231 replies to this topic

[Phoebus]

 

https://joshmitteldo...-fraction-cure/

 

Harold doesn’t have the funding or the university infrastructure that these people have, but by his report he has leapfrogged their research.  He claims to have isolated the crucial molecules in young blood plasma, and that it is feasible in the not-too-distant future to synthesize them, so we’re not all running like vampires after 20-something men and women, bidding up the price of their blood.

His experimental results are preliminary, but impressive.  On the one hand, there are big questions that remain; on the other hand, I’ve never seen success like this from any other intervention.  (The possible exception is the Mayo Clinic’s work with senolytics, extending the lives of older mice; but the two approaches are so very different and what we know about the two is so different that there is no basis for saying one is more successful or more promising than the other.)

So, what were the results that we find so impressive?  I’ve linked to his own chart of results, and I’ve asked Harold to tell us in his own words.

 

great post, click over to read the whole thing 

[Phoebus]

here is an informal write up on the experiment
the old mice did better in the maze than the control by far and even did better than the young mice
https://drive.google...obV-Un4Z8v/view

 

in 30 days the muscles strength of the old mice went from far below the young mice to nearly equal grip strength same as above

 

I am looking ahead to envision an elixir that brings you back to apparent youth in a week and a day with no side effects. Time will tell, but I feel that the results we have at this point justify optimism.
— Harold Katcher

 

 

Harold Katcher on February 5, 2019 at 8:54 pm said:


Say, when I first heard the results, I was astonished. It’s not that I expected it to fail, I didn’t, but I didn’t expect it to succeed as well as it did. So clearly I made some correct assumptions along the way. So will it work, or will it fade away to obscurity? This all depends on whether my view of aging is correct or not (and several other things as well, which I would love to explain once I feel ‘safe’). The basic thesis is that cellular age-phenotype is not a product of a cell’s history, and that the cellular aging that accompanies the aging of the organism, is not the cause of aging but the result of aging.
By this logic, if I can change the age-phenotype of the cells by using the body’s own messaging system, then the age phenotype of the organism will follow. As that seems to be the case, I’m most likely correct in my hypothesis, certainly these proof-of-principle experiments support it. So then if what I already stated is the case, then proper age-reversal in merely a matter of engineering. And that’s the stage we’re at. There has never been anything like this before, because there has never been the proper understanding of aging before.

Edited by caliban, 22 September 2021 - 09:19 AM.

[HighDesertWizard]

I admire Dr. Harold Katcher very much.

 

His 2013 and 2015 articles are two of the most important reviews of the literature I've ever read.

 

Still, can anyone explain how the positive behavioral changes he describes differ, even slightly, from the benefits Rhonda Patrick explains are a result of hyperthermic-conditioning?

 

I can't.

 

I predict...

 

It will turn out that the independent variable(s) driving the positive outcomes Dr. Katcher describes will be Heat Shock Protein(s), and, most likely, Heat Shock Protein 70.

-- Steve Buss, February 6, 2019

 

How could it be anything else?

 

 

 

 

Still, this tentative study by Dr. Katcher is important. precisely because it highlights the emerging evidence that...

 

An Ancient "Heat Shock" and OSKM Related Epigenetic Turn Initiates an Aging Process in Humans that can be Modulated

Edited by HighDesertWizard, 06 February 2019 - 04:44 PM.

[HighDesertWizard]

I admire Dr. Harold Katcher very much.

 

His 2013 and 2015 articles are two of the most important reviews of the literature I've ever read.

 

Still, can anyone explain how the positive behavioral changes he describes differ, even slightly, from the benefits Rhonda Patrick explains are a result of hyperthermic-conditioning?

 

I can't.

 

I predict...

 

It will turn out that the independent variable(s) driving the positive outcomes Dr. Katcher describes will be Heat Shock Protein(s), and, most likely, Heat Shock Protein 70.

-- Steve Buss, February 6, 2019

 

How could it be anything else?

 

< Video Link SNIP >

 

 

 

Still, this tentative study by Dr. Katcher is important. precisely because it highlights the emerging evidence that...

 

An Ancient "Heat Shock" and OSKM Related Epigenetic Turn Initiates an Aging Process in Humans that can be Modulated

 

I stand by my prediction that Heat Shock Protein(s) will be implicated when Dr. Katcher's is able to unveil the independent variables implicated in his study data summary.

 

That said, I was wrong in saying that a difference doesn't exist between what's going on in Dr. Katcher's study and what Rhonda Patrick is talking about in the video. And I realize the difference has to do with a topic, a critique, of the central conjecture of that thread above about Heat Shock. I've been warming up to make that critique of the conjecture and Dr. Katcher's great new study data is a trigger for getting into it.

 

Thanks, Dr. Katcher!

 

I'll post a link to that analysis when it's posted in that other thread.

 

Edited by HighDesertWizard, 06 February 2019 - 08:12 PM.

[Mind]

 

 

So then if what I already stated is the case, then proper age-reversal in merely a matter of engineering.

 

Hmmmm? Where have I heard that before? Oh, now I remember....mainstream researchers have been trashing the SENS foundation for over 15 years for saying the exact same thing. Just had to put that out there.

 

Otherwise, I look forward to the point when Dr. Katcher has human trials completed (or convinced self-experimenters to try these potential rejuvenation factors). Some people have already pointed out that one of these "young blood" factors has already been found and is producing dramatic results in humans - GDF11. https://www.longecit...xogenous-gdf11/

 

 

[QuestforLife]

I stand by my prediction that Heat Shock Protein(s) will be implicated when Dr. Katcher's is able to unveil the independent variables implicated in his study data summary.

