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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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#31 Turnbuckle

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Posted 08 November 2018 - 10:26 AM

I still don't see any studies in normal mice showing enhanced longevity. As for heat shock protein, that does look interesting, though the plots are focusing only on one aspect of longevity. And even with these positive cardio effects for sauna use, aren't there other explanations? As in reduction of stress? Or different lifestyles? Because if heat shock proteins were really so protective, wouldn't one see these effects in those living in tropical areas? Looking at a world map of heart attack data, there is no obvious correlation.


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#32 HighDesertWizard

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Posted 08 November 2018 - 11:05 AM

Studies on my mind, realizations from existing knowledge...

Seems to me that this study is as good a gateway as any to the literature laying the basis for DIY reprogramming. It doesn't reference HSPs, but it does speak to the importance of NF-kB.

 

MYm75Bvl.png

 

It's incredible really, in discussions of epigenetic reprogramming, we only talk about the OSKM Yamanaka factors. Meanwhile, multiple studies have explicitly found, both, that NF-kB activation is required, and NF-kB inhibited in different steps. So should we be talking about (N)OSKM? I think yes.

 

2012, Activation of Innate Immunity is Required for Efficient Nuclear Reprogramming

 

 

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

 

 

I think the following is a critical dimension of this puzzle to reflect on, QuestforLife... Here's a gem... Breathe in the larger meaning...

  • Speaking of NF-kB Inhibition, The Inflammatory Reflex, and NF-kB Inhibition in Splenic Macrophages...

The reduced Transcription of Inflammatory Cytokines in Splenic Macrophages via triggering TIR is due to a transformation of Macrophage Phenotype from M1 to M2 by NF-kB inhibition by the a7 nAch Receptors...

 

-->> Kevin Tracey explicitly makes that point in either one or both of the two longer talks he gave in 2017 and 2018. I'll have the study link later that supports this statement.

 

With that as background, consider this...

 

2018, Cryptococcal Heat Shock Protein 70 Homolog Ssa1 Contributes to Pulmonary Expansion of Cryptococcus neoformans during the Afferent Phase of the Immune Response by Promoting Macrophage M2 Polarization

 

2016, IL-10 is required for polarization of macrophages to M2-like phenotype by mycobacterial DnaK (heat shock protein 70)

 

That last point is a big puzzle piece I think...

 

What does it tell us?

 

Two ancient, evolutionarily conserved mechanisms in humans (TIR and the HS Response), both, demonstrated to have profoundly positive impacts on survival probability in humans, have an impact via Macrophage phenotype transformation.

 

Breathe the meaning of that in...

 

Evolution managed, through emergent processes, to establish two very different mechanisms within us that accomplish at least one thing in common: Transform Macrophage Phenotypes from M1 to M2...

 

Seems to me that, if Mother Nature "thought" it worthwhile to accomplish that goal, perhaps I, too, should focus on that M1 to M2 transformation...

 

That transformation implicates all that we know is important... NF-kB, the HS response, inflammation, survival probability, and even the epigenetic turn of this thread's conjecture related to schizophrenia...

 

2014, Role of Microglial M1/M2 Polarization in Relapse and Remission of Psychiatric Disorders and Diseases

 

:)


Edited by HighDesertWizard, 08 November 2018 - 11:20 AM.


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#33 HighDesertWizard

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Posted 08 November 2018 - 07:15 PM

To be deleted... An accidental double post by me...

Edited by HighDesertWizard, 09 November 2018 - 02:40 AM.


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#34 HighDesertWizard

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Posted 08 November 2018 - 07:55 PM

Bingo!

 

1989, Attenuated Induction of Heat Shock Gene Expression in Aging Diploid Fibroblasts

 

We examined the effects of cellular aging on the regulation of heat shock gene expression in IMR-90 human diploid fibroblasts. Heat shock (42-43 “C) and canavanine (200-400 Ng/ml) were used to evoke the heat shock response in these cells. We showed that heat shock induced the synthesis of proteins with apparent molecular weights of 98,000, 89,000, 78,000, 72,000, 64,000, 50,000 and 25,000, with heat shock protein (HSP) 89 and 72 being most prominent. Canavanine induced the synthesis of the four high molecular weight HSPs, particularly HSP 89 and HSP 78, without noticeably enhancing synthesis of the low molecular weight HSPs. We found that, while a similar series of HSPs were induced in the young and old cells, there was a marked decrease in the magnitude of this induction in the old cells. Using cells with defined population doubling levels, we observed a direct correlation of the inducibility of HSP synthesis and the replicative potential of the cells used. Analyses of the amount of translatable and hybridizable mRNA, by the methods of in vitro translation and Northern blot hybridization, demonstrated that the induction of HSP synthesis can be accounted for by increases in their mRNA. Nuclear runoff transcription provided evidence that the decrease in inducible expression of the HSPs in aging IMR-90 cells was attributable to a transcriptional mechanism. This conclusion was substantiated by analysis of the hsp 70 promoter activity in transient expression assay of the hsp 70 promoter-chloramphenicol acetyltransferase construct. We propose that there is an age-associated dysfunction in the signaling mechanism of the heat shock response.


