231 replies to this topic

[albedo]

Impressive study learned from Josh’s blog.

What do you think ? To me it looks pretty amazing if confirmed!

Reversing age: dual species measurement of epigenetic age with a single clock

https://doi.org/10.1...20.05.07.082917  

• dual species, rats and humans, widely different in lifespan
• short term (!) injections (!) (vs. heterochronic parabiosis) of plasma fractions
• multiple tissues (blood, liver, heart, hypothalamus) !
• reversal of clinical biomarkers !
• aging unlikely to be stochastic but programmed?
• Looks like soon to be commercialized!

"...The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging ..."

 

Also, as per Josh Mitteldorf's blog:

 

"These results bring together three threads that have been gaining credibility over the last decade. Mutually reinforcing, the three have a strength that none of them could offer separately.

•     The root cause of aging is epigenetic progression = changes in gene expression over a lifetime.
•     Methylation patterns in nuclear DNA are not merely a marker of aging, but its primary source. Thus aging can be reversed by reprogramming DNA methylation.
•     Information about the body’s age state is transmitted system-wide via signal molecules in the blood. Locally, tissues respond to these signals and adopt a young or an old cellular phenotype as they are directed."

[albedo]

Commented by LEAF here:

https://www.lifespan...y-half-in-rats/

 

"...Crucially, plasma treatment of the old rats reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats. According to the six epigenetic clocks, the plasma fraction treatment rejuvenated liver by 73.4%, blood by 52%, heart by 52%, and hypothalamus by 11%. The rejuvenation effects are even more pronounced if we use the final versions of our epigenetic clocks: liver 75%, blood 66%, heart 57%, hypothalamus 19%. According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%...."

 

"...If these results are correct, then the epigenetic age of these rats has essentially been halved and returned to a level seen in young rats. On top of these epigenetic clock measurements, a number of other aging biomarkers saw improvement:

• Pro-inflammatory cytokines IL-6 and TNFa were reset to a lower, more youthful, level
• Blood triglycerides were reduced to a youthful level
• HDL cholesterol were increased to a youthful level
• Blood glucose levels dropped to more youthful levels
• Cognition became more youthful according to tests in a Barnes Maze
• Glutathione (GSH), superoxide dismutase (SOD), and some other antioxidant levels were reset to more youthful levels..."

 

"...Taken as a whole, these results and similarly focused studies further support that methylation patterns in nuclear DNA are not merely the hands of a clock indicating cellular age but are also the workings of that clock. This is further evidence that epigenetic aging is one of the primary reasons we age and that its reversal could have big ramifications for human aging and healthy longevity if successfully translated..."

[Engadin]

Mind, my advice: follow the comments by the hour. Very tasty ones today:

 

 

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A question: Michael Sansom on May 11, 2020 at 2:22 pm said:

 

"Akshay,

 

I think last year you were talking about this treatment being a transdermal patch. From the above it sounds like it is now IV. Did the transdermal patch not work out? I’m not really surprised if so as the amount of a compound you can actually get through the skin on a practical basis is usually quite small and normally only works well on compounds that are effective in very small doses (fentanyl being a good example – normally dosed in micrograms)."

 

 

The answer: 

 

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So topical & dermal patch look to be pre-ready and IV molecule treatment in the pipeline.

 

 

Another good point: potential senolytics sinergy.

 

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Edited by Engadin, 11 May 2020 - 08:14 PM.

[Decimus]

This is obviously very interesting. I’ve leaned towards the programmed theory of aging for the past decade or so. The only caveat I can see is if epigentic clocks do not comprehensively measure aging as well as we think they do. Since they’re so new I wouldn’t be surprised that in terms of “full rejuvenation” they miss some aspects. Which makes me wonder why he didn’t release the lifespan increase (unless of course the trial is still ongoing).

[kurt9]

Well given that the biggest risk factor for bad outcome from COVID-19 is aging, you would think the world would be all over this like a cheap suit on a hot day. Ya' think?

[smithx]

I believe major rejuvenation has been achieved in a mammal, using a relatively benign intervention that shows promise of scaling up to humans. I’m going to stake my reputation on it.

https://joshmitteldo...n-breakthrough/

 

Some secret combination of factors found in young blood. We've discussed some such factors before in this forum. Thoughts?