 

That said, I was wrong in saying that a difference doesn't exist between what's going on in Dr. Katcher's study and what Rhonda Patrick is talking about in the video. And I realize the difference has to do with a topic, a critique, of the central conjecture of that thread above about Heat Shock. I've been warming up to make that critique of the conjecture and Dr. Katcher's great new study data is a trigger for getting into it.

 

Thanks, Dr. Katcher!

 

I'll post a link to that analysis when it's posted in that other thread.

 

 

Show me the study that shows HSP reduces protein and bilirubin to near youthful levels, reduces glucose from diabetic to approaching normal, reduces triglycerides from high to normal, raises HDL, lowers cholesterol to youthful levels, raises albumin to near youthful levels, lowers creatinine to youthful levels, corrects BUN towards healthy levels, etc, etc, etc. Oh and restores youthful levels of glutathione, catalase and SOD in multiple organs. AND behaviorally restores old mice to the physical strength and mental agility of young mice.  

 

Katcher claims to have done all this.

 

Doubtful HSP is the only factor, although it probably is one of them

Edited by QuestforLife, 08 February 2019 - 10:38 AM.

[Rocket]

Hmmmm? Where have I heard that before? Oh, now I remember....mainstream researchers have been trashing the SENS foundation for over 15 years for saying the exact same thing. Just had to put that out there.

 

Otherwise, I look forward to the point when Dr. Katcher has human trials completed (or convinced self-experimenters to try these potential rejuvenation factors). Some people have already pointed out that one of these "young blood" factors has already been found and is producing dramatic results in humans - GDF11. https://www.longecit...xogenous-gdf11/

 

No offense but I find Steve Perry's claims total bunk. For starters GDF11 is similar to myostatin. Yet SP professes to have gained muscle mass without doing anything. I believe 5 lbs. (Notice how people on forums always say "yeah I took this supplement and gained 5lbs.") People don't gain 5lbs of muscle by doing nothing. People on REAL human growth hormone don't gain 5lbs of muscle by doing nothing.

 

People's weight fluctuates 5lbs because of water...... 

 

I and others that I know have experimented with GDF11 with ZERO effects whatsoever. The only person I recall ever saying the GDF11 did anything for him was the poster Daredevil who said he would inject himself with it because it was "a pick me up" when he felt low on energy for a given day.

 

Steve Perry was also trying to open an anti-aging clinic. Like they say in politics, "follow the money."

Edited by Rocket, 08 February 2019 - 02:20 PM.

[Mind]

No offense but I find Steve Perry's claims total bunk. For starters GDF11 is similar to myostatin. Yet SP professes to have gained muscle mass without doing anything. I believe 5 lbs. (Notice how people on forums always say "yeah I took this supplement and gained 5lbs.") People don't gain 5lbs of muscle by doing nothing. People on REAL human growth hormone don't gain 5lbs of muscle by doing nothing.

 

People's weight fluctuates 5lbs because of water...... 

 

I and others that I know have experimented with GDF11 with ZERO effects whatsoever. The only person I recall ever saying the GDF11 did anything for him was the poster Daredevil who said he would inject himself with it because it was "a pick me up" when he felt low on energy for a given day.

 

Steve Perry was also trying to open an anti-aging clinic. Like they say in politics, "follow the money."

 

I think you are being a little harsh on Steve Perry. His effort seems a lot more structured and science-based than a lot of other "supplement" hawkers out there. People who use his service are required to take a multitude of biomarker and other age-related tests. https://gdf11rejuven...ding-biomarkers

 

If the data he has presented at various conferences is legit and not totally fake, then GDF11 does have some age-reversal properties. His data shows that everyone who takes GDF11 under his supervision has improved reaction time. It seems unlikely that hundreds of people could all be experiencing a placebo effect in this regard. It is tough to fake reaction time.

[HighDesertWizard]

Show me the study that shows HSP reduces protein and bilirubin to near youthful levels, reduces glucose from diabetic to approaching normal, reduces triglycerides from high to normal, raises HDL, lowers cholesterol to youthful levels, raises albumin to near youthful levels, lowers creatinine to youthful levels, corrects BUN towards healthy levels, etc, etc, etc. Oh and restores youthful levels of glutathione, catalase and SOD in multiple organs. AND behaviorally restores old mice to the physical strength and mental agility of young mice.  
 
Katcher claims to have done all this.
 
Doubtful HSP is the only factor, although it probably is one of them

 
QuestforLife... Thank you for your pointed question. It set me on a path of study-finding discovery last evening that I'm still reeling from. Keep the critiques coming, please.   
 
-------
I've been a fan of Dr Katcher's for years now. I remember being powerfully impacted by his 2013 literature review, Studies that Shed New Light on Aging, and found his 2015 review, Towards an Evidence-based Model of Aging. even more significant. I summarized the key elements of Dr Katcher's 2nd article here at Longecity back in 2015.
 
For years now, Dr Katcher, among our movement's less well-known thought leaders, has been among the most astute. So I'm extremely interested in whatever Dr Katcher's up to and not surprised that he's found something significant... 
 
And, make no mistake, assuming Katcher's study finding data is accurate, he's on to something important.

 

In several posts about this in the next bit of time, I'll explain why I think so.

 

-------

 

QuestforLife...

 

I suggest the issue should be decomposed into 3 parts. 1) the study independent variables and Heat Shock Proteins, 2) "youthful level effects" and recent knowledge we have about Heat Shock, and 3) what we might do about this.