Edited by HighDesertWizard, 08 November 2018 - 07:57 PM.


#35 HighDesertWizard

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Posted 09 November 2018 - 04:28 AM

I still don't see any studies in normal mice showing enhanced longevity. As for heat shock protein, that does look interesting, though the plots are focusing only on one aspect of longevity. And even with these positive cardio effects for sauna use, aren't there other explanations? As in reduction of stress? Or different lifestyles? Because if heat shock proteins were really so protective, wouldn't one see these effects in those living in tropical areas? Looking at a world map of heart attack data, there is no obvious correlation.

 
I haven't spent much time looking for enhanced longevity in mice vis-a-vis hsp expression.
 
Will c. elegans work for you as a substitute?
 

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

 

 

About the question of whether Sauna is a potent inducer of the Heat Shock response... 

 

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

 
 
:)


Edited by HighDesertWizard, 09 November 2018 - 05:22 AM.


#36 HighDesertWizard

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Posted 09 November 2018 - 04:51 AM

A "Heat Shock" and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans that can be Modulated

 

I don't know about you but I'm feeling increasingly fond of the current phrasing of this thread's conjecture.

 

The evidence supporting it appears to be both broad and deep.

 

It is a Good Explanation in the sense that Deutsch and Popper have spoken about Good Explanations especially in this youtube video.

  • It's Bold, it's (relatively) Hard-to-Vary, and it is composed of multiple Falsifiable Sub-Conjecture Elements.
  • I don't believe the conjecture as stated can be falsified.

Most important...

  • I know a relatively easy way (just Data Science / Machine Learning vis-a-vis already existing human study data) to make a single Conjecture-Falsification-Experiment-Attempt that could Falsify / break the back of the entire conjecture.

Imagine it...

  • We already know increased Stress Response can increase survival probability.
  • The falsification attempt fails to falsify the conjecture.
  • ....
  • ....
  • ....

:)


Edited by HighDesertWizard, 09 November 2018 - 05:54 AM.


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#37 Turnbuckle

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Posted 09 November 2018 - 11:31 AM

 
I haven't spent much time looking for enhanced longevity in mice vis-a-vis hsp expression.
 
Will c. elegans work for you as a substitute?
 

 

About the question of whether Sauna is a potent inducer of the Heat Shock response... 

 

 
 
:)

 

How much longer did they live?


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#38 QuestforLife

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Posted 09 November 2018 - 11:32 AM

I still don't see any studies in normal mice showing enhanced longevity.


We are still waiting for Belmonte to repeat his groundbreaking regeneration of age accelarated mice with normal, wild type mice. He has published this recently, which focusses on using OSKM factors to regenerate wounds:

https://www.nature.c...1586-018-0477-4
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#39 Turnbuckle

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Posted 09 November 2018 - 11:34 AM

We are still waiting for Belmonte to repeat his groundbreaking regeneration of age accelarated mice with normal, wild type mice. He has published this recently, which focusses on using OSKM factors to regenerate wounds:

https://www.nature.c...1586-018-0477-4

 

 

I don't know why people have stopped posting the relevant passages. 



#40 HighDesertWizard

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Posted 10 November 2018 - 08:03 PM

Studies on my mind, realizations from existing knowledge...

Seems to me that this study is as good a gateway as any to the literature laying the basis for DIY reprogramming. It doesn't reference HSPs, but it does speak to the importance of NF-kB.

 

MYm75Bvl.png

 

 

 

The basic idea many, including me, are pursuing...

 

--> When cells become senescent, they lose track of what kind of cells they are, setting the stage for Epigenetic Reprogramming via Re-Differentiation...

 

--> Question: To what degree does a senescent cell losing track of what it is account for the negative effects it has on our health? I don't know the answer to that question, but I'd like to figure out the answer.

 

--> Question: Is there an innate function within us that keeps that Reprogramming process going on within us when we're young but, for some reasons, declines in effectiveness as we age? If yes, what is it?

  • The objective of this forum thread is to fully explore the science and practice of the Stress Response, the "Heat Shock" Response, being that mechanism.

And check it out... Even reason is appears aware of the reality in his forum post this morning...

 

I wonder what the reality of senescent cells becoming something de-differentiated and prepped for reprogramming means for what many beleive is the right approach : i.e., Remove Them...

 

I suggest a path of exploration is timely and urgent... Let's figure out to what degree conscious and deliberate triggering of the Heat Shock Response can establish a "younger" biological age...

 

Fibroblasts in Old Skin Lose their Functional Identity

 

Researchers here describe the character of fibroblasts in old skin as a loss of characteristic function and identity. The fibroblasts begin to take on aspects of other cell types, and thus the character of skin changes for the worse. In the publicity materials this decline in cell function is described as a cause of aging, but that should probably be taken to mean that the researchers consider it a contributing cause to age-related pathology rather than a root cause of aging per se. Dysfunction of this nature has all the signs of being a downstream consequence in aging, cellular misbehavior that is a reaction to earlier processes, such as the accumulation of molecular damage within and between cells, or the changes in cell signaling that results from that damage.

