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An Ancient "Heat Shock"/NRF2/Pluripotency Related Epigenetic Turn* Accelerates Human Aging** and These can be Modulated

aging switch seth grant psd-95 nf-kb heat shock protein senescence sasp nrf2 morimoto survival

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#1 HighDesertWizard

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Posted 21 October 2018 - 05:35 PM


"Explanations that transform the world are the beginning of infinity" -- David Deutsch

 

I’m a Fallibilist, persuaded by the arguments of David Deutsch and Karl Popper. That means I’m never certain about anything. And as a result, I find adventure in making conjectures about reality in public if I believe they cannot be easily falsified.

 

And if the stakes are high, the conjecture is 3 to 4 standard deviations away from the current consensus bulge (even while it cannot be easily falsified), well, then, making, exploring, and tweaking the conjecture in public is exhilarating!

 

And such is the case with this conjecture.

 

A Heat Shock Protein-Related Switch Initiates the Aging Process in Humans

____________________________

 

In this forum thread, I'll document evidence related to this conjecture and welcome feedback and questions, both of support and criticism.

 

I’ll ask Longecity Leadership to provide me with edit capabilities of a moderator for this thread. Please don’t comment until they have.

  • In this Opening Post, I’ll sketch the argument and some evidence for the conjecture. I'll tweak this opening post for errors of language, lists of and links to evidence, and logic.
  • In Post 2, I’ll state and maintain a more detailed status and summary of the evidence for and against the conjecture as it evolves in the thread discussion. By November 1st, Post 2 should very closely approximate the opening post.
  • In Post 3, I'll summarize the most significant implications of the conjecture as I understand them.
  • In Post 4, I’ll summarize ways we might leverage the conjecture for health and survival probability benefit, also updated as the discussion evolves.
  • I'll update posts 2, 3, and 4 as the time, evidence, and the thread discussion evolves. I'll try to keep the most significant info current in those posts.

I’ve been researching and thinking about the evidence for this conjecture for many months now. I don't believe it can be easily falsified. My hunch is that it will pass attempts to falsify it, but I don't know that for certain. So I’m exhilarated to post it, looking forward to the discussion that follows.
____________________________

 

Three years ago, I knew next to nothing about Heat Shock Proteins. There are a number of them it turns out. I knew about the concept of hormesis, that some kinds of stress might be health enhancing, but didn’t think much about it.

 

But in 2016, I learned of two studies from 2015 that captured my attention and imagination.

  • Richard Morimoto’s team at Northwestern found that a heat shock protein-related aging switch got flipped in c elegans around the time of sexual maturity.

Repression of the heat shock response is a programmed event at the onset of reproduction

  • 2015 also witnessed the publication of the now-well-known Finnish Sauna Study. Frequent and, more importantly, extended, time in saunas, it turns out, dramatically increased survival probability in human males.

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

 

I've previously posted about the key image from this study in a forum thread established to document the importance of NF-kB Inhibition for increasing Survival Probability.

 

xtaOIKN.png

 

 

Around that same time, I also became aware...

  • of Rhonda Patrick’s short video lectures about the benefits of Sauna and Heat Shock Proteins
  • that an acquaintance had begun selling the Avacen device, approved by the FDA, for pain relief. Its health effects are profound even if the device itself was too expensive. It quickly became apparent to me that the Avacen was triggering HSP expression. I mention the Avacen, not to promote it, but to mention all the factors that captured my attention at the time.

I’ve worked as a professional database, data analytics, and data science software engineer for close to 35 years in large enterprise contexts where the truth about what the data means sometimes gets confusing. I’ve learned to trust my intuition when disparate bits of information might be reframed in a way not previously seen. Many times, that reframing goes nowhere but, once in a while, it can lead to helpful ways to reimagine reality. During those days, not so long ago, I knew something important was going on vis-a-vis HSPs that I didn't believe others or I understood and I was determined to figure out what it was.

 

After reflecting on the facts described above, I became intensely interested in the question and a key requirement proceeding from it.

  • Might the HSP-related Aging Switch that Morimoto’s team found in c elegans be preserved in mammals, including in humans?
  • For reasons I've described here, I believed that an aging switch must be related to an increase in NF-kB expression.

To pursue the question further, then, I needed first to determine that a decline in HSP expression hypothesized by a switch would result in increased inflammation expression.

 

You'll notice that I resolved this NF-kB question for myself in that same Longecity post in which the Sauna study Survival Curve is posted.

 

NUDt7TG.jpg
____________________________

 

At that time, July 2017, I'd come around to the view that there was something profoundly important missing in the body of science about Heat Shock Proteins and I was determined to figure out what it was.

  • enhanced my personal regimen by increasing ingestion of substances and investigation of techniques that might trigger Heat Shock Protein in myself and friends and loved ones by means known to be healthful.
    • My purchase of a PEMF mat is a few weeks away. Take a look at the science and then the reviews of PEMF product offerings.
  • Put my self on alert to find a study showing that there did exist a Heat Shock Protein-related aging switch.

____________________________

 

Bingo!

 

In 2017, Seth Grant's team at Edinburgh published a study I imagined might be on the horizon, demonstrating the existence of an aging switch in humans.

 

Ø A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia
 

We’re covering a lot of ground in this opening post and I can’t describe the significance of each point in detail. You'll need to do your own homework. That said, please note two points of evidence from the Seth Grant study illustrated in Figure 1.

  • graphic display of data illustrating gene expression turning points is striking in demonstrating the existence of an aging switch.

TzzqOEYl.jpg

  • The gene expressions associated with the switch shown in the figure above can be used to predict actual age. The current version is not as accurate as the comparable age prediction technique developed by Horvath, but it’s not bad. And the gene expressions upon which the predictive technique is based are the genes highlighted in the switch pics above. I believe this is an extremely significant fact for the future.

sm9vCIdl.jpg

 

 

 

Dr Grant gave a 38 minute talk including Q & A about the study in 2017. It's entitled, The Time of Your Life.

 

 

 

Now, obviously, the fact that Grant’s team found this switch in mice and in humans doesn’t mean that they or anyone else has demonstrated that it is Heat Shock Protein-related. As far as I know, no one has.
____________________________

 

I’ve spent the last 6 months trying to figure out if evidence has been published that establishes whether this "switch" is heat shock protein-related, or not.

 

In what follows below, I provide reference links from two bodies of evidence that lead me to a conclusion about that question and to making this post about my conclusion: The Conjecture being the thread subject.
____________________________

 

A Heat Shock Protein-Related Switch Initiates the Aging Process in Humans

 

1 – Heat Shock Proteins are implicated vis-à-vis PSD-95 expression and in Schizophrenia

 

Grant’s team found that the genes underlying the switch are related to a cognitive disorder, schizophrenia, and to a specific biological object, Post-Synaptic Density 95.

  • I’ve figured that, if the switch found is Heat Shock Protein-related, we should expect to find studies demonstrating that HSPs are related to both of those variables.
  • Do those expected studies exist? Yes. But is HSP expression related to both Schizophrenia and PSD 95 "profound enough" that my conjecture is warranted?
  • I believe the answer is yes, or at least "yes-enough", that my conjecture cannot easily, or at all be Falsified, given present knowledge.