 

But before we can begin, we need all the information available on the table about the Katcher study findings. You didn't mention a few elements that are among the most important.

 

In this first of at least 3 reply-posts to the issue you raise, let's make sure all the important context and other variables are on the table.

 

• Billirubin
• Glucose
• Triglycerides
• HDL
• Cholesterol
• Albumin
• Creatinine
• BUN
• Glutathione
• Catalase
• SOD
• Nrf2
• TNF
• IL-6
• Autophagy
• Mitophagy
• Ubiquitin Proteasome System
• DNA Repair Systems
• Physical strength
• Mental agility 

Last but not least, we have additional statements by Katcher and his Indian partner showing up in Mitteldorf's blog post or a comment on that blog post.
 

1 - By Katcher

 

We have addressed several different problems:

• Identification and purification of youth-inducing factors and a process for their large-scale production. Our processes are scalable from microliters to metric tonnes
• Raw material supply: we have gone beyond the need to obtain blood from young people, our sources are virtually limitless
• Removal of the effects of ‘pro-aging-factors’.  We have discovered a way to do that, one hidden in plain sight. (Emphasis added)

2 - By his Indian partner (aka, Akshay Atomic Bliss)

 

we targeted agonists of Nrf2, autophagy, mitophagy, ubiquitin proteasome system and DNA repair systems. We used proprietary synergies and conjugates to improve bioavailability. Bioavailability can not be highlighted enough

Edited by HighDesertWizard, 09 February 2019 - 10:46 PM.

[Mind]

 

 

Steve Perry was also trying to open an anti-aging clinic. Like they say in politics, "follow the money."

 

It is common for people who discover something new, beneficial, and/or useful to capitalize upon it in market economies. This is not an a priori reason to dismiss Steve Perry and GDF11. If Dr. Katcher has found some rejuvenation factors, and they work, then I hope he starts a clinic or finds a way to distribute the treatments around the world. If he saves humans from aging, he deserves a lot of wealth/fame/fortune.

[QuestforLife]

 
QuestforLife...  Keep the critiques coming, please.   
 

-------

 

• Removal of the effects of ‘pro-aging-factors’.  We have discovered a way to do that, one hidden in plain sight. (Emphasis added)

2 - By his Indian partner (aka, Akshay Atomic Bliss)

 

we targeted agonists of Nrf2, autophagy, mitophagy, ubiquitin proteasome system and DNA repair systems. We used proprietary synergies and conjugates to improve bioavailability. Bioavailability can not be highlighted enough

 

I'll keep asking if you keep answering

 

I wonder about the 'hidden in plain sight' comment. My guess would be something simple, like blood donation.

 

Intriguing the pathways Akshay refers to. We know how to address these, to some extent, only none of us has being addressing all of them...

[HighDesertWizard]

I'll keep asking if you keep answering

 

I wonder about the 'hidden in plain sight' comment. My guess would be something simple, like blood donation.

 

Intriguing the pathways Akshay refers to. We know how to address these, to some extent, only none of us has being addressing all of them...

 

Thanks. I've got a long first post-answer mostly done, just needs a bit of tweaking.

 

Two points for now...

• It's not blood donation. Katcher himself eliminated that as the explanation with these sentences.

Although transfusion technologies for humans are mature and quite safe, transfusing small animals requires state-of-the-art lab techniques. Try as we might, we could not perform plasma exchange in rats. Time was growing short (I was on a two-month visa) so what to do? I made the decision to completely change my approach: yes I believed HPE would work, but I decided to leap ahead, to see if we could make the process of HPE into a marketable product.

• Akshay's comment about bioavailability speaks to the question of dosing required to get an extraordinary response.

We used proprietary synergies and conjugates to improve bioavailability. Bioavailability cannot be highlighted enough

Edited by HighDesertWizard, 11 February 2019 - 04:03 PM.

[HighDesertWizard]

As far as I know, at present, there is no experiment that shows definitively that Heat Shock is the most significant independent variable of the Katcher experiment.

 

I assume, of course, that Dr Katcher's statement of what the experiment results are are correct and that I've understood them correctly. (It's More Likely that I've misunderstood them than that Dr Katcher has mis-stated them. We're talking about Dr Katcher here, jeez!)

 

 

All that said, I've spent some time investigating whether some experiment shows a relationship of each of the variables of Dr Katcher and his partner have written are important and Heat Shock Proteins. Info about that appears below...

 

 

Cholesterol

2002, Hyperlipidemia induced by high cholesterol diet inhibits heat shock response in rat hearts

 

Glutathione

2018, Glutathione modulates the expression of heat shock proteins via the transcription factors BZIP10 and MYB21 in Arabidopsis

 

Catalase

1999, Catalase activity is necessary for heat-shock recovery in Aspergillus nidulans germlings

2017, Anti-heat Shock 70 kDa Protein Antibody Induced Neuronal Cell Death

 

Nrf2

2018, NRF2 transcriptionally activates the heat shock factor 1 promoter under oxidative stress and affects survival and migration potential of MCF7 cells

 

Albumin

2007, Changes in albumin precursor and heat shock protein 70 expression and their potential role in response to corneal epithelial wound repair

 

Autophagy

2015, Heat shock response and autophagy--cooperation and control

 

Bilirubin

2013, The Effect of Different Doses of Aerobic Exercise Training on Total Bilirubin Levels

 

BUN

2011, Induction of stress response proteins and experimental renal ischemia/reperfusion

 

Creatinine

2016, Higher urine heat shock protein 70/creatinine ratio in type 1 diabetes mellitus

 