 

Results look great, but without disclosure of what exactly the fraction is, there's no way for anyone to replicate.
 

Reversing age: dual species measurement of epigenetic age with a single clock

 

... Crucially, plasma treatment of the old rats [109 weeks] reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats [30 weeks]….According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%. In other words, the treatment more than halved the epigenetic age.

 

https://www.biorxiv....2917v1.full.pdf

[Harkijn]

Yes, we have something very important here, but we don't yet know what it is .

Perhaps more readers will dive into Josh Mitteldorf's blog and (importantly) its comment section, if I add that dr. Katcher eyes a supplementation consisting of four injections only. He thinks the relevant molecules can relatively easily be synthesized so this may even be an affordable approach.

[orion22]

"breakthrough"=scam

[albedo]

Started new thread also here, just in case, maybe not in the right topic area?

https://www.longecit...ndpost&p=891854

 

[Ducky-001]

David Sinclair's reaction - https://twitter.com/...912928695857152

 

[Harkijn]

@ Albedo, I think your thread and this one will go very well together. I hope that the readers whose initial interest is in  a possible near-term rejuvenation supp  will also want to take a look at a discussion of the wider ranging outcomes and implications of this publication. And yes. it all needs to be confirmed......

[albedo]

Dr Harold Katcher seems having had the guts to write this already in 2015, then keep going (w/ understandably lot of difficulties) leveraging accumulating evidence and now executing on his vision. Hopefully the study will be validated and research translated.

 

"...The derived principles indicate that exogenous control of age-phenotype at cellular and higher levels of biological organization is possible..."

 

"...While there is much we do not know about the soluble factors that bring about cellular rejuvenation in heterochronic transplantation and parabiosis studies, we have found some substances, like CCL-11 (‘eostatin’) [17], accumulate with aging in both human and rodent brains. CCL-11 actually can be shown to inhibit neurogenesis and degrade cognitive ability to much the same degree as aging. Other substances, the product of the GDF11 gene, the protein BMP-11 (a member of the bone morphogenetic protein family), has been shown to return muscle satellite cells to youthful functioning [18], while oxytocin [56], has been shown to have similar effects on skeletal muscle. We know that several tissue clocks dependent on the SCN in the hypothalamus are dependent on gonadotrophin releasing factor, and that this affects lifespan [47], as re-provision of the ‘hormone’ increases lifespan. Since there are many tissues that age, it would seem that the ages of all these various cell and tissue age-phenotypes might be determined by different factors or combinations of factors. GDF-11 as all of the other age-determining molecules (ADM) is a signaling factor, and as a member of the bone morphogenic protein family is involved in development so that its loss with age may very well contribute to the muscle loss experienced by the elderly, but what is perhaps more interesting is a quote from the Sinha (and Amy Wagers) paper [57]; “Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells)..."

 

"...If these aforementioned principles are correct, it should be easy to verify, and if so, then whole organism rejuvenation might require little more than changing the concentrations of all age-determining molecules (ADMs) of the bloodstream and the various stem cell niche environments to youthful levels for a time sufficient to cause rejuvenation at the cellular level; once cells start secreting factors appropriate to their new, younger, age-phenotypes, cognate changes should propagate through the hierarchical levels...."

 

Katcher HL. Towards an evidence-based model of aging. Curr Aging Sci. 2015;8(1):46-55.

https://www.ncbi.nlm...pubmed/26054348

 

 

 

[rodentman]

From lifespan.io   https://www.lifespan...y-half-in-rats/

 

While there are likely hundreds of factors in blood that may play a role in aging, the evidence is increasingly supporting the idea that a handful of key factors sit at the top of the process and regulate the hundreds of factors below. In other words, targeting these key factors may reverse epigenetic aging and restore youthful tissue function in aged individuals...

 

The researchers delivered Elixir, an undisclosed mixture of plasma fractions presumably isolated from young rat plasma, to aged rats. They state that their technique is based on heterochronic parabiosis but forgoes the need to physically join an old and young animal together so that they share circulatory systems.

 

_______________________

 

So  they used a handful of blood factors chosen based upon heterochronic parabiosis.  If so, I'm guessing GDF-11 was one of the factors they choose... 

