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

aging reversal epigenetics dna methylation clock heterochronic parabiosis programmed aging

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#1 albedo

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Posted 11 May 2020 - 07:27 PM


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."

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#2 albedo

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Posted 11 May 2020 - 07:39 PM

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..."


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#3 albedo

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Posted 12 May 2020 - 08:56 PM

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

 

 

 


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#4 rodentman

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Posted 13 May 2020 - 06:51 AM

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... 

 

 


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#5 albedo

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Posted 13 May 2020 - 10:02 AM

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.

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#6 albedo

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Posted 13 May 2020 - 10:23 AM

...

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 :-)
 



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#7 albedo

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Posted 13 May 2020 - 10:52 AM

Some comments from Dr David Sinclair:

https://threader.app...912928695857152


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#8 rodentman

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Posted 13 May 2020 - 06:32 PM

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.


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#9 VP.

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Posted 14 May 2020 - 07:47 PM

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


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#10 VP.

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Posted 14 May 2020 - 08:24 PM

" 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



#11 albedo

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Posted 14 May 2020 - 09:37 PM

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!
 



#12 albedo

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Posted 14 May 2020 - 09:43 PM

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?
 



#13 albedo

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Posted 14 May 2020 - 10:01 PM

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.



#14 VP.

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Posted 15 May 2020 - 03:57 AM

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.

 


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#15 albedo

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Posted 15 May 2020 - 11:23 AM

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..."



#16 albedo

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Posted 15 May 2020 - 11:56 AM

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/


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#17 Harkijn

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Posted 15 May 2020 - 03:33 PM

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 :) .


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#18 albedo

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Posted 16 May 2020 - 12:40 PM

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/


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#19 albedo

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Posted 16 May 2020 - 12:50 PM

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 :-)

Attached File  nrf2.PNG   52.61KB   0 downloads
 



#20 albedo

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Posted 16 May 2020 - 09:07 PM

....

 

“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/

 



#21 VP.

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Posted 18 May 2020 - 04:05 PM

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/

I know they found "significant" results with just a herbal formula years ago. It's possible Alkahest has found many of the same constituents as Harold but they are going the slow single disease FDA  route. 

 

Thank you Patricio. Yes 45 would be too young for proposed trial. We would like to see significant reversal. But let us see what protocol is designed by Harold. We have had 3 major trials: First one on 10 natural extracts. Each one selected to upregulate a key known repair system whose efficiency goes down with aging. We have had very encouraging results with that but it wont quantify as systemic compared with Elixir. We followed this with 2 trials of Elixir: single dose 30 days and repeat dose 155 days. You have the result of that. Although I cant disclose about ElixirI will say this: Harold came up with brilliant work due to which hopefully we wont have scaling issues and prices will remain reasonable.

 

https://joshmitteldo...rough/#comments

Edited by VP., 18 May 2020 - 04:08 PM.


#22 VP.

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Posted 18 May 2020 - 04:09 PM

Other companies are searching the same area. https://www.theguard...nts-mice-plasma

 

I have no idea how Harold leapfrogged such well funded labs. 



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#23 VP.

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Posted 19 May 2020 - 02:01 PM

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

Harold has decided to do the AMA after publication of the study. 


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#24 albedo

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Posted 21 May 2020 - 07:57 AM

Dr. Oliver Medvedik will discuss the study in the LEAF Journal Club on May 21st, 1:00 PM EDT, live on Facebook.

https://www.lifespan...ic-age-in-rats/


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#25 albedo

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Posted 23 May 2020 - 05:09 PM

I think informative from Akshai:

 

"...we have three products developed: natural extracts mix, young plasma fractions: Elixir and powerful anti aging molecule: gel and transdermal patch. We have completed pre-clinical trials in all three..."

 

https://joshmitteldo...rough/#comments


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#26 albedo

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Posted 25 May 2020 - 05:06 PM

Dr. Oliver Medvedik will discuss the study in the LEAF Journal Club on May 21st, 1:00 PM EDT, live on Facebook.

https://www.lifespan...ic-age-in-rats/

Recorded session:

https://www.lifespan...ic-age-in-rats/

 



#27 albedo

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Posted 26 May 2020 - 03:50 PM

 

In case you missed, there were quite harsh comments by Didier Coeurnelle, mainly wrt the lifespan study which I understand is in progress.

While waiting for that, here is a potentially contradictory study posted on Josh's blog and Harold Katcher's reply:

 

"...in addition, this is still somehow in contradiction with

https://onlinelibrar...111/acel.12897"

 

"...Yes, that’s a question that has been bothering me since Amy Wagers post-doc, Shane Mayack and her papers were retracted from Nature and Blood. What Shane, who said she was innocent of everything, but made a mistake on which illustrations she used (one used previously), showed(she said) that blood cells weren’t affected by the rejuvenating factors in the blood (heterochronic parabiosis) but instead were rejuvenated (after a time) by bone marrow stromal cells. So, that was always a worry of mine – but the rats showed no ill effects at any time, I really don’t know about how good their immune systems were as we never challenged them, what I do know is that the chronic inflammation due to aging (present in all terrestrial vertebrates) disappeared. 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..." (Harold Katcher)

https://joshmitteldo...rough/#comments

 

 

 



#28 rodentman

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Posted 26 May 2020 - 04:38 PM

 

In case you missed, there were quite harsh comments by Didier Coeurnelle, mainly wrt the lifespan study which I understand is in progress.

While waiting for that, here is a potentially contradictory study posted on Josh's blog and Harold Katcher's reply:

 

"...in addition, this is still somehow in contradiction with

https://onlinelibrar...111/acel.12897"

 

"...Yes, that’s a question that has been bothering me since Amy Wagers post-doc, Shane Mayack and her papers were retracted from Nature and Blood. What Shane, who said she was innocent of everything, but made a mistake on which illustrations she used (one used previously), showed(she said) that blood cells weren’t affected by the rejuvenating factors in the blood (heterochronic parabiosis) but instead were rejuvenated (after a time) by bone marrow stromal cells. So, that was always a worry of mine – but the rats showed no ill effects at any time, I really don’t know about how good their immune systems were as we never challenged them, what I do know is that the chronic inflammation due to aging (present in all terrestrial vertebrates) disappeared. 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..." (Harold Katcher)

https://joshmitteldo...rough/#comments

 

 

 

 

 

Thanks for keeping us updated on all this. 

 

I don't understand why there are some who dismiss the entire study due to the fact that there wasn't a life-span study; especially in light of the lock-down.  Obviously a life-span study will be included, just as a full peer-review of everything will be on the horizon.  And it's extremely hard to believe that S. Horvath would co-author a scam, or a very poorly setup experiment, that consistently came up with inaccurate data.


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#29 p75213

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Posted 26 May 2020 - 07:44 PM

I couldn't listen to that. Just too many ums and arhs. I mean nearly every 2nd word. Very frustrating.
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#30 albedo

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Posted 01 June 2020 - 08:02 PM

This presentation by Steven Braithwaite, CSO of Alkahest, seems to me hinting to a serious competitive approach (which is great!) maybe for some of the end-points:


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Also tagged with one or more of these keywords: aging reversal, epigenetics, dna methylation clock, heterochronic parabiosis, programmed aging

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