in academic circles that we

get so in the Weeds about trying to

figure out the mechanisms that we lose

sight of the very pragmatic aspects of

potentially having an impact even before

we NE necessarily completely understand

the mechanisms so I agree completely

with um Dr Catcher on on that on both of

those points um the area where I

disagree a little bit is I don't think

it's as black and white this idea that

you know that the wear and tear model of

Aging is mutually exclusive with the

idea that there are circulating

extrinsic factors that can also have an

effect on Aging um and and I think in

fact you know this is this is perhaps a

semantic argument but you know it it

seems kind of self-evident to me that

aging is in fact driven at least to some

extent by damage um that's almost

definition right that that the

functional declines and things that go

along with aging are caused by different

types of damage I think we can debate

what the types of damage are how they

derive how important different types of

damage protein misfolding oxidative

stress you know other all the different

types of damage that you can see even in

the Hallmark of Aging we can talk about

the relative importance of each of those

but clearly biological aging is caused

to some extent by damage and that's not

mutually exclusive with the idea that

there are circulating factors that can

rejuvenate regenerate function in cells

at least in part by repairing or

degrading the damage so I didn't quite

understand why it felt like it needed to

be such a black and white argument I

don't think it does I think both of

those things can be true and almost

certainly are at least partially correct

in terms of our understanding of

biological aging today um so I don't I

don't really get the argument there okay

so that was one place where I had a

little bit of a a disagreement I think

the other place where I I disagree with

Dr catcher's um interpretation then and

now probably is I'm not really convinced

that the assumption that heterochronic

par biosis circulating factors and as

we'll discuss um in a minute

E5 are able to fully

rejuvenate cells tissues organs and I

would I would go as as far as to say

even the you know current um excitement

about around epigenetic reprogramming

again I haven't seen any data that makes

me really believe that at the tissue

organ whole animal level you can fully

rejuvenate or restore function so I

think that remains to be proven I'm not

saying that it's not possible I'm not

saying that doesn't happen in a subset

of cells but whether or not you can do

that in the context of a more complex

tissue organ whole animal system I think

remains to be determined so I think

that's an assumption where there's

really not much data to support that at

at this point and again it was an

assumption that was sort of made in that

article and I think this is an

assumption that the people who want to

argue that that they are reversing aging

are making even if they don't realize it

and that really I think is where the

disagreement lies um okay so let's move

on to E5 and talk about what we know or

at least what I could find in the

literature and and in other um sources

on YouTube and blogs and things like

that so again I think for the past

several years E5 has been sort of touted

in at least some circles as this miracle

formula for

quote unquote reversing aging um but as

I mentioned until recently we didn't

really know what it was and that sort of

contributed to the mystery around it and

in fact it seems like this was sort of

an intentional effort to kind of create

this mystery sort of feeling I'm sure

there were there were efforts here

around protecting intellectual property

and generating media attention but I

mean the reality is in the scientific

Community the way that the scientific

Community is able to evaluate these

things is when they're published in the

literature and the whole point of

publication is to assess whether or not

their results can withstand peer review

and replication and so unfortunately we

haven't had an opportunity to really

look at much of many of the claims

around E5 in that context to the best of

my knowledge the first paper describing

E5 in any type of detail at all is the

one that that I alluded to earlier and

that we'll we'll do a little bit of a

deeper dive on so there's one

publication it is peerreview it was

published in the journal geroscience but

as far as I know there have been no

efforts to replicate this um

independently so that's kind of where

we're at um there were also a whole

bunch of claims made around lifespan

extension from E5 which I'll um take a

look at as well there I don't think we

have any published data um there's a lot

that's been made of a rat named SEMA uh

this rat had been G given E5 and has

been claimed to be supposedly the

longest lived rat ever um I think any of

you who watch this podcast regularly can

probably guess my opinion of doing

science this way so it certainly is not

in keeping with what the expectations

are for doing rigorous science and I

think in many ways it's actually been

counterproductive to moving this

research forward the progress here has