HSPs and The Time of Our Lives Independent Variable Study Links

 

 

HSPs and Schizophrenia

There are more studies I could include in the list above for HSP and Schizophrenia. I imagine some of the additional studies might be posted later in this forum thread.

 

 

HSPs and PSD-95

Now I've had everything written above in mind for at least 5 months, but I wasn't convinced myself of the conjecture, let alone imagine it was convincing enough to post. Something more was needed to make the case for the conjecture.

 

I believe I recently found it.
____________________________

 

2 – Heat Shock Proteins are implicated as important in the OSKM, Induced Pluripotent Stem Cell (iPSC), literature

 

In December 2016, the Salk Institute Bel Monte team published a study showing that Aging could be Reversed in Rodents via an epigenetic mechanism triggered by the OSKM "Yamanake Factors". A few months later, the Blasco team in Spain followed up with a study showing that when the Salk team techniques were followed there were positive impacts on Telomere-related variables.

If the aging switch Grant's team found is, in fact, heat shock protein-related, then, the factors manipulated by the OSKM rejuvenation experiments ought also to be heat shock protein-related.

 

Right? Well, I think they must and here's what I found without much effort in a first search.

 

HSPs, the OSKM “Yamanaka Factors”, and iPSCs

 

Many of us are familiar with the high information content of Vincent Giuliano's posts on his Anti-AgingFirewalls blog. His most recent blog post (Sept 2, 2018) speaks to the relationship of senescent cells triggering the Yamanaka OSKM factors. It's a brilliant post and it's worthwhile to review his summary below.

 

Vincent Giuliano @ AGING, CELL AND TISSUE REPAIR, RENEWAL AND REGENERATION, INFLAMMATION AND THE SASP
"The basic message in a nutshell

 

"When we are young and peppy, cell and organ regeneration and renewal go on as background processes in our body all the time. Here is how it works: molecular distress signals such as associated with injuries, inflammation, or cell senescence, trigger the partial regression of normal mature body cells back to earlier less differentiated epigenetic states. This is a process of de-differentiation, one that moves cells backwards in their developmental trajectory towards becoming stem cell, but that stops short of going all the way. Then these de-differentiated cells re-differentiate so as to create healthy new cells. And renew organs, as needed. If the injury is to cells that are supposedly permanent and do not reproduce, such as neurons in the brain, no problem. In this case neighboring microglial de-differentiate and then re-differentiate changing their identity to becoming neurons. The de-differentiation takes place with the body using the same factors that Yamanaka and other researchers have used to de-differentiate cells in-vitro removed from the body: Oct3/4, Sox2, Klf4, and c-Myc, commonly referred to as OSKM. All this happens on the local level when needed, whether within the heart, the brain, the liver or elsewhere. As we grow older, however, typical changes occur that effectively slows down or stops this renewal process. These include certain epigenetic changes associated with aging, and states of chronic inflammation. These inhibiting factors appear to be only partially understood as of now. Despite this, the very good news appears to be that to a large extent we may be able to control and reverse the adverse epigenetic changes and neutralize chronic inflammation. We already know the interventions that do this, and they are very simple and broadly available. We don’t need additional scientific breakthroughs; we don’t need extremely expensive new drugs or high-technology treatments. This may be the blockbuster news with regard to antiaging approaches that we have been waiting for for so many years. Here, now."

 

__________

In light of Giulano's fantastic literature review, I'll close with three study references about Heat Shock and Senescence / SASP in a specific context to drive home the point of the importance of Heat Shock Proteins and Heat Therapy.

"At early stages of atherosclerosis, senescent foam cells promoted the expression of inflammatory cytokines. At later stages, they promoted the expression of matrix metalloproteases implicated in the rupture of atherosclerotic plaque, which can lead to blood clots. Experimental removal of the senescent cells had beneficial effects at both stages of the disease."

"Unhealthy lifestyle persistently feeds forward inflammation in metabolic organs thus imposing senescence-associated secretory phenotype (SASP), as observed in obesity and type 2 diabetes. However, SASP blocks physiological resolution of inflammation by suppressing the anti-inflammatory and anti-senescent heat shock (HS) response, i.e., the gene program centered in heat shock factor-1 (HSF1)-dependent expression heat shock proteins (HSPs). As SASP-inducing factors are not removed, leading to the perpetuation of inflammation, we argued that SIRT1-HSF1-HSP axis might also be suppressed in atherosclerosis, which could be reversible by heat treatment (HT), the most powerful HS response trigger.... HT completely reversed suppression of the above HS response proteins, while markedly inhibiting both VCAM1 expression and NF-κB DNA-binding activity. Also, HT dramatically reduced plasma levels of TG, total cholesterol, LDL-cholesterol, oxidative stress, fasting glucose and insulin resistance while rising HDL-cholesterol levels. HT also decreased body weight gain, visceral fat, cellular infiltration and aortic fatty streaks, and heart ventricular congestive hypertrophy, thereby improving aortic blood flow and myocardial performance (Tei) indices. Remarkably, heat-treated mice stopped dying after the third HT session (= 8 human years), suggesting a curative effect. Therefore, evolution of atherosclerosis is associated with suppression of the anti-inflammatory and anti-senescent SIRT1-HSF1-HSP molecular axis, which is refreshed by chronic heat treatment."

 

 

Caveats...

  • I claim no deep or broad knowledge of HSPs, OSKM, PSD-95. I haven't made any coherent and integrated statement about how HSPs actually work. In this opening post, I've merely highlighted puzzle pieces that I'm convinced will be important to put the entire aging / rejuvenation puzzle together.
     
  • I'll be tweaking this opening post for a week or two, after which I won't touch it.
  • You may disagree that there is a Heat Shock Protein-related Aging Switch in Humans... Fantastic!

Well, except for one thing. Seth Grant's study says there IS an Aging Switch in Humans. It needs to be replicated of course. In the meatime, if you don't think it's Heat Shock Protein-related, then, please, tell us, what kind of switch is it?

 

I've sketched my hypothesis about what it is. Post Yours!   :)  

 

Please don't post to this thread until I have posts 2, 3, and 4 up...

 

Cheers!

 

Steve

Y


Edited by HighDesertWizard, 02 March 2019 - 05:55 PM.

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#2 HighDesertWizard

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Posted 22 October 2018 - 03:32 PM

In this post, I’ll state and maintain a more detailed summary and status of the evidence and argument for the conjecture as it evolves in the thread discussion.
 
The point is to provide a summary of the discussion as it has evolved at the thread top so those new to the discussion can get up to speed quickly without having to wade through the whole thread.
 
 
 
2018-10-25
 
It has been pointed out to me that, strictly speaking, aging developments begin even in youth. I want to acknowledge this point. I believe this is true.
 
I've thought about renaming the thread to be technically correct. If you think I should, say so below.
 