With age, our tissues lose their function and capacity to regenerate after being damaged. The main conclusion drawn from recent findings is that these fibroblasts lose their cell identity, as if they had "forgotten" what they are, and consequently their activity is altered, thus affecting tissue. The new study reveals the cellular and molecular pathways affected by ageing and proposes that they could be manipulated to delay or even reverse the skin ageing process.

Dermal fibroblasts are key for the production of collagen and other proteins that make up the dermis and that preserve the skin's function as a barrier. The activity of these cells is also crucial for the repair of skin damage. As we age, the dermis loses its capacity to produce collagen, and consequently its capacity to repair wounds is also significantly impaired. A single-cell analysis confirmed the loss of fibroblast identity in aged animals. Using sophisticated computational tools, scientists observed that aged fibroblasts show a less defined molecular conformation compared to young fibroblasts and come to resemble the undefined cell states observed in newborn animals.

"The elderly face many problems in this regard because their skin does not heal properly and its barrier properties are decreased, thus increasing the risk of skin infections and systemic infections. The notion that the loss of cell identity is one of the underlying causes of ageing is interesting and one that we believe hasn't been considered before."

 

Link: http://www.crg.eu/en...ty-and-function


Edited by HighDesertWizard, 10 November 2018 - 08:07 PM.

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#41 Nate-2004

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Posted 10 November 2018 - 10:41 PM

HDW, what's the word on that PEMF pad you were going to get? I think this one is fine, the fakespot score is an A but it only has 10 reviews. There's another similar one that scored an F with 145 reviews.

 

What about far infrared lamps instead? How does that differ from PEMF?


Edited by Nate-2004, 10 November 2018 - 10:41 PM.

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#42 HighDesertWizard

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Posted 11 November 2018 - 01:10 PM

The importance of Heat Shock Factor 1 and the Stress Response, aka, "Heat Shock Response", are implicated in the literature about the Sirtuins, NAD+, Calorie Restriction, and Fasting...

 

I haven't digested the details or meaning of the studies shown below. I'm just documenting the fact of the relationship of HSPs to that body of literature...

 

 

 

2017, The heat shock factor HSF1 juggles protein quality control and metabolic regulation

 

Transcriptional regulators often act as central hubs to integrate multiple nutrient and stress signals. In this issue, Qiao et al. (2017. J. Cell Biol. https://doi.org/10.1083/ jcb.201607091) demonstrate how heat shock factor 1 (HSF1) uncouples metabolic control from proteostatic regulation and unveils HSF1 as a critical transcriptional regulator of NAD+ metabolism.

 

 

 

6W1McVql.png

 

 

2013, The SIRT1 Modulators AROS and DBC1 Regulate HSF1 Activity and the Heat Shock Response

 

OFJqPfYh.png

 

 

 
9TPIBnZ.png
 
 

 

CONCLUSION:

Ramadan fasting increases serum HSP70 and improves serum lipid profile.


Edited by HighDesertWizard, 11 November 2018 - 03:47 PM.

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#43 HighDesertWizard

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Posted 11 November 2018 - 04:53 PM

 

 

This will be interesting to those who believe, as I do, that one key to achieving extreme longevity is to not die of any specific disorder...

 

2012, Beta-Lapachone, a Modulator of NAD Metabolism, Prevents Health Declines in Aged Mice

 

NADH-quinone oxidoreductase 1 (NQO1) modulates cellular NAD+/NADH ratio which has been associated with the aging and anti-aging mechanisms of calorie restriction (CR). Here, we demonstrate that the facilitation of NQO1 activity by feeding β-lapachone (βL), an exogenous NQO1 co-substrate, prevented age-dependent decline of motor and cognitive function in aged mice. βL-fed mice did not alter their food-intake or locomotor activity but did increase their energy expenditure as measured by oxygen consumption and heat generation. Mitochondrial structure and numbers were disorganized and decreased in the muscles of control diet group but those defects were less severe in βL-fed aged mice. Furthermore, for a subset of genes associated with energy metabolism, mice fed the βL-diet showed similar changes in gene expression to the CR group (fed 70% of the control diet). These results support the potentiation of NQO1 activity by a βL diet and could be an option for preventing age-related decline of muscle and brain functions.

7F4wdEXh.png

 

 

And if the above findings are true, then, we should expect to find studies like the ones easily found below, right?

 

2016, β-Lapachone Induces NAD(P)H:Quinone Oxidoreductase-1- and Oxidative Stress-Dependent Heat Shock Protein 90 Cleavage and Inhibits Tumor Growth and Angiogenesis

 

2018, Heat shock increases expression of NAD(P)H:quinone oxidoreductase (NQO1), mediator of beta-lapachone cytotoxicity, by increasing NQO1 gene activity and via Hsp70-mediated stabilisation of NQO1 protein


Edited by HighDesertWizard, 11 November 2018 - 05:17 PM.