been very very slow and I think it's

been slowed in part because of the lack

of transparency around what actually

been done what are the data what do the

quality of the experiments look like and

the scientific Community can't evaluate

it so a lot of people just don't pay any

attention and and I can't really blame

them for that um so again I want to be

clear I'm not questioning Dr catchers or

his colleagues honesty or Integrity

personally um but I think we have to

recognize this field is full of the

history of questionable science Fringe

sort of communities uh snake oil and

people doing weird stuff and so there's

going to be a lot of skepticism about

results that are presented in a

nonserious manner and I'm sorry but

YouTube is not the place to first

present your data to the scientific

Community if your goal is to be taken

seriously and specifically with respect

to the lifespan data on the rats treated

with E5 and SEMA as far as I know as I

said I don't think that data has been

published yet so we're sort of working

in the dark

um but I think let's just assume for a

minute that the data that's been put out

into the public domain um is correct and

let's let's give the benefit of the

doubt let's just assume that the data is

correct the experiments were done well

and see how that Stacks up just to sort

of you know just to set a framework as

we try to evaluate how E5 fits into the

larger context of the field okay so what

do we know about these rats treated with

E5 so the only data I could find comes

from the blog of Josh

middledorf um and it's my understanding

that Dr Catcher shared this data with Dr

middledorf so uh this is the plot from

Dr middledorf blog where it's showing

the survival of eight rats that were

treated with

E5 uh and it's not plotted the way that

probably most of you are used to seeing

this kind of data this is showing

mortality uh uh for each animal but we

can can see the eight points we can see

what their reported lifespan was and we

can convert this to sort of the the kind

of plots that we're looking to which

I'll do in a minute I think one thing

that's immediately obvious though for

even from this plot is that there's one

rat that appears to be an outlier and

that's the longest lived rat so you can

see all of the other rats die between

1150 and 1250 days or close to 1,50 days

um and then there's this one rat that

lives looks like 1460 days or something

like that and that's SEMA so this is

always a little bit of a red flag right

there is something called

outlier phenomenon and there is a

statistical test you can do to determine

if there if when you have a data set if

the data point that looks to be abnormal

is in fact statistically an outlier and

it turns out if you apply that to this

data set it is indeed the fact that SEMA

is a statistical outlier and so what

that means is that typically if you

wanted to do a statistical comparison

between say this group and a different

group you would leave the outlier data

point out so that's just worth knowing I

think again we will we will give the

best possible interpretation here and

keep SEMA in the data set but it is

worth noting that SEMA is abnormal and

all of the other rats all had this uh uh

survival uh values that that were much

shorter than that in the 1150 to 1250

again I want you to now think back to

what I talked about before about the

maximum lifespan of the rats in the

heterochronic parabiosis experiment

right in that same ballpark so the idea

that this is

dramatically better than the experiment

that was done using heterochronic

parabiosis in the 1970s these data don't

really seem to support that um so that's

just worth noting okay so SEMA is a

statistical outlier what is SEMA the

longest lived sprag Dolly rat ever I I

don't know I mean that's that's really

hard to evaluate that's what has been

claim been claimed I have no idea if

that's true the Guinness Book of World

Records disagrees for what that's worth

um but I think we can again start to ask

how impressive is this effect um there

are some complications here so you know

I suggested that it that if we take SEMA

out it doesn't look like it's a huge

difference between the heterochronic

heterochronic parabiosis experiment what

we don't know is you know was there a

control group um if there was were the

animals randomized was there any

censoring and in particular when was the

treatment started this is really

important because if all a if the

treatment was started at young age and

eight out of eight animals lived to be

over 1150 days old that's pretty

compelling to me that looks like a

pretty interesting result if the

treatment was started at a thousand days

that's less compelling because any

animals that died before the treatment

was started or before the treatment

ended were sens out of the data so we

don't know the answer to that it would

be interesting to know because that

helps sort of place this in the context

of the larger

literature um okay so regardless let's

again take the most charitable view

possible and see how this Stacks up to

other impressive interventions in the

literature now that's challenging to do

because there hasn't been a lot of work