DNA Repair Systems

2017, Heat shock proteins and DNA repair mechanisms: an updated overview

 

Glucose

2018, Skeletal muscle‐specific overexpression of heat shock protein 72 improves skeletal muscle insulin‐stimulated glucose uptake but does not alter whole body metabolism

 

HDL

2016, Heat shock protein expression affects high-density lipoprotein function in atherosclerosis

 

IL-6

2010, Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3

 

Mental agility

2013, The α Crystallin Domain of Small Heat Shock Protein b8 (Hspb8) Acts as Survival and Differentiation Factor in Adult Hippocampal Neurogenesis

2011, Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1

 

Mitophagy

2018, Hsp70 participates in PINK1-mediated mitophagy by regulating the stability of PINK1

 

Physical strength

2018, Exercise, heat shock proteins and insulin resistance

 

SOD

2014, Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs

 

TNF

1993, Overexpression of major heat shock protein hsp70 inhibits tumor necrosis factor-induced activation of phospholipase A2

2009, Dynamic effect of heat shock pretreatment on apoptotic responses to TNF-alpha in liver cells

 

Triglycerides

 

Ubiquitin Proteasome System

2016, HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans

Edited by HighDesertWizard, 12 February 2019 - 07:27 AM.

[HighDesertWizard]

Show me the study that shows HSP reduces protein and bilirubin to near youthful levels, reduces glucose from diabetic to approaching normal, reduces triglycerides from high to normal, raises HDL, lowers cholesterol to youthful levels, raises albumin to near youthful levels, lowers creatinine to youthful levels, corrects BUN towards healthy levels, etc, etc, etc. Oh and restores youthful levels of glutathione, catalase and SOD in multiple organs. AND behaviorally restores old mice to the physical strength and mental agility of young mice.  
 
Katcher claims to have done all this.
 
Doubtful HSP is the only factor, although it probably is one of them

 
QuestforLife... I believe my post immediately above provides study links showing overwhelming evidence that one or more Heat Shock Proteins are implicated in the Katcher study findings.
 
This conclusion is almost certainly true also because the positive health and youthfulness impact of the Katcher experiment FITS with other evidence showing that Heat Shock Protein expression can have profound effects on Survival Probability.
 

2015, Fitness predicts long-term survival after a cardiovascular event: a prospective cohort study
 

 
2015, Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events
 
j

 

 

Another important question is this... Are there additional reasons we should grant credibility to the Katcher study result?

 

I think the answer to the question is yes and I'll explain why in a bit.

Edited by HighDesertWizard, 14 February 2019 - 01:28 AM.

[VP.]

Dr. Akshay has operated a blog for years and the theories he had prior to his study may give clues as to what they did in their experiment. Perhaps they somehow manipulated Thioredoxin levels? Please read his posts. Very interesting. 

 

https://blissatomic.blogspot.com/

Edited by VP., 14 February 2019 - 08:10 PM.

[Ovidus]

Guys, 

 

Is everyone out of their minds?

"...claims to have isolated..."

 

and then in Katcher's own words (from the link on Josh's blog)
"Our first pass was to try a combination of known herbal supplements that are known to bind with the targets we’d identified. "

 

Two guys working without the support of an enormous lab and a giant network not just "isolate" or "identify" the factors in blood that lead to aging. 
Such an effort required en enormous amount of resources. Something similar was accomplished in Harvard by the lab of Amy Wagers -it is a monumental undertaking. 

These 2 people have identified the factors, have conducted experiments to reduce the concentrations in the blood, failed at that and devised another method (which was hiding "in plain sight") and also have pulled up the herbal supplements that bind with these targets???
 

Sorry, this is BS.

Each of those steps in isolation is beyond he scope of their ability. It doesn't matter how many literature reviews they write or what kind of nice guys they are

[QuestforLife]

 
QuestforLife... I believe my post immediately above provides study links showing overwhelming evidence that one or more Heat Shock Proteins are implicated in the Katcher study findings.
 
This conclusion is almost certainly true also because the positive health and youthfulness impact of the Katcher experiment FITS with other evidence showing that Heat Shock Protein expression can have profound effects on Survival Probability.
 

 

 

Another important question is this... Are there additional reasons we should grant credibility to the Katcher study result?

 

I think the answer to the question is yes and I'll explain why in a bit.

 

I think you've proven that HSP is involved in the pathways used in the claimed rejuvenation; you haven't proven that HSP is the lynchpin or upstream cause of all the benefits.

 

As to the skepticism of Katcher's results (not from you HDW) - yes skepticism is warranted until more details are released, however we shouldn't assume that breakthroughs will always come out of the biggest labs with the most funding, history shows that new discoveries and paradigm shifts in understanding often come from unexpected directions. 

[VP.]

 

Sorry, this is BS.

Each of those steps in isolation is beyond he scope of their ability. It doesn't matter how many literature reviews they write or what kind of nice guys they are

 

I agree with you Ovidus. Just too good to be true but in their defence, they have been working on this for 6 years and maybe, just maybe they found something that others have overlooked. Also, why would they lie? An error is out of the question. It would have to be outright fraud.  Fame or fortune?  The procedure is so simple (so they say) that it can be repeated under controlled conditions in a few months. They talked about their fantastic results last June in Josh's blog but only now gave out details? Why wait? It's not unheard of for one man to change science even in recent memory. Remember stomach ulcers? http://discovermagaz...medical-mystery

 

All we can do is wait and remember extraordinary claims require extraordinary evidence. 