 

 

[albedo]

Some quotes I find relevant from Harold Kletcher (source Josh's blog, status May 13 2020)

 

"...So, if nothing else, I can definitively say that chronic inflammation due to aging can be reversed with factors present in young blood. Hey, it’s a beginning and with great potential to end the diseases of aging, many of which have an inflammatory component...."

 

"...Correct Josh, we’re going legit. No OTC stuff (requires injections, but if things scale, once every several years). This is not based on ‘theory’ (say mitochondrial aging or ‘wear and tear’) but on experimental evidence. Theory comes in explaining our results, not achieving them, but there is a theory becoming clear, one very different from the commonsense view of ‘wear and tear’ aging..." (my note: I guess this is exactly the point he makes in his paper of 2015 I reported in my previous post)

 

(edit: add links)

Edited by albedo, 13 May 2020 - 10:30 AM.

[albedo]

...

So  they used a handful of blood factors chosen based upon heterochronic parabiosis.  If so, I'm guessing GDF-11 was one of the factors they choose... 

 

Yes, maybe or maybe not, I guess we only need to wait before we know more. It is what struck me in the paper I quoted (mostly the second quote) in my previous post. I also know you are following Steve Perry's self-experimentation on this which is good. Will see ...

In the meantime let's hope the paper will be published, the research translated to human, the product safe and accessible to all. The proof-of-concept of reversing clinical relevant age biomarkers (inflammation is impressive) in mammals is really important, IMHO, but I learned not to get too much ahead of myself :-)
 

[albedo]

Some comments from Dr David Sinclair:

https://threader.app...912928695857152

[rodentman]

Interesting bit of info:

 

We have two separate products: one is a very powrrful anti aging molecule already tested on Harold with amazing effect (all his aging spots from his arms disappeared in a week). This product we wish to sell as a topical gel and transdermal patch. The gel will fall under cosmetic category with FDA so may be out early. Patch needs a FDA clearance so may take longer.
Apart from this is our flagship product code named Elixir which would be administered as injections or IV. The paper listed here by Josh is on Elixir results. I hope this clears the confusion. Good news for all of us anti-agers is that both the products should be affordable.

[VP.]

Prof Katcher is doing an AMA on Reddit: https://www.reddit.c...th_rats_plasma/

[VP.]

" We think about all sorts of things Michael, but it seems that the effects of blue stuff are considerably more than skin deep. I’m not here to advertise anything, but it seems to affect my coordination and had hair grow back on my scalp and I no longer apply it to my skin. Some other time perhaps. Yes, there are amazing things that Big Pharma won’t touch as there’s not enough profit in them (they can’t be patented). So I guess we’re somewhat the same, but we know what to do and have proven it – for us, it’s not the money. However, money allows you to do things". Harold Katcher

 

A hint of what they are doing? 

GarborB from Josh's blog: 

 

Evaluation of umbilical cord serum therapy for persistent corneal epithelial defects
2003

They created eyedrops from umbilical cord blood plasma and treated eye conditions.
They did not remove the albumin though so it was probably too diluted to have a strong effect.

From Harold’s comment above I guess they remove albumin, as he referred to the Elixir as blue stuff, which is probably because of Blue Sepharose chromaography.

 

Also I found this company they are into umibilical cord blood based therapy
http://www.saneron-ccel.com/news.html

[albedo]

Yes, maybe or maybe not, I guess we only need to wait before we know more. It is what struck me in the paper I quoted (mostly the second quote) in my previous post. I also know you are following Steve Perry's self-experimentation on this which is good. Will see ...

In the meantime let's hope the paper will be published, the research translated to human, the product safe and accessible to all. The proof-of-concept of reversing clinical relevant age biomarkers (inflammation is impressive) in mammals is really important, IMHO, but I learned not to get too much ahead of myself :-)
 

 

@rodentman

I am sorry, my bad, I just realize you are also experimenting with GDF-11 hence you must have done your own research and have much insight into lot of this. Thank you for posting!
 

[albedo]

Prof Katcher is doing an AMA on Reddit: https://www.reddit.c...th_rats_plasma/

 

Thank you. I will try to skim through the comments there but 2.4k is quite scaring...anything you found already interesting?
 