done in rats at least in the last 30 40

years in the field so we don't have a

lot of contemporary data to compare to

um uh what we can do though is take a

look at you know one of the more

impressive Mouse experiments and say how

does this stack up the first thing we

want to do though is ask if we look at

sprag Dolly rats and we compare them to

you know the typically used Mouse

strains in longevity experiments today

c-57 black 6 um 3 what do the survival

curves look like comparing the sprag

dolly rats to to c-57 Black C for

example so we can find historical data

on sprag Dolly rats um you can see in

this figure here a representative curve

for both male and female sprag Dolly

rats uh as well as a different strain of

rat we can extract that data it turns

out it's about 29.5 months for median

lifespan for female sprig doly rats

which is pretty comparable to c-57 Black

6 or um 3 mice um right in the same

ballpark we can extract that data and we

can just ask a very simple question if

we now compare the historical data for

sprag Dolly rats to the E5 treated rats

that um were plotted on Josh middledorf

blog we can see the effect looks pretty

impressive right so it looks like there

is a very strong rightward shift in the

survival data um obviously incomplete

curves here but it looks pretty

impressive now again we don't know when

the E5 treatment was started that could

obviously skew things out uh pretty late

but it looks like a reasonable lifespan

extension from the E5 treatment compared

to historical sprig Dolly controls again

we don't have the the Matched controls I

don't even know if there were matched

controls in this particular

experiment um of course we'll note that

the survival curve looks pretty strange

it's almost a straight line down except

for SEMA which is an outlier um that

could just be have to do with the fact

if the treatment was started late all of

the mortality is going to be compressed

into this very short window um but it

does not look like you would expect for

a typical kinetics for a survival curve

um and again we don't know when the

treatment was started how long it was

done did any animals die during the

treatment period Etc um okay so now

let's ask the question how does that

compare to a classic experiment using

arguably the gold standard intervention

for increasing lifespan in rodents

caloric restriction and so we can look

at a an experiment that was done by Roy

Walford and Rick windr uh published in

the Journal of nutrition in 1986 to my

mind this is a really useful goalpost

here because it is as far as I know the

largest lifespan extension in an

absolute sense and by absolute I mean

look at the absolute median and maximum

lifespan of the control and treatment

groups it's the largest effect that I'm

aware of in an absolute sense from a

non- gentic intervention now why is it

important to say that non- gentic

intervention anytime you make a genetic

intervention in the growth pathway so

growth hormone igf-1 even mtor during

development you stunt growth so you get

very small animals and I think we know

with some degree of certainty that that

the body size effect plays a role on

longevity so you might be able to do

better in an absolute sense than this

experiment if you you know really really

minimize growth hormone and igf-1

signaling during development but we

don't know how much of that life span

benefit comes from the fact that the

animals are very small body size versus

a

post-developmental intervention like

caloric restriction rap ay and E5 so I

think it's just important from an Apples

to Apples perspective to limit ourselves

to um non- gentic postdevelopmental

interventions okay so I like this

experiment for that reason and so this

again is a classic experiment uh wiri

and Walford looked at multiple levels of

restriction ranging from a very small

restriction in the like 10 to 15% range

all the way up to about a 60%

restriction in caloric intake

interestingly they saw the biggest

effect on lifespan in the group that was

most restricted and I don't think we

actually know the answer to this

question of you know in this context if

you could repeat this experiment today

could you get an even bigger effect if

you restricted further obviously making

sure that the mice weren't malnourished

or or didn't have any significant

deficiencies I don't think we know the

answer to that is 60% the maximum maybe

um but uh it's an interesting question

uh to to to wonder whether you they

could have pushed the lifespan effect

further um regardless we can now ask a

question which is if we look at their

control animals so it's worth saying

wrick and Walford in this experiment

were not working in either black 6 or

umet 3 they were working in a different

hybrid strain called C3 B10 rf0 that

those that that that that um name really

refers to the strains that were used to

create this hybrid strain the hybrid

strain is potentially important because

this is more akin to the um 3 Model

where you are using uh animals that are

more genetically homogeneous than than a

really inbread strain like c-57 black 6

this is a combination of more than one

genetic background that's what we mean