That said, I believe that a profoundly more significant HSP Switch is thrown in our mid-20s that begins the truly serious aging process in us. And that switch makes whatever occurred at an earlier time small in comparison. So, at least for now, I'm happy with this thread title.
 
 
 
2018-10-29
 
I've decided to rename this thread whenever I'm clear that the impulse of the Conjecture current thread title can be enhanced. The pre-change and post-change names are as follows

  • A Heat Shock Protein-Related Switch Initiates the Aging Process in Humans
  • A Heat Shock and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans

The rationale for the name change goes like this...

  • I decided on the original name before I had fully absorbed the meaning of the multiple studies listed in the opening post showing that HSPs "regulated" iPSC processes. Including the "iPSC Related" phrase is entirely appropriate and better highlights the importance of determining whether the conjecture explains something important about aging.
  • I've replaced the word Switch with a phrase having an explicitly biological meaning, "Epigenetic Turn". IMO, the word Switch is an apt word to characterize the peak gene expression shown in a diagram of the opening post, but, at least for now, I prefer to use less "loaded" phrases.
  • I've replaced the word "the" with the word "an" to address the concern mentioned above about some important epigenetic processes going on in youth. The point of the "the-to-an" change is to recognize this fact.
  • I consciously continue not to use the word Program in the thread title for various reasons.

 
 
2018-10-29
 
I renamed the thread again today so that 'Heat Shock' became "'Heat Shock'". As I understand it, by random historical accident, our innate stress response got the name Heat Shock Protein because the first variable to impact the stress response was Heat.
 
 
 
2018-11-14
 

The conjecture that is the title of this thread is composed of 4 sub-conjectures that have varying degrees of evidence support. Each of the 4 sub-conjectures is an important topic for discussion on its own. To sharpen the focus and discussion, I believe it would be useful to distinguish them explicitly and to identify posts by which sub-conjecture is being discussed. The 4 conjectures are distinguished below with different kinds of font highlighting.
 
From this point forward, I'll attempt to address only one sub-conjecture phrase per post unless I'm addressing the thread title conjecture itself. I'll also edit my previous posts and insert the appropriate sub-conjecture phrase as I have time to do so.
 
Feel free to do the same in your posts to this thread.
 
I have no idea how this will turn out, but my hunch is that it will be helpful.
 
:)
 
xIEGBLyh.png
 
Brief descriptions of these 4 sub-conjectures appear below.
 
 
4hZYnwuh.png
 
There is an established literature about the relationship of the Stress Response, aka, "Heat Shock", is related to OSKM, iPSC, Reprogramming.
 

 
kaSskMdh.png
 
This sub-conjecture is a statement summarizing one key finding of the Seth Grant / Nathan Skene / Marcia Roy study entitled, A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia, discussed in the opening post.
 

 
CwxbAxUh.png
 
This sub-conjecture concerns the proposition that the ancient heat shock-related gene expression turn Richard Morimoto found in c. elegans in 2015 is the "approximately" the same epigenetic turn identified by the team led by Seth Grant.
 

 
K2Yf6W4h.png
 
This sub-conjecture concerns the reason many of us, especially me, are interested in this topic. Can we modulate aging in some way by leveraging a "heat shock" related process in ourselves?
 
I suggest we have the ability and means to find out if we try.
 
:)


Edited by HighDesertWizard, 15 November 2018 - 03:43 AM.

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#3 HighDesertWizard

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Posted 22 October 2018 - 03:37 PM

Post 3...

  • In Post 3, I'll summarize the most significant implications of the conjecture as I understand them.

I don't have moderator capability yet, but I've asked to be given it by Longecity leadership...

 

The key reason I want it...

  • To provide a summary view at the top of the thread of the discussion as it has evolved... I want you not to have to read the whole thread to know what's happened within it...

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#4 HighDesertWizard

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Posted 22 October 2018 - 03:40 PM

Post 4...

  • In Post 4, I’ll summarize ways we might leverage the conjecture for health and survival probability benefit, also updated as the discussion evolves.

I don't have moderator capability yet, but I've asked to be given it by Longecity leadership...

 

The key reason I want it...

  • To provide a summary view at the top of the thread of the discussion as it has evolved... I want you not to have to read the whole thread to know what's happened within it.

 

Feel free to post to this thread now. I don't have moderator capability to tweak the Opening Post and edit posts 2, 3, and 4... But I expect it momentarily...

 

In the meantime, I look forward to your thoughts and comments...


Edited by HighDesertWizard, 22 October 2018 - 03:42 PM.


#5 Nate-2004

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Posted 22 October 2018 - 08:59 PM

There is a Rhonda Patrick interview with a guy stating that (Around 45-55mins in) hyperthermic (or is it hypOthermic?) therapy like sauna can help schizophrenics significantly. Based on all the above, any theories as to why?

 


Edited by Nate-2004, 22 October 2018 - 09:37 PM.


#6 HighDesertWizard

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Posted 23 October 2018 - 12:13 AM

There is a Rhonda Patrick interview with a guy stating that hyperthermic therapy like sauna can help schizophrenics significantly. Based on all the above, any theories as to why?

 

"https://www.youtube.com/watch?v=6DtJGJWjDys&t=2394s"

 

K2Yf6W4h.png

 

Nate... Thanks for your comment. I'm a fan of Rhonda Patrick but I didn't know about that interview and video.

 

I don't know what more I can add now to what I've written above.

 

IMO, the fact that HSP 70 polymorphisms are implicated in schizophrenia is one component of my conjecture argument that the switch Seth Grant's team found is HSP related.

 

Neuroinflammation is believed to be a cause of schizophrenia.

 

We know that, in some contexts, some types of HSP expression inhibit inflammation, in others, trigger it. I'm not clear that the various HSP-contexts and types and their inflammatory consequences have been sorted out. I included the HSP intra-cellular diagram in the mix of the opening post to highlight the paradoxical character of HSP expression.

 

Evidently, from your video link, we know it's highly probable that hyperthermic therapy can help in schizophrenia. That fits with the essential argument I made in the opening post.


Edited by HighDesertWizard, 15 November 2018 - 03:45 AM.


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#7 HighDesertWizard

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Posted 23 October 2018 - 01:33 AM

This, my first non-opening-non-admin-non-question-answer post with evidence to support the conjecture...

 

K2Yf6W4h.png

 

I'd forgotten all about this until today. I'd forgotten that, more than a year ago, in another thread, I noticed Butyrate induced PSCs...

 

So it turns out that Butyrate impacts HSP 70 Expression...

 

To be clear about this... I'm confused by the science posted below. Some of it runs counter to what I was expecting... But all that means is that I'm missing important knowledge...

 

1997 - Modulation of heat-shock protein 70 (HSP70) gene expression by sodium butyrate in U-937 promonocytic cells: relationships with differentiation and apoptosis

 

From the abstract

 

The administration of sodium butyrate at 0.75 mM induced the functional differentiation of U-937 human promonocytic leukemia cells with negligible cell mortality. However, the drug rapidly caused cell death with characteristics of apoptosis when used at concentrations of 5 mM and above. In addition, butyrate stimulated the expression of the stress-responsive heat-shock protein 70 (HSP70) gene when applied at both differentiation-inducing and apoptosis-inducing concentrations.

