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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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#121 albedo

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Posted 05 January 2019 - 01:58 PM

Hi HDW! I wonder if you have seen this 2017 study on the compounds, also natural, researched by machine learning methods as mimetic of metformin and rapamycin. The link to HSP90 is interesting in particular for EGCG (green tea):

 

"...Like the metformin DNN classifier, the rapamycin classifier also revealed a clear standout amongst the compounds for rapamycin similarity, geldanamycin. Geldanamycin is an inhibitor of Hsp90 [178], which is an oncogenic target molecule overexpressed in many tumors [115,179]. Geldanamcyin is an inhibitor of mTOR signaling as well [115] While initially promising as an potent anticancer agent [115,179,180], its hepatotoxicity has precluded its clinical use [180,181]; however, several less toxic derivatives have been developed [182], with 17AEP-GA and 17DMAG
recently demonstrating growth suppression of multiple myeloma cells similar to geldanamycin [181]. Geldanamycin analog development is still an active area of research [182–185], with other analogs being recently shown to be effective against breast cancer cells [182,185]. In addition to geldanamycin, at least two of the other rapamycin hits in this study, radicicol and EGCG are also Hsp90 inhibitors [183,184]...
."

 

Aliper A, Jellen L, Cortese F, et al. Towards natural mimetics of metformin and rapamycin. Aging (Albany NY). 2017;9(11):2245-2268.



#122 HighDesertWizard

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Posted 06 January 2019 - 06:48 AM

Hi HDW! I wonder if you have seen this 2017 study on the compounds, also natural, researched by machine learning methods as mimetic of metformin and rapamycin. The link to HSP90 is interesting in particular for EGCG (green tea):

 

"...Like the metformin DNN classifier, the rapamycin classifier also revealed a clear standout amongst the compounds for rapamycin similarity, geldanamycin. Geldanamycin is an inhibitor of Hsp90 [178], which is an oncogenic target molecule overexpressed in many tumors [115,179]. Geldanamcyin is an inhibitor of mTOR signaling as well [115] While initially promising as an potent anticancer agent [115,179,180], its hepatotoxicity has precluded its clinical use [180,181]; however, several less toxic derivatives have been developed [182], with 17AEP-GA and 17DMAG
recently demonstrating growth suppression of multiple myeloma cells similar to geldanamycin [181]. Geldanamycin analog development is still an active area of research [182–185], with other analogs being recently shown to be effective against breast cancer cells [182,185]. In addition to geldanamycin, at least two of the other rapamycin hits in this study, radicicol and EGCG are also Hsp90 inhibitors [183,184]...
."

 

Aliper A, Jellen L, Cortese F, et al. Towards natural mimetics of metformin and rapamycin. Aging (Albany NY). 2017;9(11):2245-2268.

 

Albedo... This is useful info...

 

I haven't posted in a while. I experience paralyzing writer's block fear from time to time. I've got fresh anecdotal stories and new actionable study discoveries to share, but I'm paralyzed when it comes to posting about it. And then there's so much to catch up on.

 

Your posts helped me to overcome the block today.

 

Thank you!



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#123 HighDesertWizard

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Posted 06 January 2019 - 07:31 AM

Hi HDW! I wonder if you have seen this 2017 study on the compounds, also natural, researched by machine learning methods as mimetic of metformin and rapamycin. The link to HSP90 is interesting in particular for EGCG (green tea):

 

"...Like the metformin DNN classifier, the rapamycin classifier also revealed a clear standout amongst the compounds for rapamycin similarity, geldanamycin. Geldanamycin is an inhibitor of Hsp90 [178], which is an oncogenic target molecule overexpressed in many tumors [115,179]. Geldanamcyin is an inhibitor of mTOR signaling as well [115] While initially promising as an potent anticancer agent [115,179,180], its hepatotoxicity has precluded its clinical use [180,181]; however, several less toxic derivatives have been developed [182], with 17AEP-GA and 17DMAG
recently demonstrating growth suppression of multiple myeloma cells similar to geldanamycin [181]. Geldanamycin analog development is still an active area of research [182–185], with other analogs being recently shown to be effective against breast cancer cells [182,185]. In addition to geldanamycin, at least two of the other rapamycin hits in this study, radicicol and EGCG are also Hsp90 inhibitors [183,184]...
."