by hybrid so in any case C3 B10

rf0 um has a lifespan that's comparable

to c-57 black six and if we actually

look at the control lifespan so these

are the animals that were fed at libidum

allowed to eat as much as they wanted

you can see it's very very similar to

control sprag Dolly rats that I showed

you earlier so these curves are almost

right on top of each other and I think

that means it's reasonable to do the

comparison where now I'm going to

compare the effects of the 60% caloric

restriction to what uh Dr Catcher has

suggested were the lifespan of the rats

treated with E5 because the control

lifespans are comparable again it's not

perfect it's not Apples to Apples but

it's kind of the best we can do I think

it seems reasonable to make this

comparison and so when we can do that

what you can see immediately is that

even the best case interpretation with

this E5 experiment is it's nowhere near

as good as 60% caloric restriction in

terms of the absolute effect on median

and maximum lifespan that's important to

know and in fact I'll probably come back

to this in future episodes I would

suggest anytime you hear somebody

start talking in a very excited way

about the latest greatest longevity

intervention ask have you measured

lifespan and if the answer is yes

compare the lifespan effect to this

experiment um this is part of the reason

why I have suggested that the field has

stagnated in some ways in terms of

longevity intervention Discovery and

that'll be a theme that I that I come

back to but I think for the purposes of

today's episode it's just worth

appreciating even the very very best

case interpretation of the E5 data with

all of its

flaws it's nowhere near as effective as

this 40-year-old experiment from Rick

weinrick and Roy Walford so that doesn't

mean it's not animportant it doesn't

mean it's not interesting it doesn't

mean it's not a nice effect but it's not

as if aging has been reversed and we've

created the longest lived rodent ever

just not the case Okay so that's just

useful to put into context I believe

okay so what can we conclude from this

point like I do believe that E5 probably

increases lifespan in rats I also

believe that the quality of this data is

not up to the expected scientific

standards of the field and so it's

really hard to have confidence about how

big the effect is maybe it's as big as

it looks like from the data points that

we have maybe it's bigger if you did a

really well controlled study with 40

animals maybe you'd see an even larger

effect maybe it would be smaller I don't

know but I do believe it probably does

have an effect on lifespan that's

positive and indeed that's what we would

expect if you have purified some of the

factors that account for the lifespan

benefits from heterochronic parabiosis

which we've known about since the 60s

and 70s so it's just unclear how far the

how large the effect really is um okay

so that's the lifespan piece now let's

take a look at the recently published

paper which again did not have any

lifespan data in it and let's see what

they actually did so this is this paper

titled reversal of biological age in

multiple rat organs by Young porene

plasma fraction published in the Journal

of geroscience so first of all I have to

say this paper was very very difficult

to actually parse what was done there

are multiple group groups multiple

locations not always clear which animals

were used for which analyses um in fact

had to go to the supplemental table

where there's a kind of a complicated

figure that that attempts to show which

animals were used for which experiments

and what the sample sizes were so I

apologize if I don't get this completely

right again it was confusing and it took

a lot of time even just to to to really

try to figure out in my view what was

actually done so if we go to

supplemental figure one it's again

complicated diagram but the best I can

figure out is that there were a couple

of small E5 experiments done at Juan and

that's the company uh in India that Dr

Catcher founded another experiment was

done which I think was a plasma exchange

fraction it's not clear whether that's

the same as E5 or not but certainly

related that was only done in male rats

um that was done at L Plata University

in Argentina and again recall E5 is the

exosomal fraction from the plasma of

piglets so again unclear whether this

plasma exchange fraction is identical to

E5 or related in some way but um let's

just assume they're the same for the

purposes of of the rest of this

conversation okay so in uh experiment

number one this was done at Juan they

looked at inflammatory factors il6 tnf

Alpha and grip strength again very small

cohort sizes six control six treated

with E5 both males and females treatment

started at 20 6 months improvements seen

in the parameters that they were looking

at so couple of inflammatory markers and

uh grip strength assessment in the rats

uh experiment two looked at DNA

methylation um so this is the epigenetic

Aging uh signatures or the epigenetic

Aging clocks as people call them in

eight control nine treated animals I

don't didn't see that it specified the

sex again treatment started at 26 months