 

2003 - Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB

 

2005 - Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology

 

4hZYnwuh.png

 

The conceptual net finding of this post...

 

At least one substance has been found implicated in profound Human IPSC processes. IPSCs, because they have been implicated in Rejuvenation are also implicated in Aging (and a switch?). And that same substance has been found impactful on HSP 70.

 

The possibility of Falsifying the conjecture this thread opened with yesterday just got smaller...

 

:)


Edited by HighDesertWizard, 15 November 2018 - 03:47 AM.

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#8 HighDesertWizard

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Posted 23 October 2018 - 01:54 AM

K2Yf6W4h.png

 

Links to PEMF / Heat Shock Protein Studies...

 

Mostly Positive Reviews of PEMF Mats at Amazon... Not trying to advertise anything to benefit some manufacturer... I'm just sayin' that we should consider all the evidence, including anecdotal customer satisfaction stories if they're available. Mostly positive reviews should absolutely be expected if something as profound as the conjecture of this thread is actually true...

 

The one shown in the pic is more of a top of the line PEMF Mat... Not sure I want to spend that much... But soon I'll have one...

 

:)

 

reZQeuAl.png


Edited by HighDesertWizard, 15 November 2018 - 03:48 AM.


#9 Nate-2004

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Posted 23 October 2018 - 05:32 PM

How would this mat compare to spending 20 mins in the sauna 4 times a week?


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#10 HighDesertWizard

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Posted 25 October 2018 - 02:14 PM

K2Yf6W4h.png

 

How would this mat compare to spending 20 mins in the sauna 4 times a week?

 

Hi Nate... That's a great question. I don't know the answer.

 

What I do know is that, even if I had a sauna, I wouldn't use it 4 times a week. I'd get busy and always Intend to use it, but then, life happens and I wouldn't.

 

A mat is something I'd use. So, for me, getting a mat makes sense.

 

That said, your question suggests that having a single measure of HSP related impact would be a good thing and I completely agree about that.

 

Thanks for asking a great question!


Edited by HighDesertWizard, 15 November 2018 - 03:49 AM.


#11 Nate-2004

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Posted 25 October 2018 - 06:30 PM

I have a strict gym / sauna schedule, I go Mon, Tues, Weds and Fri every week during my lunch break. I exercise for 20 mins, then sauna for 20 mins. It's basically required. I can't not do it because I'll be depressed if I ever stop. 2 years 9 months of consistency and counting, though I do take breaks during vacations.

 

I know the average 80 to 90 degree celsius standard sauna (with the rocks and heater) has no PEMF like the mat does, I'm wondering if the mat does something different, perhaps by stimulating the vagus nerve. Not sure if it does this in the same way the guy in the video you posted describes it, as that requires an implant and just 5 mins a day of some specific kind of electrical stimulation I think.

 


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#12 HighDesertWizard

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Posted 26 October 2018 - 03:27 AM

I have a strict gym / sauna schedule, I go Mon, Tues, Weds and Fri every week during my lunch break. I exercise for 20 mins, then sauna for 20 mins. It's basically required. I can't not do it because I'll be depressed if I ever stop. 2 years 9 months of consistency and counting, though I do take breaks during vacations.

 

I know the average 80 to 90 degree celsius standard sauna (with the rocks and heater) has no PEMF like the mat does, I'm wondering if the mat does something different, perhaps by stimulating the vagus nerve. Not sure if it does this in the same way the guy in the video you posted describes it, as that requires an implant and just 5 mins a day of some specific kind of electrical stimulation I think.

 

Great question, Nate.

 

I should reiterate that my knowledge of both heat shock protein and PEMF isn't great. That's a state I intend to change but at this point, I need to be careful not to get even the basic info wrong.

  • Exercise and sauna have both been shown to trigger heat shock protein.
  • There is a relationship between Vagal activity and heat shock protein expression but it's not especially voluminous. But what does exist is not insignificant. You'll recall from the SMILE Learning Log Threads that the primary neurotransmitter of vagal activity is acetylcholine. Take a peek at the tip of that literature iceberg. It's not time yet for me to dig into that.

"... Here, we show in C. elegans that a moderate increase in physiological cholinergic signaling at the neuromuscular junction (NMJ) induces the calcium (Ca2+)-dependent activation of HSF-1 in post-synaptic muscle cells, resulting in suppression of protein misfolding. This protective effect on muscle cell protein homeostasis was identified in an unbiased genome-wide screening for modifiers of protein aggregation, and is triggered by downregulation of gei-11, a Myb-family factor and proposed regulator of the L-type acetylcholine receptor (AChR). This, in-turn, activates the voltage-gated Ca2+ channel, EGL-19, and the sarcoplasmic reticulum ryanodine receptor in response to acetylcholine signaling..."

"To develop an alternative to hyperthermia for the induction of hsp70 for presurgical cytoprotection, we investigated the optimal exposure conditions for magnetic field induction of hsp70. Normal human breast cells (HTB124) were exposed to 60-Hz magnetic fields and hsp70 levels were measured following three different exposure conditions: continuous exposure up to 3 h, a single 20-min exposure, and a single 20-min exposure followed by repeated 20-min exposures at different field strengths. In cells exposed continuously for 3 h, hsp70 levels peaked (46%) within 20 min and returned to control levels by 2 h. Following a single 20-min exposure, the return of hsp70 levels to control values extended to more than 3 h. When cells underwent a 20-min exposure followed by repeated 20-min exposures (restimulation) with different field strengths, additional increases in hsp70 levels were induced: 31% at 1 h, 41% at 2 h, and 30% at 3 h."

Check out the wound pictures and the increased healing rate image.

  • And a look at customer reviews of PEMF products are positive in a way that correlates with what one would expect from the science.

My girlfriend just purchased a heated-PEMF mat at my continual urging for her back and arthritis pain as well as for overall health and I'm getting one in mid-November. We're unpacking hers this weekend and I'm looking forward to taking it for a spin..

 

I should say... I have no body pain to speak of... I'm getting a mat for longevity purposes...

 

There are mats that only do heat and others that only do PEMF. I'm thinking that having a mat that does both is a good thing. I'm continuing to figure out which one to get.

 

Multiple study references in the opening post point to a profound HSP relationship, perhaps regulatory, to Pluripotency and OSKM Re-Programming.

 

I'm in to spend years getting the kind of handle on this science in this thread that I have on the science of The Inflammatory Reflex. A PEMF Mat is just one way to intervene to trigger HSPs.

 

But today, I'm a newbie. I hope a good many folks at Longecity will join me on this learning journey.

 

:)


Edited by HighDesertWizard, 26 October 2018 - 03:36 AM.

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#13 HighDesertWizard

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Posted 26 October 2018 - 04:22 AM

I've updated post #2 as follows...

 

In this post, I’ll state and maintain a more detailed summary and status of the evidence and argument for the conjecture as it evolves in the thread discussion.