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#44 HighDesertWizard

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Posted 11 November 2018 - 09:17 PM

HDW, what's the word on that PEMF pad you were going to get? I think this one is fine, the fakespot score is an A but it only has 10 reviews. There's another similar one that scored an F with 145 reviews.

 

What about far infrared lamps instead? How does that differ from PEMF?

 

Hi Nate... Thanks for prompting me to provide a status...

 

What we've bought... My girlfriend bought the exact product you provide a link for in an "Open Box" state at eBay, same dimensions, 72" x 24", for $540 + shipping. I haven't seen that price since. I bought the same product from the same vendor at eBay in the next larger size 76 x 32 for my parents. If they use it, I'll buy another one for myself. If they don't, I'll use the one I bought them.

 

My girlfriend is already attached to the mat. It gets hot and is very relaxing. I got a bit of sweat going while trying it without trying to really jack up my temperature using the metallic covering while on the mat. I hope we'll have lots of body temperature data from using the mat by year end. The point of having the mat is to get our internal body temperature up. I expect we should be able to get our internal temperatures up in Fahrenheit a degree or two.

 

See these two links for info.

 

Speaking of body temperatures, might it be possible for you to record your temperature while you're in the sauna?

 

I have it in mind to kick off a new regimen for myself that is focused on reducing my MyDNAge via dramatically increasing Heat Shock Protein expression within myself.

  • I already have 1 Teloyears age test result and 1 MyDNAge age test result completed. Those test results are posted here at Longecity.
  • Before year end, I'll take a LifeLength test to measure Telomere Length and a 2nd MyDNAge test within a few minutes of each other as a baseline for this 2019 regimen test.
  • There are some things I want/need to do before beginning this new project to establish this n = 1 experiment as credible.
  • I'll also be posting about that in the Longecity Biomarkers category of posts.

Edited by HighDesertWizard, 11 November 2018 - 09:33 PM.


#45 HighDesertWizard

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Posted 11 November 2018 - 10:20 PM

A study about survival in rats via the triggering heat shock protein...

 

1994, Sodium arsenite induces heat shock protein-72 kilodalton expression in the lungs and protects rats against sepsis

 

OBJECTIVE:

To examine the hypothesis that induction of heat shock proteins by a nonthermal mechanism would confer protection against experimental sepsis.

DESIGN:

Prospective, blind, randomized, laboratory study.

SETTING:

University research laboratory.

SUBJECTS:

Sixty-two adult male Sprague-Dawley rats (weight range 250 to 350 g).

INTERVENTIONS:

Administration of sodium arsenite or saline in an animal model of sepsis by cecal ligation and perforation.

MEASUREMENTS AND MAIN RESULTS:

Sixty-two rats were randomly divided into two groups: group 1 received sodium arsenite (6 mg/kg iv) and group 2 received saline injection, in a blinded fashion. Eighteen hours after receiving sodium arsenite or saline, cecal ligation and perforation were performed and the animals were monitored for mortality for 96 hrs. Sodium arsenite injection, in the absence of an increase in body temperature, induced heat shock protein of 72-kilodalton molecular weight expression in the lung, which was detected 2 hrs after injection, peaked between 9 and 24 hrs, and returned to baseline by 48 hrs. Prior administration of sodium arsenite conferred significant protection against cecal ligation and perforation-induced mortality at 18 hrs (p = .002) and 24 hrs (p v .026) after cecal ligation and perforation, and correlated with expression of heat shock proteins in the lungs. However, at 48 and 96 hrs, when heat shock protein expression returned to basal values, the mortality rates of both groups were indistinguishable.

CONCLUSIONS:

We conclude that in vivo injection of sodium arsenite induces expression of HSP-72 in the lungs, and confers transient protection against experimental sepsis during the period that heat shock proteins are also expressed.

 

 

There are many other studies showing rodents with increased Heat Shock Expression having higher survival probability odds than those who don't in specific disease/disorder circumstances.

 

And, of course, there are the two studies in wild-type humans provided above.

 

I may get around to looking for more survival studies but, I'm convinced of the importance of these studies.

 

Many of these studies amount to explicit or implicit validation of The Cytokine Theory of Disease. That's what Kevin Tracey says about his work.

 

 

Richard Morimoto’s 2015 study is a key to the argument about HS in this thread. The link to it is below and Figure 7 is pasted in.

 

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

 

 

DLaqGb9l.png

 


Edited by HighDesertWizard, 11 November 2018 - 10:21 PM.


#46 HighDesertWizard

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Posted 12 November 2018 - 08:54 PM

In the next few days, I'll be enhancing conjecture-element visibility and traceability in my posts...

 

I'm also thinking seriously about renaming the thread again... 

 

Instead of ...

 

A "Heat Shock" and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans that can be Modulated

 

... it would be ...

 

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

 

... or should it be ...

 

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

 

Thoughts?


Edited by HighDesertWizard, 12 November 2018 - 09:00 PM.


#47 Nate-2004

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Posted 12 November 2018 - 11:26 PM

 

Hi Nate... Thanks for prompting me to provide a status...