[HighDesertWizard]

Sorry, this is BS.
Each of those steps in isolation is beyond he scope of their ability. It doesn't matter how many literature reviews they write or what kind of nice guys they are

 

As to the skepticism of Katcher's results (not from you HDW)

 

I agree with you Ovidus. Just too good to be true...

 

Perhaps I should have made caveats about whether Dr Katcher's study result finding could be taken for granted more directly or more often. I certainly never intended to convey that those results should be taken at face value, at this point.
 
So, QuestforLife, I did intend to say and did say that I was assuming Dr Katcher's study result findings were "correct" (i.e., actually achieved through rigorous methods) and I understood the findings correctly.
 
 

Still, this tentative study by Dr. Katcher is important

 
 

As far as I know, at present, there is no experiment that shows definitively that Heat Shock is the most significant independent variable of the Katcher experiment.
 
I assume, of course, that Dr Katcher's statement of what the experiment results are are correct and that I've understood them correctly. (It's More Likely that I've misunderstood them than that Dr Katcher has mis-stated them. We're talking about Dr Katcher here, jeez!)

 
I appreciate all 3 comments. I'll have a longer reply containing evidence and argument that addresses the questions of why I think Katcher's study is remarkable and how we can know that it is.... Assuming the study result findings can be replicated.

 
Two additional points in the meantime...
 
A - There are 3 Truth Claims at issue for me, not just one...
 
1 - Katcher is claiming remarkable results in his study. He also states that his study results ought to be replicated and he intends to try to replicate them.
 
2 - I'm claiming that the results he's published so far, if they can be replicated, implicate Heat Shock Protein.

• Please note, my claim may be false while his results may be replicated.
• I've provided study links upthread that documents my travels through the literature to come to that conclusion.

3 - In a post to follow soon (assuming I don't get distracted or otherwise occupied), I will...

• claim and provide evidence from two bodies of literature that suggest Katcher is onto something important if his results can be replicated
  • The Inflammatory Reflex
  • The literature underlying the argument I've been making about Heat Shock and Seth Grant's Epigenetic turn finding
• suggest what questions we should be asking that can lead us to action

B - Most people underestimate how much new knowledge growth has taken place recently about subjects they think they understand. 
 
I believe only recently discovered, ancient evolutionary conserved mechanisms are implicated in Katcher's study findings in one way or another, IF his findings can be replicated. I suggest we take the fact of the existence of TIR seriously and the probable fact of the existence of a Heat Shock related Switch seriously to take action on Katcher's findings.

 

The REASON I take his study more seriously is because I see a relationship in his findings to those two mechanisms.
 

I'll try to explain more in a future post.

 

 

 

 

 

Among my favorite, David Deutsch quotations is this one from a TED talk entitled A new way to explain explanation.

 

But we know about ... things.

How?

[Do y]ou know what the clinching evidence was that space-time is curved?

It was a photograph, not of space-time, but of an eclipse, with a dot there rather than there.

And the evidence for evolution? Some rocks and some finches.

And parallel universes? Again: dots there, rather than there, on a screen.

What we see, in all these cases, bears no resemblance to the reality that we conclude is responsible

... only a long chain of theoretical reasoning and interpretation connects them.

 

Edited by HighDesertWizard, 15 February 2019 - 06:37 PM.

[HighDesertWizard]

I don't know. What do you think?

 

The first three study graphic figures are from studies about The Inflammatory Reflex.... Are they finches, rocks, photographs, or dots on a screen. They are important.

 

The fourth diagram is from Katcher's tentative study findings.

 

Understanding of the meaning of the first three graphic figures tell me that, if Katcher's findings can be replicated, he is onto something really important.

 

Please explain why I shouldn't think so. Feel free to ask questions to clarify details.

 

 

 

 

 

 

 

 

 

Edited by HighDesertWizard, 15 February 2019 - 07:04 PM.

[Avatar of Horus]

Very good results, congrats to the researchers; of course knowing the details would be good, but the patent need to be filed, etc. so it's ok.

Also moving the testing to dogs seems to be the good direction.

 

Before these above, not much can be said, only some initial things:

The results are in line with what have been seen with the previous studies in this type of research, i.e. the young blood / extracellular environment, but several questions remain, like:

will it work in higher mammals, like humans (preliminary data suggest that it might);

will it extend the lifespan too, that is will the restored health in these organs/tissues translate into life extension (because the processes that are responsible for the lifespan are not well known at this point in biology), and to what extent;

what is happening to the senescent cells, are they rejuvenated so they stop producing the SASP and/or the various self-destructive proteins, or do the cells of the immune system become more engaging and help repair / remodel the given tissues;

etc.

[ambivalent]

The extraordinary claim resulted from the extraordinary evidence, all that is required is repeatability. So often, it seems, skepticism is an automated response to negate any threat to status posed by the affliction of being 'easily duped'.  Is it unbelievable that two diligent people spending years of research yield remarkable results? No, not if they're doing the right things. Aubrey de Grey in a podcast on longecity a while back admonished the sens-dwarfing Calico for their non-translatable research methodologies, citing his organisation's low-budget over-achievements as evidence. 

 

Biology is not a closed, understood system - no amount of resource can cover the entire solution space, so we go with best guesses, which will often be flawed and when research coalesces on the these approaches, the process of discovery is subverted. 

 

This particular study is of course surprising, but coherent with the study demonstrating the regenerative effects of shared blood mentioned and consistent with Sinclair's NAD discovery proving old bodies can produce young cells with the right resources.  