 

The point is to provide a summary of the discussion as it has evolved at the thread top so those new to the discussion can get up to speed quickly without having to wade through the whole thread.

 

 

 

It has been pointed out to me that, strictly speaking, aging developments begin even in youth. I want to acknowledge this point. I believe this is true.

 

I've thought about renaming the thread to be technically correct. If you think I should, say so below.

 

That said, I believe that a profoundly more significant HSP Switch is thrown in our mid-20s that begins the truly serious aging process in us. And that switch makes whatever occurred at an earlier time small in comparison. So, at least for now, I'm happy with this thread title.

 



#14 HighDesertWizard

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Posted 29 October 2018 - 02:19 PM

I've updated post #2 as follows on 2018-10-29...

 

 

 

In this post, I’ll state and maintain a more detailed summary and status of the evidence and argument for the conjecture as it evolves in the thread discussion.

 

The point is to provide a summary of the discussion as it has evolved at the thread top so those new to the discussion can get up to speed quickly without having to wade through the whole thread.

 

 

 

2018-10-25
 

It has been pointed out to me that, strictly speaking, aging developments begin even in youth. I want to acknowledge this point. I believe this is true.

 

I've thought about renaming the thread to be technically correct. If you think I should, say so below.

 

That said, I believe that a profoundly more significant HSP Switch is thrown in our mid-20s that begins the truly serious aging process in us. And that switch makes whatever occurred at an earlier time small in comparison. So, at least for now, I'm happy with this thread title.

 

 

 
2018-10-29
 
I've decided to rename this thread whenever I'm clear that the impulse of the Conjecture current thread title can be enhanced. The pre-change and post-change names are as follows
  • A Heat Shock Protein-Related Switch Initiates the Aging Process in Humans
  • A Heat Shock and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans
The rationale for the name change goes like this...
  • I decided on the original name before I had fully absorbed the meaning of the multiple studies listed in the opening post showing that HSPs "regulated" iPSC processes. Including the "iPSC Related" phrase is entirely appropriate and better highlights the importance of determining whether the conjecture explains something important about aging.
  • I've replaced the word Switch with a phrase having an explicitly biological meaning, "Epigenetic Turn". IMO, the word Switch is an apt word to characterize the peak gene expression shown in a diagram of the opening post, but, at least for now, I prefer to use less "loaded" phrases.
  • I've replaced the word "the" with the word "an" to address the concern mentioned above about some important epigenetic processes going on in youth. The point of the "the-to-an" change is to recognize this fact.
  • I consciously continue not to use the word Program in the thread title for various reasons.

 

 

 
2018-10-29
 
I renamed the thread again today so that 'Heat Shock' became "'Heat Shock'". As I understand it, by random historical accident, our innate stress response got the name Heat Shock Protein because the first variable to impact the stress response was Heat.

 

 

 


Edited by HighDesertWizard, 29 October 2018 - 04:33 PM.


#15 HighDesertWizard

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Posted 29 October 2018 - 03:02 PM

Why the conjecture of this thread is important to me, even for us, to resolve as true or false...

 

The conjecture declares that a causal relationship exists among at least 3 important concepts and bodies of evidence related to aging.

  • An Epigenetic Turn of a specific set of genes has been shown significantly correlated with Aging in mice and in humans
    • The implicated genes are related both to Schizophrenia and PSD-95 at a minimum
  • Heat Shock
    • has been implicated in significant relationships with PSD-95
    • has been implicated in significant relationships with schizophrenia
    • repression has been shown to exist in c Elegans as a kind of Switch related to Aging
    • triggering therapies have been shown to provide significantly increased health and lifespans in human experiments
    • has been implicated in significant relationships to Senescence and SASP
    • regulates Induced Pluripotent Stem Cell (iPSC) Reprogramming related factors
  • Induced Pluripotent Stem Cells (iPSCs)
    • reprogramming has been shown to Reverse Aging Symptoms In-Vivo in rodents
    • have been implicated in significant relationships with Senescence and SASP

These bodies of literature reference each other in information-rich ways indicative of profound relationships among them that we don't presentaly understand. Better understanding might result in significant benefit when that understanding is properly leveraged.

 

There are billions of humans alive younger than the age that the epigenetic turn is supposed to take place. Very interesting and knowledge increasing monitoring-only studies might be performed to better understand aging with these younger humans. We older humans might benefit from those monitoring-studies.

 

I'm convinced that many facts related to the conjecture are already known and published, or soon will be, and that pursuing evidence related to the conjecture is among the best and fastest ways to get at questions and procedures of Do-It-Yourself Aging-Related Reprogramming.

 

I'm convinced that careful evidence study, analysis, discussion, and reflection is essential to accomplishing this.

 

I'm participating in the Longecity sponsored Biomarkers trial. My results ain't too bad. I've been working on the Telomere Length angle for a while now, at Longecity and in my personal regimen. I can't prove it but I believe my regimen is the thing responsible for my Teloyears test result. I'm taking another one soon.

 

But I want to improve my Biological, Epigenetic (MyDNAge) Age test result.

 

That's why I'm here doing this thread.

 

--------------

 

I do this kind of specific knowledge-domain discovery for a living as a database app software engineer. I make lots of mistakes. But I'm ruthless when it comes to reversing course and changing my mind when I find I am in error. In my universe, I get fired if I refuse to quickly admit error.

 

I have a list of tasks that I know need doing to fully explore the conjecture of this thread. This topic is important enough that I'll do all the tasks myself, working on them part-time, one by one, if I have to, unless and until the evidence tells me it's not worth it.

 

Exploring the conjecture will go faster if I have help doing the tasks that need doing. If you're interested, have good search and information presentation skills, and you'd like to contribute to figuring out what gives with this conjecture, but you're not sure how, send me a message. Let's talk and I'll give you a specific task to get a comprehensive handle on that will help to determine the particular color and shape of the conjecture puzzle pieces.

:imminst:  :)  :cool:  :)  :imminst:


Edited by HighDesertWizard, 29 October 2018 - 04:17 PM.

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#16 HighDesertWizard

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Posted 29 October 2018 - 04:30 PM

I'm a database application software engineer.

 

I always take on the hardest problems of a project first when thinking through the design and development of an application. If I can't solve the hard problems, effort put into the easy problems won't matter. And once the App Dsn/Dev hard problems have known solutions the easy problems are just that: easy problems.

 

So, please... Don't ask me if I take Omega 3s, Vitamin d3, Curcumin (Revgenetics BTW), Galantamine, Vitamin K, a great Probiotic, and a whole lot more. Of course, I do that stuff in larger doses, probably, than you do. That's the no-brainer, easy stuff.

 

Isn't the Biological - Epigenetic Age - iPSC set of problems our current hardest, hard problem? And don't we, optimally, want some DIY way of triggering In Vivo Reprogramming in ourselves?

 

That's why I'm here doing this.