 

Aliper A, Jellen L, Cortese F, et al. Towards natural mimetics of metformin and rapamycin. Aging (Albany NY). 2017;9(11):2245-2268.

 

 

Albedo... This is useful info...

 

 

A few thoughts...

 

About larger "Heat Shock Protein" questions...

  • "Heat Shock Protein/s" is/are not a single substance having a single, binary positive or negative health effect.
     
  • In the study Albedo references, HSP 90 appears as a negative-for-health culprit as well as in many, many, many others.
    • See what should be, now, considered "old news".
    • Normally, I'd hesitate to say anything about HSP 90 without a study reference link showing that sometimes HSP 90 plays a helpful-for-health role because my intuition, today, tells me that it must.
      • But I've been infected with writer's block for several weeks now and I'm trying to break the fever.
      • So... I'm determined to post this comment this evening and get back to the detail of a study link, pro or con to today's intuition, at some point...
      • :)  :|?  :|?  :)
  • HSP 70 / 72(?) have been shown to have both positive and negative health effects, but My-Sense-of-The-Literature is that HSP 70 has the most consistently positive health effects.
     
  • HSP 27... Noticing it's positive health effects too.
     
  • So, put abstractly because It's ALWAYS in the Back of Our Minds that there are multiple studies showing that HSP 70 Regulates OCT4 (see Opening Post), the First Draft Version of The-Question to be asking is...
    • What are the study contexts in which Positive-For-Health impacts have been shown to be associated with Heat Shock Proteins? And which one (i.e., which HSP?).

Posted!

 

:)


Edited by HighDesertWizard, 06 January 2019 - 07:42 AM.

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#124 HighDesertWizard

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Posted 10 January 2019 - 10:20 AM

I'm now able to raise my temperature by 1.5o to 2.0o F by laying on the Heat/PEMF mat I began to use about a month ago and referenced upthread. But that's not enough. I'm intent on replicating the 3.0o temperature increase that Nate is getting by using a Sauna.

 

I've also learned some interesting things and had some interesting experiences lately while attempting to get my temperature higher. I summarize these experiences below in a set of bullet points.

 

1. Learned something from a friend

 

I have a friend in his early 80s who's been taking hot baths for 20 years when he gets sick. He increased the frequency of these baths from only when he got sick to taking them every day a couple years ago after I began to talk about the importance of heat shock proteinHe now takes one or two baths per dayHe recently told me about his experience with topical Capsaicin-triggering pain relievers. I've encouraged him to report on his anecdotal experiences here at Longecity. I don't know if he'll do that.

 

The upshot is this: use of the pain-relieving roll-on, Pain Bloc, has caused arthritic pain in his ankle to be relieved for a few months at a time.   -->> I've used an eBay link for the product in the previous sentence because the product site url is not a secure https site. That product url is painbloc24.com.

 

I'll be getting more details of the exact technique he used to achieve that result.

 

2. Pain Bloc does, in fact, relieve the extremely minor pain I feel in my knees from time to time when I don't take omega-3s for a couple days in a row. And another friend's arthritic neck pain has been significantly reduced with its use also.

 

Please note... It's important to be careful in using it. This Capsaicin herbal topical is extremely potent and is the burning sensation if it's used casually.

 

Cayenne Pepper is a Capsaicin-related herb and I've also begun to take it more consistently, in multiple doses per day. The combination of cayenne pepper with the use of Pain Bloc appears to raise my average temperature by 1/2 to 1° or even more. Haven't done it enough yet to know what the more precise average increase in temperature might be.