 

What we've bought... My girlfriend bought the exact product you provide a link for in an "Open Box" state at eBay, same dimensions, 72" x 24", for $540 + shipping. I haven't seen that price since. I bought the same product from the same vendor at eBay in the next larger size 76 x 32 for my parents. If they use it, I'll buy another one for myself. If they don't, I'll use the one I bought them.

 

My girlfriend is already attached to the mat. It gets hot and is very relaxing. I got a bit of sweat going while trying it without trying to really jack up my temperature using the metallic covering while on the mat. I hope we'll have lots of body temperature data from using the mat by year end. The point of having the mat is to get our internal body temperature up. I expect we should be able to get our internal temperatures up in Fahrenheit a degree or two.

 

See these two links for info.

 

Speaking of body temperatures, might it be possible for you to record your temperature while you're in the sauna?

 

I have it in mind to kick off a new regimen for myself that is focused on reducing my MyDNAge via dramatically increasing Heat Shock Protein expression within myself.

  • I already have 1 Teloyears age test result and 1 MyDNAge age test result completed. Those test results are posted here at Longecity.
  • Before year end, I'll take a LifeLength test to measure Telomere Length and a 2nd MyDNAge test within a few minutes of each other as a baseline for this 2019 regimen test.
  • There are some things I want/need to do before beginning this new project to establish this n = 1 experiment as credible.
  • I'll also be posting about that in the Longecity Biomarkers category of posts.

 

 

Well, I don't know about rectally measuring my temperature in a sauna LOL. I suppose if 20 mins of sauna use would increase internal temperature by 1.5c, that's sort of a fever, which matches something you linked earlier. I could use an old fashioned mouth thermometer though, or maybe one of those electronic ear thermometers the second I get out of the sauna.

 

I was wondering about the PEMF though, how does that change things compared to just heat (re: the pad you bought)? I can't imagine it'd do the same level of effectiveness as an 80+ degree dry sauna, but the PEMF is what's different. Also, in the study you link on safety, what they don't measure with the mist sauna is whether it has the same physiological responses. We're still stuck with only the confirmed data regarding the 80 - 90 degree dry saunas. They'd have to redo all those studies.

 

By the way I've been using the sauna for about 2.5 years now I think, 4x weekly for 20 mins each time, pretty consistently give or take a week here and there. My latest test for CRP came out to a tiny 0.2 mmol/L - This is what a 25 year old would have.  I plan to test again using MyDNAge soon. I want to do a few things before I pay that kind of money to retest.


Edited by Nate-2004, 12 November 2018 - 11:31 PM.

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#48 HighDesertWizard

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Posted 13 November 2018 - 01:50 AM

I was wondering about the PEMF though, how does that change things compared to just heat (re: the pad you bought)? I can't imagine it'd do the same level of effectiveness as an 80+ degree dry sauna, but the PEMF is what's different.

 

By the way I've been using the sauna for about 2.5 years now I think, 4x weekly for 20 mins each time, pretty consistently give or take a week here and there. My latest test for CRP came out to a tiny 0.2 mmol/L - This is what a 25 year old would have.  I plan to test again using MyDNAge soon. I want to do a few things before I pay that kind of money to retest.

 

One of the things I like about those Healthy Line PEMF mats is that they support both heat and PEMF.

 

 

About the heat... Based on previous experience, I'm confident I could get my temperature up at least one degree using it. I've been pursuing this heat shock idea for about 18 months now. Late in 2017, while doing a long commute, I put on a heated vest, a sweat suit, and turned up the heater in my car while driving. (I never said I wasn't crazy.) And I spent money on one of those handheld forehead thermometers so I could easily take my temperature with in a couple seconds.

 

I got my temperature up to 102o F for a while. Felt fine. Just had a fever.

 

I've had trouble finding a study that definitively laid out how high a dry infrared sauna actually gets a person's internal temperature. And, of course, we need to find out if we are to replicate the survival probability context of that 2015 Sauna study image I posted in the opening post without doing a sauna.

 

-->> Think about the Meier Kaplan Hazard Curves in that study (link in the opening post). The most benefit was achieved by those who remained in the sauna longest. Until there's a study telling us differently, I take that to mean that getting the internal body temperature higher for longer is better. Within reason of course.

 

 

About PEMF... I'm no expert about this topic. I'm not clear at all about the relative benefit of heat vs PEMF. I notice that there are several frequencies of PEMF that in use with reported different benefits. I doubt the list below is anything close to comprehensive.

 

 

I believe this... Whatever approach you are most apt to use consistently every day is the best approach for you, whether that be fasting, exercise, heat, PEMF, and/or whatever other crazy thing turns out to trigger Heat Shock. And if there are two different things that make sense to you and work for you to do consistently, then do both.

 

I like the PEMF mat idea because it can be used while resting, reading, watching TV with friends/family on the sofa. Have an old, tired, and/or in-pain dog or cat? Put it on the floor and plug it in and see what happens...  ;)

 

I found the PEMF frequency chart below here. I have no idea whether the information provided is accurate/useful or not.

 

RSr9Du2h.png


Edited by HighDesertWizard, 13 November 2018 - 02:10 AM.