 

I think it is, and what that means to me is this... We need to poke and prod and try to get at it in every which way we can. And that means when a study like Seth Grant's Schizophrenia / PSD-95 study pops up it's time to press the pedal to the metal on a conjecture about it because of new info provided by the new study.  And it really doesn't matter if the conjecture is right or wrong. We might discover that it's wrong, but then we'll know WHY it's wrong, and that will set us up to form a better conjecture...

 

And, BTW, about the possibility of doing it DIY... I'm not alone in thinking it may be possible...

 

See Vince Giuliano's latest blog entry... I quote his summary at length in the opening post.

 

If Vincent Giuliano thinks it may be possible, my friends, so do I...

 

:|?


Edited by HighDesertWizard, 29 October 2018 - 05:18 PM.

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#17 HighDesertWizard

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Posted 30 October 2018 - 03:33 AM

CwxbAxUh.png

 

Bingo!

 

The abstract of the 2015 study kicking off this thread, Repression of the heat shock response is a programmed event at the onset of reproduction, reads as follows...

 

... Here, we show that in C. elegans, the HSR declines precipitously over a four hour 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...

 

In their remarkable study published in 2017 and referenced upthread as study link and video, Seth Grant's team found that the gene expression data that turned in humans in their mid-20s could be manipulated, via machine learning techniques, to predict actual age with a relatively high degree of accuracy. These same genes are implicated as important in schizophrenia and PSD-95.

 

The conjecture of this thread is that this Epigenetic Turn of Genes associated with schizophrenia and PSD-95 might well be a roughly comparable, evolutionarily conserved Repression of the Heat Shock Response discovered in c elegans by Morimoto, et al, in 2015.

The text below is from the 1st study above and the diagram is from the 2nd.

 

... Huang et al. observed that the prefrontal cortex of a subset of subjects with schizophrenia show, in comparison to matched controls, a shift from the H3K4me3 to the H3K27me3 mark in chromatin... This observation is of interest given that deficits in GAD67 RNA are considered to be among the most frequently replicated findings in schizophrenia postmortem brain[53], potentially affecting widespread portions of the cerebral cortex, the hippocampus and other areas of forebrain, and even the cerebellar cortex... While underlying molecular mechanisms remain to be explored, these findings nonetheless provide some of the first examples how genetic and epigenetic factors could interact and contribute to dysregulated gene expression and eventually, cortical dysfunction and psychosis.

 

2yhFlvbl.png

 

 

 

The point here is not that anything has been "proved". As noted in the opening post, I don't believe in the possibility of proving anything infallibly.

 

That said, we now know that there is a roughly comparable chromatin expression change related to the heat shock response in c elegans and in schizophrenia in humans. This is a gene level evidence complement to the other evidence cited in the opening post that demonstrated a relationship of the heat shock response to schizophrenia.

 

It's not that anything is proven, it's that this thread now contains evidence content that makes its Title conjecture harder to falsify.

 

Please try though...

 

Shockingly Early: Chromatin-Mediated Loss of the Heat Shock Response

 

yxiih2fl.png

 

 

I'd try to say more, but I'm already in over my head...

 

:)


Edited by HighDesertWizard, 15 November 2018 - 03:50 AM.


#18 HighDesertWizard

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Posted 30 October 2018 - 02:35 PM

Just reflecting on the evidence for the conjecture posted so far to this thread...
 
When I renamed the conjecture yesterday, I believed it to be true. I like the new conjecture formulation, but I have a new title in mind that I believe better captures the range of evidence discussed so far.
 
Here's the change I'm thinking about making...
 
From.... A "Heat Shock" and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans
To......... A "Heat Shock" and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans that can be Modulated
 
That's what the 2015 Finnish Sauna Study that I posted an image from in the opening post showed right? Just hanging out in a sauna can make for a significant survival probability odds change. Why? Because Heat Shock Protein (probably HSP 70) is triggered.
 
This is astounding. Sit back and take a moment to reflect on this... 
  • It appears that there is likely a kind of "Switch" in humans that represses Heat Shock Protein expression as we age. This might be an evolutionarily conserved trigger from as early as the origins of c elegans.
  • But it's NOT that the potential benefit of heat shock protein expression is biologically repressed.
  • It's just that the EXPRESSION of HSP that implicates, that triggers, that benefit is repressed.
  • So if we trigger HSP ourselves, in just the right way, then, the benefit evolutionarily preserved can be recovered.

Right? Is there a reason why we shouldn't think about the evidence above in that way?

 

It's astounding. New science from the last 4 years, changes the game of life.

 

What do you think? What am I missing? What's the argument missing? Where does the argument go wrong? Where is the evidence weak? You can't hurt my feelings. Please get tough...

 

:)

 

Does anyone have thoughts about this new thread title conjecture idea? If no one does, I'm making the change.

 

:)


Edited by HighDesertWizard, 30 October 2018 - 03:43 PM.


#19 HighDesertWizard

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Posted 02 November 2018 - 09:02 PM

K2Yf6W4h.png

 

I'd like to turn attention to the diagram within the Seth Grant 2017 study that showed actual age could be predicted with accuracy in mice and relatively good accuracy in humans. I've drawn a blue upwardly sloping line above the dots representing people we're especially interested in.

 

Wouldn't it be great if we knew who they were, how they lived their lives, and what practices they engaged in that enabled them to have a dramatically lower Predicted vs. Actual Age?

 

 

JrsiLIeh.png

 

The conjecture of this thread is that increased Heat Shock Protein expression is the most probable common cause of their dramatically lower predicted age.

 

But we don't know who they are. Too bad. But do we have data that can be expressed in a comparably drawn diagram?

 

I believe there is.

 

Longecity has an aging biomarkers program and about 20 people are participating in it. Here's a spreadsheet graph of their results.

 

YdUTsqgh.png

 

Notice...

  • there are several Longecity members with a lower MyDNAge test result than their actual age
  • let's assume the MyDNAge test result provides rough test result comparability to the Grant Age Estimation algorithm.
  • there are 6 members highlighted in yellow with an estimated age score significantly lower than their actual age
  • this is anecdotal data of course, that's a given
  • but if HSP expression is really as key to epigenetic age, shouldn't member descriptions of their practices include references to HSP promoting activities?

Let's take a look to see... What do the 6 members have to say about their routines...

 

bobolander... "I'm happily married, live a stress-free lifestyle in a retirement community with my wife - we're both tennis players, playing every morning and on rainy mornings do a light workout in the gym"

droplet... "I exercise regularly"

Harkinj... "I work out 2 -3 times a week. HIIT and resistance training"

Mind... "Exercise: I typically get a lot of exercise. I play a few sports, run a bit, lift weights, do a little cardio. More than half of my exercise is just being active outside taking care of the garden landscaping, hunting, hiking, fishing shoveling snow"

Turnbuckle... From other posts he's made we know he regularly engages in exercise. Also, he attributes his lower epigenetic age to a C60-related formulation

Yuri Deigin... "I do go to the gym 2-3 times a week for some weight training and very mild cardio; I also hit the sauna every visit"

zzchristianzz... "I have kept a daily phisical activity routine for over 15 years through biking and walking every single day for at least one hour, sometimes 2"

 

What about the other members who have provided MyDNAge test results?