of old so that's another a related

endpoint that was studied here in this

study um glycan age was also assessed it

wasn't completely clear to me which

cohort these animals came from it was

one of those two E5 cohorts I believe

this is the imunoglobulin G glycome so

this is another thing like the

epigenetic signature that uh has been

shown to change with age in both mice

and people and so you can create

patterns that are associated with

chronological age um also interestingly

some pattern patterns like the

epigenetic marks that are associated

with different age related diseases and

so this is another potential modality

that can be used to

assess a subset of biological aging

again six treated six control males and

females each uh and then there were also

some young controls in this group um so

again for all of the endpoints that were

looked at there's evidence that the E5

improved things meaning it shifted it

partially back towards what we would

expect to see for younger rats okay uh

the llata experiment which was this

plasma exchange fraction had six control

young 30 weeks old six old controls and

six old plasma fraction treated the

outcomes here were a little bit more

comprehensive body weight one assessment

of cognition the Barnes maze some blood

parameters again a couple of

inflammatory markers il6 tnf Alpha um

some histopathology which is nice to see

changes in organ pathology um one sence

marker so sence Associated beta galac

toase this is really it's it's certainly

the classical marker for sence um I

think probably everybody in the sence

field would agree this is no longer a

gold standard marker or certainly not

the gold standard marker for sessen and

really nobody uses sa beta gal alone as

an assessment of syence I say all of

that just to point out that the

interpretation here is a little bit

challenging even seeing a reduction in

sa beta gal most people in the field

would

not make would not assume that's

equivalent to a re reduction in

senescent cell burden on its own um DNA

methylation epigenetics was looked at as

well in this cohort of animals okay so

the other piece I think that's important

to note about this paper is the vast

majority of the paper is really has

nothing to do with E5 or plasma exchange

it's really about creating these

epigenetic clocks in rats showing that

in fact you can do that that you can

actually align those to some extent with

the existing clocks in rodents or in

humans or other animals so most of this

paper is really a methodological tool

creation paper the vast majority of

animals were used for that part and the

actual experiments on E5 or the plasma

exchange fraction

really from a uh number of animals

perspective is a is a is a very small

piece of this paper so I get why they I

get why they packaged it that way but

again I think sometimes when you do this

you know the review sort of get

overwhelmed with evaluating the the

large part of the paper they don't spend

a lot of time evaluating the smaller

part of the paper I don't know if that

happened here but I do think it's fair

to say that the cohort side izes in the

treated groups here are atypically small

for the kinds of studies that we are

used to seeing in this field take that

for what it's worth so again I think it

is in it is intriguing and compelling

that they saw improvements in multiple

age related assessments so again we had

some inflammatory markers we had

epigenetic signatures associated with

age glycan biology signatures associated

with age one assessment of cognitive

function

um and a few other sort of blood-based

parameters I think the question then is

is that sufficient to demonstrate a

reversal of biological age and again my

strong opinion is no it's not uh again

there are many many interventions

including caloric restriction which I've

already talked about including Ramy that

have been shown to have much more potent

effects on a much more diverse number

of parameters associated with biological

aging um this is a intriguing I would

say study that is suggestive that E5

plasma exchange can have a positive

benefit on a subset of healthspan

metrics in rats and on at least two

molecular signatures that tell us

something about biological aging so the

epigenetic clock and the glycan biology

but this in my mind again comes nowhere

close to demonstrating a reversal of

biological age and in fact it's really

unclear to me if you look at just the

effect size of this intervention how

this Stacks up compared to something

like rap ayon for example it's pretty

clear to me it's not as effective as uh

what has been reported with caloric

restriction previously in the literature

so that's kind of my take on how I place

the current published data and the

unpublished uh data or the data that has

been published on YouTube

um with other interventions that we know

about in the field what they didn't show

in this study as I've already mentioned

was lifespan extension nor did they

really show any structural or functional

Improvement in diverse organs and

tissues which would be nice to see so uh

again I I I obviously have been somewhat

critical of the whole body of uh work