 

3. An interesting early observation about using Pain Bloc along with the use of my heated/PEMF mat...

 

Applied Pain Bloc to a couple body location and the next day, when using the mat, my body temperature rises and I sense a higher, tolerable, heat burn sensation at the locations I applied the Pain Bloc to.


Edited by HighDesertWizard, 10 January 2019 - 10:29 AM.

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#125 QuestforLife

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Posted 10 January 2019 - 12:52 PM

 

Applied Pain Bloc to a couple body location and the next day, when using the mat, my body temperature rises and I sense a higher, tolerable, heat burn sensation at the locations I applied the Pain Bloc to.

 

 

So you are saying 'Pain Bloc' (aka capsaicin aka chilli peppers) and temperature appear to be synergistic in some way?...Makes sense!



#126 HighDesertWizard

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Posted 15 January 2019 - 12:04 PM

So you are saying 'Pain Bloc' (aka capsaicin aka chilli peppers) and temperature appear to be synergistic in some way?...Makes sense!

 

I have a few more days experience with this now. The general answer to your question is Yes. There does appear to be synergy between capsaicin application and temperature raising by other means. My sense of this is that doing both appears to increase body temperature at the topical capsaicin application location more either would by themselves. I should add that I haven't measured this effect so as to have actual evidence.

 

I'm finding that at the specific locations to which I apply Pain Bloc, when my body obviously (or by implication) has a higher temperature, I experience burning sensations of various intensities, nothing unbearable, although a little unsettling at first.

 

For example, after applying capsaicin to body locations, taking a Cayenne Pepper capsule triggers a burning sensation in those locations, even after 24 hours. I'm not sure how long the effect of the capsaicin application lasts.

 

I spoke to my friend mentioned upthread about his experience a couple days ago. He told me again that, after one application, combined with heat from his hot bath, arthritis in one of his ankles went away for months !?!?

 

I'm also finding that my average body temperature taken orally appears to be 0.5 to 1.0 degree higher. I should add that I don't have systematic and rigorous data about this.

 

This is all good news.

 

:)


Edited by HighDesertWizard, 15 January 2019 - 12:08 PM.


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#127 HighDesertWizard

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Posted 15 January 2019 - 12:18 PM

Is Older Colder or Colder Older? The Association of Age With Body Temperature in 18,630 Individuals

 

In animal studies, caloric restriction resulting in increased longevity is associated with a reduction in body temperature, which is strain specific and likely under genetic control. Small studies in humans have suggested that temperatures may be lower among elderly populations, usually attributed to loss of thermoregulation. We analyzed cross-sectional data from 18,630 white adults aged 20–98 years (mean 58.3 years) who underwent oral temperature measurement as part of a standardized health appraisal at a large U.S. health maintenance organization. Overall, women had higher mean temperatures (97.5 ± 1.2°F) than men (97.2 ± 1.1°F; p < .0001). Mean temperature decreased with age, with a difference of 0.3°F between oldest and youngest groups after controlling for sex, body mass index, and white blood cell count. The results are consistent with low body temperature as a biomarker for longevity. Prospective studies are needed to confirm whether this represents a survival advantage associated with lifetime low steady state temperature.

 

As you consider the study graphic figures below, realize that colder body temperature is not promoting longevity, at older ages, only the data of Survivors is shown.

 

It seems to me that this addition to the evidence discussed upthread makes the argument about the importance of heat shock protein and establishing a higher average body temperature all the more compelling. So, therefore, our effort to understand what's going on all the more worthwhile.

 

:)

 

 

 

Nnj8iPb.png

 

 

 

jZpmgxN.png

 

 

 

oYcIZO7.png

 

 

 

GZHYf2q.png


Edited by HighDesertWizard, 15 January 2019 - 12:28 PM.

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#128 Nate-2004

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Posted 15 January 2019 - 08:56 PM

The difference of a degree or two may matter I suppose. It makes sense that obese people would run hotter.  I wonder how this data correlates with mortality rates, especially those of normal weight who brought the average up.