 

--> I think it's fair to say that those with the lower epigenetic ages emphasized exercise in their regimen descriptions.

 

Of course, exercise triggers Heat Shock Protein expression. And the C60-related substances turnbuckle attributes his lower test result to also trigger Heat Shock Protein.

 

This data proves nothing, of course. But it is a bit of anecdotal evidence that supports the conjecture.

 

And it does another thing too. The data also suggests that we might, ourselves, do a trial that more consciously, deliberately, and systematically triggers Heat Shock Protein and then test to see if our MyDNAge test result is lower.

Right?

 

:)

 

That's what I'm going to do.


Edited by HighDesertWizard, 15 November 2018 - 03:51 AM.

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#20 Nate-2004

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Posted 06 November 2018 - 12:18 AM

You forgot me on that list, myDNAge was 45 I'm 44. As I said earlier, I exercise 4x a week consistently and spend 20 mins in the sauna afterward on each of those 4x. I started being more consistent about it roughly 2 years and 10 months ago. My DNAge test was a few months ago, taken in May I believe.


Edited by Nate-2004, 06 November 2018 - 12:21 AM.


#21 Phoebus

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Posted 06 November 2018 - 12:26 AM

I thought MyDNAge basically correlated with your physical age and was an inaccurate measurement of biological age? 

 

thats what Michael posted a couple weeks ago 


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#22 QuestforLife

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Posted 06 November 2018 - 10:28 AM

I am personally not convinced that HSP is involved in the OSKM de-differentiation process.

 

The likelihood is that protein folding is very important during development, but once growth is complete it was advantageous to downregulate it’s activity in favour of faster, more careless protein interactions required for winning the competition to breed. 

 

Certainly re-activation might confer improved longevity because of the reduction in misfolded proteins, but not rejuvenation IMO, which is what most of us are really after.

 


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#23 HighDesertWizard

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Posted 06 November 2018 - 09:37 PM

4hZYnwuh.png

I am personally not convinced that HSP is involved in the OSKM de-differentiation process.

 

The likelihood is that protein folding is very important during development, but once growth is complete it was advantageous to downregulate it’s activity in favour of faster, more careless protein interactions required for winning the competition to breed. 

 

Certainly re-activation might confer improved longevity because of the reduction in misfolded proteins, but not rejuvenation IMO, which is what most of us are really after.

 

The path to OSKM driven reprogramming is certainly complex. My intention is to begin to explore these complexities in depth in 2019. Until then, I'll focus on establishing an intervention and testing regimen for myself and interested others to leverage the longevity benefit HSPs appear to provide. I'll be posting here about it.

 

I often see that one's perspective about what's essential for achieving a longer lifespan depends on one's age. We all know they're likely in the cards but we don't know when knowledge required to achieve them will exist in the public domain. Being 39, QuestforLife, provides you with a 24-year advantage over me in case it takes longer for the knowledge to exist. Is it surprising, then, that I'm more interested than you in leveraging a longevity benefit HSP expression has been shown to provide so that I increase the probability of my surviving into that time of increased knowledge?

_________

 

Of course, it's important to recognize that there are many types of HSPs performing multiple, sometimes contradictory functions.

 

I admit to ignorance about many things while being awestruck by the increasing number of recent studies showing HSPs to have some relationship to iPSC regulation. The opening post listed some titles, here are a few more among many. It is in this complicated soup that the knowledge will be found.

 

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

 

Senescence Meets Dedifferentiation

 

Senescence promotes in vivo reprogramming through p16INK 4a and IL‐6


Edited by HighDesertWizard, 15 November 2018 - 03:53 AM.


#24 HighDesertWizard

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Posted 06 November 2018 - 09:42 PM

K2Yf6W4h.png

 

You forgot me on that list, myDNAge was 45 I'm 44. As I said earlier, I exercise 4x a week consistently and spend 20 mins in the sauna afterward on each of those 4x. I started being more consistent about it roughly 2 years and 10 months ago. My DNAge test was a few months ago, taken in May I believe.

 

Hi Nate... Over time, more people will want to participate in the biomarker tracking activity. This is my hobby, not my job. And for me to do this, I need all results to show up in a single forum category, that's here. You post your results there per the instructions Mind and Caliban have sketched and I'll be happy to add them in.

 

Cheers!


Edited by HighDesertWizard, 15 November 2018 - 03:53 AM.


#25 HighDesertWizard

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Posted 06 November 2018 - 10:37 PM

K2Yf6W4h.png

 

I thought MyDNAge basically correlated with your physical age and was an inaccurate measurement of biological age? 

 

thats what Michael posted a couple weeks ago 

 

Generalizing from technical details requires great care because improperly formed generalizations can result in missed opportunities. I have no doubt that developments along the line of Horvath's more recent "An epigenetic biomarker of aging for lifespan and healthspan" might someday be a significantly better than his original Epigenetic-Aging-Clock technology licensed for testing as MyDNAge.

 

Fact... The Machine Learning optimization target and input variables of MyDNAge are different than the target and variables of this new technique, DNAm PhenoAge.

 

The new technique is focused on optimizing for biological age, MyDNAge is not. But does that mean, as you put it, MyDNAge is an "inaccurate" measure of biological age? I'm acquainted with Machine Learning technology and I'm skeptical of the claim that it's "inaccurate". Accuracy is a relative term. I don't think we know for certain how "accurate" an indication of biological age it can provide.

 

If you're certain, please provide a set of study links supporting your certainty.

 

----------------

 

I've reposted the Kaplan-Meier curves of the Sauna study posted in the opening post. Imagine what the variance between the two groups on the right might look like given another 10 to 20 years. Evidently, triggering this "heat shock" mechanism in us is a big deal. Some questions for you and/or Michael...

  • Are you suggesting there's certainty in the literature demonstrating that those with a lower hazard risk did not have lower MyDNAge- or comparable test ages? If yes, please provide study links.
  • Are you suggesting that a well-thought-through and disciplined approach to triggering "heat shock" has zero chance of lowering a MyDNAge set of test results over time?

turnbuckle has reported a significant drop in his reported epigenetic age in a very short time. Mind reports a significantly lower MyDNAge than his actual age. Both explicitly reported that they did interventions that triggered HSPs, perhaps not even as robust as in the Sauna Study below.

 

Certainty without evidence is the enemy of rapid progress.

 

I've been looking for a way that I can trigger HSPs every day in a way consistent with my lifestyle for 18 months now. I believe I've figured out what device I can use to do it.

 

I'd love to get help thinking through how to sequence my Telomere-related and Epigenetic-related interventions.

 

:)

 

xtaOIKN.png


Edited by HighDesertWizard, 15 November 2018 - 03:54 AM.


#26 HighDesertWizard

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Posted 07 November 2018 - 06:00 AM

4hZYnwuh.png

I am personally not convinced that HSP is involved in the OSKM de-differentiation process.

 

QuestforLife... I appreciate the intelligence and knowledge I see in many of your posts. So I'm extremely puzzled by that statement...