here and the way that it has been

presented to the scientific community at

least until recently um I do want to say

like if you ask me is this interesting

I'd say hell yes this is really really

really interesting but it's also not

something I'm going to get super excited

about until we see high quality data and

we have a feel for exactly how effective

this E5 treatment is especially compared

to other things that we know a lot about

in this field so yeah it's really

exciting and I I think there are real

opportunities here to identify in more

detail the factors that are mediating

these effects potentially to develop

therapeutic treatments even before we

know what those factors are but again

when people start talking about

reversing biological aging I'm going to

push back and say no improving a few age

related phenotypes or measures of health

is not reversing biological aging it

just isn't um or at least it it is not

proof that you have accomplished that

okay so I think one interesting question

here is is this pragmatic so you

know let's just say even if it's not

reversing biological aging that it could

have some health benefits in people is

the E5 Model A pragmatic approach I

honestly don't think we have enough

information from this paper to know

again the methods here in my view were

not up to the standards we would expect

of allowing an independent researcher to

attempt to reproduce the study there's

not enough information provided on how

the E5 was purified to allow an

independent group to at least easily

attempt to reproduce this study so we

don't really know some of the

information we would need to know to

really ask this question of could you

pragmatically do this in humans so we'll

make some assumptions so they did say

they get about 1.5 lers of blood from a

60 kilogram piglet okay so that's how

much blood you can get um they also said

that you get you need about or they used

in this study 1.43 G of precipitate

that's the E5 itself per 500 G rat and

that's given every other day for a total

of four injections so that's a treatment

period and that's done at Baseline and

then in at at 95 days at least in one of

the the studies okay so the precipitate

this is where we don't actually know

like how much blood do you need to

fractionate out the episomes to get 1 43

gram of precipitate no idea um so we

just have to guess we don't know what

the yield is and that's what I mean also

mean by I don't think an independent lab

could could reproduce this because

there's just not enough information

given on the protocol but let's be

generous and let's assume that one pig

is a sufficient for one course for one

rat again total guess 1.5 lers of blood

yields 1.43 grams of precipitate so

typical person has about 100x the blood

of a rat so that would mean that we

would assume the need to sacrifice 100

piglets per person per course of

treatment we don't know how many

treatments we would need but let's say

one treatment a year okay I guess then

the question is you know is that

practical I don't know is that ethical

that's an important question I mean yeah

I get it we sacrifice a lot of animals

for f food stock every every day right

so I think these are interesting

questions to think about though if we

try to scale this to a million 100

million a billion people um is that

pragmatic and I think you could

certainly make a case that you know a

lot of effort should be put into

figuring out what are the factors that

are really driving this effect so that

maybe more specific therapies can be

created maybe the factors themselves can

be directly synthesized things like that

I'm sure that I'm sure that that's what

Dr Catcher And The colleagues at juen

are doing there are other people working

on this but it is useful to again as we

start to think about this and try to put

it in perspective how close are we to

actually seeing this be a viable

therapeutic strategy it's useful to to

think about like what would it actually

mean to try to reduce this to uh

practice um and again I'll come back to

the idea that I think progress would

actually happen a lot quicker if there

was a bit more transparency and a bit

more um publication in the scientific

literature and a bit less publication on

the internet but that's just my opinion

so that is uh my take on the current

status of E5 where it sort of fits into

the larger body of literature in the

field especially around other

interventions that we're thinking about

I hope you all enjoyed this episode or

at least found it uh informative even if

you didn't like what I had to say uh I

want to mention that for the data

extraction that I used here I used a uh

piece of software called plot digitizer

very nice way to pull data from

graphical images um and get it into a

format so I could do those direct

comparisons between for example the

sprag dolly rats and the c-57 black 6

layering on top of that the caloric

restriction experiment so pretty cool

piece of software that I found at least

to be very useful for this episode and

I'm sure others um so as always uh if

you have any questions or comments

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you all next time on the optisan podcast