[albedo]

I am also following Josh's blog comments.

I do no know you but sometimes I feel the expertise level of people commenting in there is pretty high and people do not care replying to questions considered too naive. I also struggled in other occasions with this. I posted a question on the methodology of using the variable relative age= age/max-lifespan. It must be so naive not deserving a reply and I report it here just in case someone can put my mind to rest :-)

"Thank you posting this impressive work!
Let me write this anyway in this expert panel! Can someone helps dissipate a (likely naïve) doubt: while allowing comparison between different species, if max life span is important to study, is it possible that the process of somehow normalizing the curves via the relative age (age/maxlifespan) is factoring out exactly the signal we want to investigate, i.e. the difference in life span?"

Thank you any consideration you might give.

[VP.]

Thank you. I will try to skim through the comments there but 2.4k is quite scaring...anything you found already interesting?
 

No comments on Reddit from the Authors yet. Both Askhay and Harold have made comments over the years at Josh's blog. Just do a word search. Here is a new one that was interesting from today. They couldn't complete a longevity study on the rats because the University was in lock down so the rats died. Askhay had this to say: 

Thank you Martin. We will have 2 of our own labs and a few reputed third party labs conducting multiple trials that are planned. For example we have a double dose trial to check the response curve, we have a old infertile female trial to see if they become fertile again, we have old dogs trial and possibly a old marmoset trial. Any of these can be extended assuming we have sufficient resources a lifespan trial.

 

[albedo]

A clarification from Akshay in the Josh's blog comment section I find useful to also report here:

 

"...Michael we have two distinct products. Flagship is Elixir which will now move towards an FDA application. We have a separate product which is a very powerful anti aging molecule for which we are following the same strategy suggested by you. This gel is the one that removed the age spots for Harold. We were planning to have this available online by Christmas but now I am not sure exact timing but its iminent. If this gel is successful it will provide any additional funding required for getting Elixir to market..."

[albedo]

Here is a thread into the paper via the Nrf2 path. Encouraging for those (I do for what it matters) trying to increase intake of sulforaphane:

https://surfaceyourr...d-sulforaphane/

[Harkijn]

Thanks for this link Albedo! I was not really aware of the connection between the new research and SFN though I should have been. Anyway I have been happily chomping away at the Brassicas for quite a number of years  and I am now extra motivated to make my morning watercress salad .

[albedo]

Sorry if you have already seen this (short) first reaction from the Longevity Technology group. I found interesting two comments in particular:

 

“I figured out how to gather all the factors required to rejuvenate our rats into a single product,” he says. “I gave our final product the running title of ‘elixir’ – after the ‘elixir vitae’ of the ancients. Elixir has been described as a ‘plasma fraction’ but that would be inadequate as it is the unique product of a unique process (though its constituents are all present in young plasma). Once it is revealed, Elixir will start a tsunami of new research (including our own).” (H. Katcher)

 

"My concern with blood rejuvenating factors is that they may also contribute to cancer,” he said on Twitter. “We’ve known for decades of factors in blood (growth hormone) that can improve function in the short term but are detrimental long term (eg. cancer).” (João Pedro Magalhães)

 

https://www.longevit...creates-a-stir/

[albedo]

Thanks for this link Albedo! I was not really aware of the connection between the new research and SFN though I should have been. Anyway I have been happily chomping away at the Brassicas for quite a number of years  and I am now extra motivated to make my morning watercress salad .

 

Yes I agree with you Harkijn :-)

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[albedo]

....

 

“I figured out how to gather all the factors required to rejuvenate our rats into a single product,” he says. “I gave our final product the running title of ‘elixir’ – after the ‘elixir vitae’ of the ancients. Elixir has been described as a ‘plasma fraction’ but that would be inadequate as it is the unique product of a unique process (though its constituents are all present in young plasma). Once it is revealed, Elixir will start a tsunami of new research (including our own).” (H. Katcher)

 

......

 

If "plasma fraction" is inadequate to describe the work on Elixir, would here reside the main difference with previous work e.g. by Wyss-Coray team at Alkahest? Just wonder.

https://www.longevit...asma-therapies/

 

[MikeDC]

Without another research group confirming this, I would regard this as a scam.