If you really are "not convinced HSP is involved in the OSKM" in-vivo reprogramming process, then...

  • how do you explain the findings of the multiple studies referenced in this thread's opening post (toward the bottom) indicating that the HS / OSKM / pluripotency relationship is a biologically intimate one?

In that portion of the opening post, I cited just a few of the many I could have cited. And with that many studies suggesting a regulatory, causal, and / or even just an association relationship, their combined weight gets my attention.

Evidence. At the end of the day, that's all that matters. Opinion? Being "personally convinced"? It's not worth much.

Convince me, please. Can you convince me that I should ignore those studies?

I deliberately created an out for you in the way I worded a quotation of your statement. I'll respect your use of it.

:)


Edited by HighDesertWizard, 15 November 2018 - 03:55 AM.


#27 QuestforLife

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Posted 07 November 2018 - 10:50 AM

QuestforLife... I appreciate the intelligence and knowledge I see in many of your posts. So I'm extremely puzzled by that statement...

If you really are "not convinced HSP is involved in the OSKM" in-vivo reprogramming process, then...

  • how do you explain the findings of the multiple studies referenced in this thread's opening post (toward the bottom) indicating that the HS / OSKM / pluripotency relationship is a biologically intimate one?
In that portion of the opening post, I cited just a few of the many I could have cited. And with that many studies suggesting a regulatory, causal, and / or even just an association relationship, their combined weight gets my attention.

Evidence. At the end of the day, that's all that matters. Opinion? Being "personally convinced"? It's not worth much.

Convince me, please. Can you convince me that I should ignore those studies?

I deliberately created an out for you in the way I worded a quotation of your statement. I'll respect your use of it.

:)

 

 

Thanks HighDesertWizard.

 

I too believe that re-programming will be a key to reversing aging. I skimmed the three papers you referenced a few posts up, and it does appear that controlled inflammation and a component of SASP, namely IL-6, is vital. In particular interest is this paper (https://www.ncbi.nlm...les/PMC5847859/), which shows young female mice are more difficult to induce de-differentiation in, due the anti-inflammatory effects of estrogen. This certainly supports the idea that tissue rejuvenation involves damage to not only attract migratory stem cells, but also potentially drives back somatic cells to a more plastic state.

 

But in all of this I've yet to see the connection to HSP. But I've leant in aging research you should follow your ideas and see what turns up, so please let us know if you find this connection or if I've missed it in your posts.

 

Something else to think about.

 

Macrophages are potent inducers of IL-6.

 

https://www.ncbi.nlm.../pubmed/9372056

 

C60 fullerene is like catnip to macrophages

 

https://onlinelibrar.../mawe.201300082 (need sci-hub to read the full paper)

 

Fever (heat like from a Sauna, so maybe there is a HSP connection?), aka the innate immune system, induced by infection, can cure cancer

 

https://www.ncbi.nlm...98/#!po=62.0000

 

I have a feeling these findings fit into the de-differentiation/rejuvenation picture somehow.


Edited by QuestforLife, 07 November 2018 - 11:23 AM.

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#28 HighDesertWizard

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Posted 07 November 2018 - 04:38 PM

Can you point to any normal (non genetically modified) mice that lived longer with OSKM?

 
Turnbuckle asks the great question in another thread...



#29 Nate-2004

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Posted 07 November 2018 - 09:24 PM

Hi Nate... Over time, more people will want to participate in the biomarker tracking activity. This is my hobby, not my job. And for me to do this, I need all results to show up in a single forum category, that's here. You post your results there per the instructions Mind and Caliban have sketched and I'll be happy to add them in.

 

Cheers!

 

I understand, same here, I posted my results in the original thread but not there. I've posted it there now.


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#30 HighDesertWizard

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Posted 08 November 2018 - 03:36 AM

Can you point to any normal (non genetically modified) mice that lived longer with OSKM?

 
My reply to Turnbuckle below is a summary of this thread's opening post/conjecture, except for the epigenetic turn component of the conjecture...
 

Great question Turnbuckle... I've also been thinking about this question lately. I'm not especially familiar with studies of mice. Will a couple of human studies do?
 
Well, ok, I can't actually point to a human study in which a positive impact on lifespan was determined definitively to be a result of the OSKM mechanism.
 
But I can point to a handful of study-content-sets that I take together as profound support for the following conjecture...

  • OSKM-Factor-Related activity is the mechanism of action explanation for increased survival probability in wild-type humans in multiple studies
I believe that...
  • the conjecture above is virtually impossible to falsify given the study-volume and study-content-density of already published study knowledge and given our existing limited knowledge
  • the independent intervention variable I have in mind (HSPs) impacting OSKM activity has an essentially indisputable positive impact on survival probability in wild-type humans.
  • it's silly not to proceed as individuals, and as a community, to try to impact that independent variable to test it because of that fact
Here is a list of the two categories of studies.
  • Heat Shock Intervention -->> in multiple studies shown to "regulate" -->> OSKM
  • Heat Shock Intervention -->> in multiple studies shown to increase -->> survival probability, and profoundly so in wild-type humans
A lot of ground is covered in the opening post of a Longecity thread I recently established, The title is a conjecture, A "Heat Shock" and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans that can be Modulated".
 
I do not believe the conjecture of that thread will ever be falsified. And I'm going to try to, both, attack it and defend it.
 
That thread's opening post contained the following list of studies.
.

HSPs, the OSKM “Yamanaka Factors”, and iPSCs

 
There are more studies not listed above that are equally relevant. Perhaps those I left out are more relevant to the question.
 
I also strongly suggest that Vincent Giuliano's recent blog post of September 2, 2018, is a must-read on this topic. I quoted his summary on this topic in the opening post referenced above.
 
 
There are multiple studies showing that Heat Shock Protein Expression is implicated in increased survival probability in humans. But let's first take note of 2 of many interventions that increase Heat Shock Protein.
 
2016, Exercise, heat shock proteins and insulin resistance
 
2017, The Effect of Hyperthermic Whole Body Heat Stimulus (Sauna) on Heat Shock Protein 70 and Skeletal Muscle Hypertrophy in Young Males during Weight Training
 
 
Let's sample just two studies, 1 for exercise and 1 for sauna vis-a-vis survival probability.
 
2015, Fitness predicts long-term survival after a cardiovascular event: a prospective cohort study
 
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2015, Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events
 
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Again, I admit that this is not definitive proof for the conjecture I stated at the beginning of this post. But I believe all knowledge is conjectural, so this is nothing new from my point of view.
 
And practically speaking, it's of no consquence...
 
Increasiong Heat Shock Protein has such profoundly positive effects on survival probability that it's a no-brainer that we should try to increase it by one of the means known to increase it in healthy ways.
 
And, then, in due time, we'll find out if the conjecture can be falsified, or not.

 


Edited by HighDesertWizard, 08 November 2018 - 10:23 AM.

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Also tagged with one or more of these keywords: aging switch, seth grant, psd-95, nf-kb, heat shock protein, senescence, sasp, nrf2, morimoto, survival

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