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#49 HighDesertWizard

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Posted 13 November 2018 - 02:06 AM

Having said I didn't know what the relative value of PEMF was to heat or exercise or fasting or calorie restriction, let's be clear that PEMF does, in fact, trigger Heat Shock...

 

2012, Pulsed Electromagnetic Field Elicits Muscle Recovery via Increase of HSP 70 Expression after Crush Injury of Rat Skeletal Muscle

 

2012, Effect of 60 Hz electromagnetic fields on the activity of hsp70 promoter: an in vivo study

 

2018, Coupling of pulsed electromagnetic fields (PEMF) therapy to molecular grounds of the cell

 

This is a review of the literature.

 

There are a lot more PEMF studies. This is the tip of the iceberg.

 

It's also worthwhile to check out the study in the opening post that highlighted the paradoxical character of heat shock expression.

 
:)

Edited by HighDesertWizard, 13 November 2018 - 02:59 AM.

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#50 HighDesertWizard

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Posted 13 November 2018 - 02:14 AM

Confounding variables (aka third variables) are variables that the researcher failed to control, or eliminate, damaging the internal validity of an experiment.

 

Variables?

 

A confounding variable, also known as a third variable or a mediator variable, influences both the independent variable and dependent variable. Being unaware of or failing to control for confounding variables may cause the researcher to analyze the resultsincorrectly. The results may show a false correlation between the dependent and independent variables, leading to an incorrect rejection of the null hypothesis.

 

p1xjgBbl.png


Edited by HighDesertWizard, 13 November 2018 - 02:14 AM.


#51 HighDesertWizard

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Posted 13 November 2018 - 02:32 AM

Hot off the press... Oct 23, 2018...

 

Let's not get distracted or lost in the shiny headlights of longevity science movement leaders looking to sell us expensive pills because they don't think we know anything about Heat Shock as a Confounding Variable...

 

And by the way, why is Leaf Science funding a study about NAD+ instead of funding studies about Heat Shock when we know so little about it?

 

Which is worse? I dunno... That they know the importance of heat shock to increasing NAD+ or that they don't?

 

Seems to me we need Longevity Science Thought Leadership that is keeping up with the literature. If they can't keep up or they fund studies that will only help folks who can afford the pills instead of funding studies to understand better how to leverage heat shock that might help Billions of people to trigger heat shock within themselves, then, IMHO, we need new leadership... (That's illions with a "B" my friends.)

 

:)

 

SR7fNQyh.png

 

2018-10-23, The Plasma NAD+ Metabolome Is Dysregulated in “Normal” Aging

 

Taken together, our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD+ metabolome. Our future research will seek to elucidate the role of modulating NAD+ metabolites in the treatment and prevention of age-related diseases.

 

qaKoDCxl.png

 


Edited by HighDesertWizard, 13 November 2018 - 02:51 AM.

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#52 HighDesertWizard

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Posted 13 November 2018 - 03:06 AM

 

And by the way, why is Leaf Science funding a study about NAD+ instead of funding studies about Heat Shock when we know so little about it?

 

Which is worse? I dunno... That they know the importance of heat shock to increasing NAD+ or that they don't?

 

Looks like I found the answer to the question... The folks at Leaf Science appear not to know...

 

2018, Why NAD+ Declines With Age

 

The word HEAT doesn't appear in the article...

 

:|?


Edited by HighDesertWizard, 13 November 2018 - 03:08 AM.

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#53 QuestforLife

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Posted 13 November 2018 - 09:14 AM

 
HighDesertWizard, on 08 Nov 2018 - 03:00 AM, said:

 

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

 

https://commons.nmu....&context=theses

 

 

In this study they didn't actually find any benefit to the induction of HSP or muscle building by using a sauna (at least not to <0.05 statistical significance), and in fact there was some evidence strength building was better without the sauna. The sauna sessions were only 15 minutes however, so this might indicate a lower bound of the time required for benefits.


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#54 HighDesertWizard

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Posted 13 November 2018 - 03:14 PM

In this study they didn't actually find any benefit to the induction of HSP or muscle building by using a sauna (at least not to <0.05 statistical significance), and in fact there was some evidence strength building was better without the sauna. The sauna sessions were only 15 minutes however, so this might indicate a lower bound of the time required for benefits.

 

Right. I provided a link to that study merely to ground belief in evidence that sauna triggers Heat Shock Protein 70 expression to a degree distinguishable from exercise alone.