 

Above anything else motivation to lie (it isn't going to be poor experimental design) seems rather thin on the ground, those in the anti-aging community share a critical common goal. It is a short, easily repeatable and so falsifiable experiment. If submitting overblown claims to generate funds for research, there'd need to be wiggle room to backpedal: there isn't any. It can't be poor design or inadequate sample size.

 

I'd put good money that he has done what he says he has, so presumably would Mittledorf.

 

 

 

 

 

Edited by ambivalent, 16 February 2019 - 04:55 PM.

[VP.]

New molecules reverse memory loss linked to depression, aging

"A single dose of these new molecules was administered in preclinical models of stress-induced memory loss. Thirty minutes later, memory performance returned to normal levels, an experiment that was reproduced more than 15 times. In another experiment involving preclinical models of aging, memory declines were rapidly reversed and performance increased to 80 per cent after administration, essentially reaching levels seen in youth or earlier stages of adulthood. This improvement lasted over two months with daily treatment".

 

https://www.scienced...90214102504.htm

 

This may be completely different from what Dr Katcher is doing but it does at least show that aging reversal is possible in the brain from a small molecule administration. Maybe this is somehow related to what Dr. Katcher is doing? The daily treatment protocol is different.  

[VP.]

 

 

will it extend the lifespan too, that is will the restored health in these organs/tissues translate into life extension (because the processes that are responsible for the lifespan are not well known at this point in biology), and to what extent;

 

 

 

This study hints that the answer might be yes.

 It is interesting to recall that in 1972, two researchers at the University of California studied the lifespans of old–young rat pairs. Older partners lived for four to five months longer than controls, suggesting for the first time that circulation of young blood might affect longevity

https://www.ncbi.nlm...les/PMC5662775/

[HighDesertWizard]

 I believe only recently discovered, ancient evolutionary conserved mechanisms are implicated in Katcher's study findings in one way or another, IF his findings can be replicated. I suggest we take the fact of the existence of TIR seriously and the probable fact of the existence of a Heat Shock related Switch seriously to take action on Katcher's findings.

 

The REASON I take his study more seriously is because I see a relationship in his findings to those two mechanisms.

 

In my previous post, I provided study graphic figures from studies of survival probability when an ancient, evolutionary preserved mechanism, The Inflammatory Reflex is triggered. What those figures show is that TNF expression in serum is negatively correlated with increased survival probability.

 

The Inflammatory Reflex exists in humans as a biological mechanism: that fact is established. Plenty of experiments to Falsify key components that make it up have been performed.

 

Although I've come to believe that a Heat Shock-related epigenetic aging switch exists in humans, a Falsifying experiment has not been performed, so we need to be more tentative in discussing it.

 

I won't repeat evidence here that it does exist when I've already provided that evidence elsewhere:

• In the opening post of this thread where I write about an intersection of the work of Richard Morimoto and Seth Grant.
• In this more recent post in that same thread I highlight that heat shock expression has been implicated as having a relationship with PSD-95 (the significant independent variable found by Seth Grant).
• Again, in the opening post of that same thread, I've cited evidence that Heat Shock "regulates" the OSKM epigenetic factors implicated in inducing Pluripotent Stem Cells.

From the Morimoto study, 2015, Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction

 

The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress. The removal of germline stem cells preserves jmjd-3.1 expression, suppresses the accumulation of H3K27me3 at stress gene loci, and maintains the HSR. These findings suggest that competing requirements of the germline and soma dictate organismal stress resistance as animals begin reproduction.

 

In addition to that evidence above, Heat Shock has complex relationships with NRF2 and TNF.

 

 

Follow the bouncing ball....  # 3....

• a7nAchR activation, associated with The Inflammatory Reflex, profoundly inhibits inflammation expression in multiple ways...
• Acetylcholine expression triggers increased NRF2 expression...
• NRF2 expression triggers increased Heat Shock Protein expression...
• NRF2 expression inhibits TNF (with crosstalk also)
• Heat Shock triggers both HSP and TNF Expression
• HSP 70 expression inhibits TNF

 

2011, TNF mediates the sustained activation of Nrf2 in human monocytes

 

2017, Nrf2 signaling pathway: Pivotal roles in inflammation

 

2009, Dynamic effect of heat shock pretreatment on apoptotic responses to TNF-alpha in liver cells

 

2008, Extracellular heat shock protein 70 inhibits tumour necrosis factor-α induced proinflammatory mediator production in fibroblast-like synoviocytes

 

Check this out...

 

2018, Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1 Cells

 

... The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs, and inhibition of H3k27me3 accumulation

 

H3k27me3, the gene that Morimoto found to Repress Heat Shock Protein, inhibits NRF2.

 

Katcher's study contains graphic figures showing increased expression of NRF2 which would trigger Heat Shock Protein expression.

 

 

 

I don't know if the results of Katcher's team can be trusted. We cannot know until the study findings are replicated in some way.

 

But no doubt... Katcher's study brief highlights the measuring of key biological substances seriously implicated with heat shock and its impact on aging.

Edited by HighDesertWizard, 17 February 2019 - 11:30 PM.

[HighDesertWizard]

I think you've proven that HSP is involved in the pathways used in the claimed rejuvenation; you haven't proven that HSP is the lynchpin or upstream cause of all the benefits.

 

I'm a fallibilist, so I don't think anything can be proven definitively.

 

And I'm not a scientist. I don't have to have anything definitively proven to take action if I believe the odds are extremely high that it would be beneficial.

 

I've been putting time into evidence gathering and posting to decide what I think the odds are that Heat Shock Protein expression is implicated as a decisive independent variable explaining Katcher's findings.

