Reversing Biological Age: Have we finally found the answer?? | 30 - LTW #5
Summary
TLDRهذا 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
🚀 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。
🌟 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。
📉 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。
🧬 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。
🔬 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。
🤔 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。
Mindmap
Keywords
💡E5
💡الاكسosomes
💡العمر الحيوي
💡التحول البيئي
💡التأثيرات ال正面 والسلبية
💡العمر الأقصى
💡الحد الأدنى للعمر
💡الحد الأقصى للعمر
💡الحد المتوسط للعمر
💡ال膳食 المحدودة
💡البيانات الغير منشورة
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
please feel free to leave them below if
you're not yet a subscriber please hit
the Subscribe button and I hope to see
you all next time on the optisan podcast
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