#55 albedo

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Posted 14 November 2018 - 01:18 PM

While implicit I guess in much of what has been posted here maybe you find useful to consider or reconsider the link of HSP70 to oxidative stress and inflammation both well studied in aging. Hopefully this is a bit new to you and if not at least a good reminder and for a me an additional pointer :)

 

"...The spontaneous ROS production negatively correlated with HSP70 (r = -0.41, P < 0.05) only in the aged group, but not in the young group. HSP70 is a very conservative family of cytoprotective proteins that are specifically induced in response to several environmental stresses at the cellular level including heat shock, cellular energy depletion, oxidative stress or inflammation. Although the role of HSP70 in the blood (i.e. extracellular HSPs) is yet not known, HSP70 (intracellular HSP70) plays an important role in cytoprotection by preventing abnormal folding of newly synthesized polypeptides, or by assisting in the repair of damaged proteins [24]. The elderly people seem to be characterized by a diminished basal expression of HSP70 and a blunted induction in response to different stress conditions [25]. Therefore, the negative correlation between spontaneous ROS production and HSP70 may indicate that the higher concentration of HSP70 in plasma protectively responds to the oxidative stress [26], which may cause lower levels of spontaneous ROS production, or vice versa..."

 

Ogawa K, Suzuki K, Okutsu M, Yamazaki K, Shinkai S. The association of elevated reactive oxygen species levels from neutrophils with low-grade inflammation in the elderly. Immun Ageing. 2008;5:13.

 

Maybe this is also something to be reported in our OSKM and Biological Age threads but not sure how...

 


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#56 HighDesertWizard

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Posted 14 November 2018 - 08:49 PM

While implicit I guess in much of what has been posted here maybe you find useful to consider or reconsider the link of HSP70 to oxidative stress and inflammation both well studied in aging. Hopefully this is a bit new to you and if not at least a good reminder and for a me an additional pointer :)

 

"...The spontaneous ROS production negatively correlated with HSP70 (r = -0.41, P < 0.05) only in the aged group, but not in the young group. HSP70 is a very conservative family of cytoprotective proteins that are specifically induced in response to several environmental stresses at the cellular level including heat shock, cellular energy depletion, oxidative stress or inflammation. Although the role of HSP70 in the blood (i.e. extracellular HSPs) is yet not known, HSP70 (intracellular HSP70) plays an important role in cytoprotection by preventing abnormal folding of newly synthesized polypeptides, or by assisting in the repair of damaged proteins [24]. The elderly people seem to be characterized by a diminished basal expression of HSP70 and a blunted induction in response to different stress conditions [25]. Therefore, the negative correlation between spontaneous ROS production and HSP70 may indicate that the higher concentration of HSP70 in plasma protectively responds to the oxidative stress [26], which may cause lower levels of spontaneous ROS production, or vice versa..."

 

Ogawa K, Suzuki K, Okutsu M, Yamazaki K, Shinkai S. The association of elevated reactive oxygen species levels from neutrophils with low-grade inflammation in the elderly. Immun Ageing. 2008;5:13.

 

Maybe this is also something to be reported in our OSKM and Biological Age threads but not sure how...

 

albedo... I hadn't seen that study. Great find! Thank you!

So we now know there are several studies showing HSP expression, even and especially HSP70, declines with aging.

The study in footnote 25 is this one.

 

2002, Age-related decrease in the inducibility of heat-shock protein 70 in human peripheral blood mononuclear cells



#57 HighDesertWizard

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Posted 14 November 2018 - 08:55 PM

I still don't see any studies in normal mice showing enhanced longevity. As for heat shock protein, that does look interesting, though the plots are focusing only on one aspect of longevity. And even with these positive cardio effects for sauna use, aren't there other explanations? As in reduction of stress? Or different lifestyles? Because if heat shock proteins were really so protective, wouldn't one see these effects in those living in tropical areas? Looking at a world map of heart attack data, there is no obvious correlation.

 

About the other explanations listed...

 

--> "reduction of stress" and "different lifestyles" are not biological explanations. A reduction of Heat Shock Protein is a biological explanation and that's what this thread is focused on.

 

And even for those particular non-biological explanations, heat shock factors could be a confounding set of variables.

 

About the world map...

 

--> I agree that there is no obvious correlation, so an explanation awaits more information.



#58 HighDesertWizard

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Posted 14 November 2018 - 09:26 PM

 

Puzzle pieces with significant meaning merit more evidence gathering time and, I think, this is one of the most significant for a reason I hinted at upthread...

 

2012, Modulation of heat shock proteins during macrophage differentiation

 

CONCLUSION:

Our study revealed that monocytes undergoing maturation differentially regulate the expression of several members of HSPs and that distinct patterns of HSP expression characterize the M1 and M2 effector stages of macrophage life.

 

2013, Activation of the stress response in macrophages alters the M1/M2 balance by enhancing bacterial killing and IL-10 expression

 

2013, Curcumin Modulates Macrophage Polarization Through the Inhibition of the Toll-Like Receptor 4 Expression and its Signaling Pathways

 

Gotta look close into this one to understand how HSPs enter the picture as a confounding variable for Curcumin's effects on macrophage polarization...

 

... Toll-like receptor 4 (TLR4), a pattern recognition receptor, plays a key role in inflammation and the immune system. TLR4 is primarily expressed in human monocytes and recognizes multiple microbial and endogenous molecules via their molecular patterns, including LPS, heat-shock proteins 60 and 70, fibrinogen, and oxidized lipids [10,11].

 

2016, Extracellular HSP110 skews macrophage polarization in colorectal cancer

 

2012, Opposing roles for heat and heat shock proteins in macrophage functions during inflammation: a function of cell activation state?