 

I think it's highly likely, say, 70% to 85% probable based on the evidence I've reviewed, some of which I've posted. And then I reviewed additional comments of Katcher's partner's blog and Mitteldorf's blog a bit...

 

"... what gives us hope is that the fundamentals behind this discovery are highly conserved in Nature across all mammals even species."

 

QuestforLife... Can you think of a mechanism other than HSP for which all the evidence I've highlighted above would line up to the degree that it does for HSP AND which is also "highly conserved in Nature across all mammals even species"

 

I can't. And that comment by Akshay's takes my belief about the odds even higher than 85%.

 

Can you give me a percentage probability you imagine is appropriate that it is primarily HSP-related?

 

So I'm now done, for a while, figuring out what I believe the essential science is that underlies what Katcher was up to. It's time now to figure out the details of what his intervention was to try to replicate that in my own life...

 

Edited by HighDesertWizard, 17 February 2019 - 11:59 PM.

[HighDesertWizard]

From the Morimoto study, 2015, Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction

 

The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress. The removal of germline stem cells preserves jmjd-3.1 expression, suppresses the accumulation of H3K27me3 at stress gene loci, and maintains the HSR. These findings suggest that competing requirements of the germline and soma dictate organismal stress resistance as animals begin reproduction.

 

In addition to that evidence above, Heat Shock has complex relationships with NRF2 and TNF.

 

Check this out...

 

2018, Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1 Cells

 

... The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs, and inhibition of H3k27me3 accumulation

 

H3k27me3, the gene that Morimoto found to Repress Heat Shock Protein, inhibits NRF2.

 

Katcher's study contains graphic figures showing increased expression of NRF2 which would trigger Heat Shock Protein expression.

 

 

 

I don't know if the results of Katcher's team can be trusted. We cannot know until the study findings are replicated in some way.

 

But no doubt... Katcher's study brief highlights the measuring of key biological substances seriously implicated with heat shock and its impact on aging.

 

Since making that post, I've found another type of evidence that I would have included in the post above had I known about it...

 

2018, Downregulated Nuclear Factor E2-Related Factor 2 (Nrf2) Aggravates Cognitive Impairments via Neuroinflammation and Synaptic Plasticity in the Senescence-Accelerated Mouse Prone 8 (SAMP8) Mouse: A Model of Accelerated Senescence

 

Background

We observed the effects of nuclear factor E2-related factor 2 (Nrf2) downregulation via intrahippocampal injection of a lentiviral vector on cognition in senescence-accelerated mouse prone 8 (SAMP8) to investigate the role of the (Nrf2)/antioxidant response element (ARE) pathway in age-related changes.

Material/Methods

< SNIP >

Results

Aging led to a decline in cognitive function compared with SAMR1 mice and the Nrf2-shRNA-lentivirus further exacerbated the cognitive impairment in SAMP8 mice. Nrf2, HO-1, PSD, and SYN levels were significantly reduced (all P<0.05) but high levels of inflammation were detected in SAMP8 mice with low expression of Nrf2. Furthermore, neurons were vacuolated, the number of organelles decreased, and the number of synapses decreased.

Conclusions

Downregulation of Nrf2 suppressed the Nrf2/ARE pathway, activated oxidative stress and neuroinflammation, and accelerated cognitive impairment in SAMP8 mice. Downregulation of Nrf2 accelerates the aging process through neuroinflammation and synaptic plasticity.

 

The text below is a paragraph from the study...

 

Spatial learning and memory impairment are early clinical features of AD caused by synaptic dysfunction rather than neuronal loss. We also measured PSD95 and SYN proteins. PSD95 and downstream molecular signals play an important role in synaptic development and neural information transfer. Previous studies in our lab showed that decreased SYN and PSD95 expression and cognitive impairment caused chronic stress in the SAMP8 mice [39]. Our study demonstrates that lower PSD95 and SYN expression in P8 mice was associated with synapse density and the degree of cognitive impairment. The correlation between synapse density and the degree of cognitive impairment is well established in patients with AD. Maintaining the expression of Nrf2/PSD95 may contribute to normal behavior in mice. The confocal microscopy results showing the reduction in the area expressing SYN indicate that Nrf2 depletion also disrupted mitochondrial function and synaptic integrity. Mitochondrial function, regulation of stress, and inflammation response all contribute to the loss of synaptic integrity, which is probably the cause of cognitive impairment in mice. Enhanced synaptic markers (SYN, PSD95, and Drebrin) modulate the synaptic structure and function of the hippocampus, all of which result in improved cognitive function [40].

 

If you're following the memes I've been writing about you know that PSD-95 is the gene that Seth Grant and his team found to be significantly implicated in an epigenetic turn. (Watch the video in the opening post of the Heat Shock related thread I've established.)

 

 

What's this mean?

 

It's more confirmation that the 2015 Morimoto Heat Shock-related Aging Switch in c elegans is very likely the same Epigenetic Turn that Seth Grant and his team found in mice and in humans in the study they published in 2017.

 

Edited by HighDesertWizard, 19 February 2019 - 02:55 AM.

[HighDesertWizard]

And again... Even tho I know the importance of asking a complete set of questions that provided info in my last two posts, I didn't ask another important question.

• Some elements that Heat Shock Proteins and the "epigenetic turn" Seth Grant and his team found in 2017 are described in this thread.
• NRF2 has a "biologically intimate" relationship with Heat Shock expression
• Like HSP, NRF2 has a relationship with H3K27ME3
• Like the findings found in Grant's 2017 study, NRF2 has a relationship with PSD-95

But Heat Shock Proteins also have a relationship, reported to be "regulatory", with OSKM induced pluripotency factors. (See this thread opening post for study references.)