 

This pic posted in the opening post is worth considering again...

 

NUDt7TG.jpg

 


Edited by HighDesertWizard, 14 November 2018 - 09:33 PM.


#59 HighDesertWizard

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Posted 15 November 2018 - 03:20 AM

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 "approximate" epigenetic turn identified by the team led by Seth Grant. ("approximate" isn't the right word here. if you know what the right word to use is, please post.)
 
 
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 - 03:59 AM.

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#60 HighDesertWizard

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Posted 15 November 2018 - 04:47 PM

One of reason's posts today is interesting because it references a decline in a longevity promoting gene as we age. Does Heat Shock have something to do with this? Is Heat Shock a Confounding Variable for Klotho? Here's the link to reason's post again, entitled...

 

Klotho Shields the Brain from the Peripheral Immune System, but Declines with Age

 

He links to this summary from the Gladstone Institute of this study entitled, Klotho controls the brain–immune system interface in the choroid plexus.

 

 

Now, a question we might ask is this...

 

Is Klotho another of those variables that Heat Shock is a Confounding Variable for like it turned out to be for NAD+?

  • The authors of the Klotho study reason highlights never put the word "heat" in the study text.
  • reason never mentions heat shock in his review of the study

Should we settle for that minimal understanding of the implications of the study?

 

 

I say no... Not ever...

 

But before we look at Klotho specifically, let's take a dive into this part of the brain called the Choroid Plexus, that's important, but I never heard of until this morning.

 

It turns out that Heat Shock Protein 90, the HSP most unfriendly to our achievement of extreme longevity, can be dominant in the choroid plexus. But notice none of the studies below reference Heat Shock in the study title.

 

2003, Stress protein expression in the Alzheimer-diseased choroid plexus

 

2004, Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease

 

2012, Involvement of the choroid plexus in the inflammatory response after acute spinal cord injury in dogs: An immunohistochemical study

 

2016, The Choroid Plexus in Healthy and Diseased Brain

 

Now the folks writing this study do mention that "the expression of heat shock proteins was altered in the choroid plexus derived from AD patients postmortem", but don't make anything of it. And notice the year, 2016. It was late in the day in 2016 not to make much of that fact, wasn't it?

 

And the study does paint a scary picture of the havoc inflammation can cause in the choroid plexus.

 

You better close your eyes before you peek at the scary picture below...

 

... of macrophages squeezing "through disrupted tight junctions into the ventricular lumen". What'dya bet those Macrophages have an M1 Inflammatory Phenotype?

 

dNUe62Hh.png

 

[ 

But getting back to Klotho and the question of whether Heat Shock Protein is a Confounding Variable for its positive longevity effects...

 

Here's another maddening study...

 

2017, Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice

 

Yes. I know. The study title doesn't reference Heat Shock Protein. But a finding about HSP70 is one of the key findings.

 

You don't have to believe me, check out the abstract statement...

 

Background

Aging augments endotoxemic cardiac dysfunction, but the mechanism remains unclear. Anti-aging protein Klotho has been found to modulate tissue inflammatory responses. We tested the hypothesis that a reduced Klotho level in aging heart plays a role in the augmented endotoxemic cardiac dysfunction.

Materials and Methods

Endotoxin (0.5 mg/kg, iv) was injected to adults (4-6 months) and aging (18-20 months) C57BL/6 mice. Recombinant Klotho (10 μg/kg, iv) was administered to a group of aging mice after endotoxin injection. Cardiac function was analyzed using a microcatheter at 24 and 48 h after endotoxin administration. Myocardial levels of Klotho and heat shock protein 70 (HSP70) were determined by immunoblotting, and plasma and myocardial cytokines were analyzed using ELISA.

Results

More severe cardiac dysfunction in aging mice were accompanied by greater cytokine levels in the plasma and myocardium. Klotho was detected in the myocardial tissue. Klotho levels were lower in aging hearts and were further reduced during endotoxemia. Myocardial HSP70 levels were correlated with Klotho levels. Recombinant Klotho increased myocardial HSP70, inhibited NF-κB activation, reduced cytokine levels, and improved cardiac function in aging endotoxemic mice. Delivery of HSP70 into cultured macrophages suppressed endotoxin-induced NF-κB activation.

Conclusions

Aging-related augmentation of inflammatory responses and cardiac dysfunction is associated with relative Klotho deficiency. Post-treatment with recombinant Klotho suppresses the inflammatory responses and improves cardiac function in aging endotoxemic mice. Klotho modulates HSP70 levels and HSP70 appears to be involved in the anti-inflammatory mechanism of Klotho. Klotho may have therapeutic potential in amelioration of aging-related endotoxemic cardiac dysfunction.

 

 

What the world is going on with these people when they apparently cannot figure out how to express a key finding of their study in the study title?

 

"Longevity science is too important to the human future to leave entirely in the hands of scientists."

-- Steve Buss, 2018

 

:)


Edited by HighDesertWizard, 15 November 2018 - 05:00 PM.

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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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