 

The question... Does NRF2 also have a "biologically intimate" relationship with the OSKM induced pluripotency factors?

 

 

 

2014, Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells

 

2014, Two-hit Reprogramming of Induced Pluripotent Stem Cells

 

2016, NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming

Edited by HighDesertWizard, 20 February 2019 - 04:04 PM.

[Engadin]

.

 

 

 

 

S O U R C E :   Josh Mitteldorf's blog 'Aging Matters'

 

naxleo posted original bioRXv's source yesterday at Longecity (Reversing age: dual species measurement of epigenetic age with a single clock)

 

 

 

 

 

 

If you eschew hyperbole and hang in for the long haul, maintaining a discipline of understatement in the midst of a flashy neon world, you may be offered a modicum of credence when you make an extraordinary announcement. No one is entitled to this courtesy twice. If the news that you trumpet to the moon does not pan out, your readers will be justified in discounting everything you say thereafter.  

 

Here goes.

 

 

 

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.

 

 

 

 

Cartoon by Maddy Ballard

 

 

 

 

In the race to effect substantial, system-wide rejuvenation, Harold Katcher is a dark horse. He has the right academic credentials and a solid history of research. In fact, in earlier life he was part of a team that discovered the breast cancer gene, brca1. I asked Harold for a biographical sketch, and have printed it in a box at the end of this posting.

 

But Katcher has no research grants or university lab or venture capital funding, no team of grad students mining databases and screening chemicals in the back room.

 

One thing Katcher has going for him is the correct theory. Most of the explosion in aging research (and virtually all the venture capital startups) are looking to treat aging at the cellular level. Their paradigm is that aging is an accumulation of molecular damage, and they see their job as engineering of appropriate repair mechanisms.

 

The truth, as Katcher understands it, is that, to a large extent, aging is coordinated system-wide via signal molecules in the blood. It was our common realization of this vision that brought Katcher and me together more than a decade ago. Katcher briefly describes his 2009 epiphany below. It was the source of his 2013 essay (it took a few years to get it into print) on the significance of parabiosis experiments for the future of aging science.

 

Of course, Katcher was not the only one to get the message about the power of signal molecules in the blood to reprogram tissues to a younger state throughout the body. The problem is that there are thousands of constituents represented in tiny concentrations in blood plasma, but conveying messages that cells read. Which of these are responsible for aging? A small number of labs, including the Conboys at Berkeley, Amy Wager at Harvard, and Tony Wyss-Coray at Stanford have been searching for the answer over the last decade and more.

 

Katcher has been able to guess or intuit or experimentally determine the answer to this question. With seed funding from Akshay Sanghavi, he set up a lab in Bangalore two years ago, and tried to rejuvenate old lab rats, using a fraction extracted from the blood of younger rats. The first round of experiments were encouraging, published in this space a year ago. He obtained the next round of funding from a reader of this blog, and had enough rats to titrate dosages experimentally, and to see if treated rats who aged again over time could be re-treated successfully.

 

There is a hole in this story that awaits the resolution of intellectual property rights. Katcher and Sanghvi have not applied for patents and have not yet found a suitable partner to provide financing for human trials. They have not revealed any details of the treatment, besides the fact that it is in four intravenous doses, and that it is derived from a fraction of blood plasma. Katcher thinks that the molecules involved will not be difficult to manufacture, so that when a product is eventually commercialized, it will not require extraction from the blood of live subjects, rodent or human.

 

We’re still waiting for longevity curves of these treated rats. In the meantime, the best available surrogate measure of age comes from methylation clocks, as developed by Steve Horvath at UCLA, and other scientists as well. Crucially, Katcher found an ally in Horvath, who didn’t just test his rejuvenated rats, but did the needed statistical analysis to develop a set of six methylation clocks specialized to rats. FIve of the clocks are optimized for different tissues, and one is calibrated across species, so that it can measure age in humans as well as corresponding age in “rat years” (about 1/40 human year). The two-species clock was a significant innovation, a first bridge for translating results from an animal model into their probable equivalent in humans.

 

In a paper posted to BioRxiv on Friday, Katcher and Horvath report results of the methylation measurements in rejuvenated rats. “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.”

 

 

 

 

Human-rat clock measure of relative age defined as age/maximum species lifespan.

 

 

 

Besides the methylation clock, the paper presents evidence of rejuvenation by many other measures. For example:

 

• IL-6, a marker of inflammation, was restored to low youthful levels
• Glutathione (GSH), superoxide dismutase (SOD), and other anti-oxidants were restored to youthful levels
• In tests of cognitive function (Barnes maze), treated rats scored better than old rats, but not as well as young rats.
• Blood triglycerides were brought down to youthful levels
• HDL cholesterol rose to youthful levels
• Blood glucose fell toward youthful levels

A major question in blood plasma rejuvenation experiments has been how often the cure must be administered. Many of the components of blood plasma are short-lived, secreted into the blood and absorbed continuously throughout the day. The good news from Katcher’s results is that it seems only four injections are needed in order to achieve rejuvenation.

 

 

 

 

 

.../...

 

 

 

 

 

T O   A C C E S S   T H E   R E S T   O F   T H E   S T U D Y,   P L E A S E   V I S I T   T H E   S O U R C E .

 

 

 

 

 

.

 

Edited by Engadin, 11 May 2020 - 10:11 AM.

[Mind]

Impressive! Kudos to Dr. Katcher for the results in mice. I look forward to human trials.