 

Brown adipose tissue is also lost with age. This only further makes the case for doing cold thermogenesis therapy and engaging in other brown adipose inducing activities/supplements. Counter-intuitively, making yourself cold for periods of an hour or so may help improve thermal regulation. Extreme temperature exposures in general may help improve body temperature regulation. 

 

I wish I could get my schizophrenic roommate to try these things consistently.


Edited by Nate-2004, 15 January 2019 - 08:57 PM.


#129 Hebbeh

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Posted 16 January 2019 - 04:57 AM

https://www.scienced...90115111936.htm

 

Fever is known to help power up our immune cells, and scientists in Shanghai
have new evidence explaining how. They found in mice that fever alters surface
proteins on immune cells like lymphocytes to make them better able to travel via
blood vessels to reach the site of infection. Their work appears on January 15 in
the journal Immunity.

"One good thing about fever is that it can promote lymphocyte trafficking to the site of infection, so you
will have more immune cells in the infected region that will get rid of the pathogen," says Shanghai
Institute of Biochemistry and Cell Biology (SIBCB) Professor and senior author JianFeng Chen.
To get to an infection, white blood cells need to adhere to the blood vessel and then transmigrate into
the infected tissue or lymph node. During this step, molecules known as integrins are expressed on the
surface of lymphocytes. Integrins are cell adhesion molecules that control lymphocyte trafficking during
inflammation.

Chen and colleagues discovered that fever increases the expression of heat shock protein 90 (Hsp 90)
in T lymphocytes. This protein binds to a type of integrin on the lymphocytes -- α4 integrins -- which
promote lymphocyte adhesion to the blood vessel and ultimately to expedited migration to the site of
infection.

The researchers learned that fever-induced Hsp90 binds to the integrin tail and induces integrin
activation. Moreover, one Hsp90 can bind to two integrins leading to a clustering of integrins on the
lymphocyte surface. As a result, the clustered integrins activate a signaling pathway that promotes
lymphocyte transmigration.

"Our findings show that this mechanism not only applies to lymphocytes but also to innate immune cells
like monocytes," says Chen. "It is a general mechanism that can apply to lots of different immune cells
expressing α4 integrins."

The team also used animal studies of bacterial infection and other fever models to confirm their
findings. When the pathway between the Hsp90 and integrin was blocked, study mice died quickly.
They also learned that this mechanism is very temperature-specific. "In this paper, we found the Hsp90
can only be induced at a temperature above 38.5°C," says Chen, explaining how the mechanism is
targeted and effective, yet reversible.

The researchers also believe other stresses, not just fever, can induce Hsp90 expression. "That's why
we think that in different situations, such as autoimmune disease and cancer, this Hsp90-α4 integrin
pathway may be involved," says Chen. In autoimmune disease, aberrant trafficking of immune cells to
different organs or tissues may lead to disease. "But if you block this pathway, you can maybe inhibit
the trafficking of the immune cells during chronic inflammation or in autoimmune diseases," he says.

Journal Reference:
1. ChangDong Lin et al. Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory
Pathway Involving Heat Shock Protein 90 and α4 Integrins. Immunity, 2019 DOI:
10.1016/j.immuni.2018.11.013


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#130 QuestforLife

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Posted 17 January 2019 - 01:26 PM

 

What is interesting about these results is that chronic, i.e. long term, elevated temperature is clearly a negative health and aging biomarker - as you might expect based on metabolic rate. But we also know from the Swedish Sauna study and others that acutely raising temperature for a short period is profoundly beneficial for lifespan, again as you might expect based on spurring regeneration. This is analogous to damaging a muscle through weight lifting in order to spur localized inflammation and rebuilding to leave it stronger than before, as opposed to a generalized raised inflammation level across the body, which may lead to autoimmunity and exhaustion of replacement cells and faster aging.



#131 HighDesertWizard

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Posted 17 January 2019 - 03:40 PM

What is interesting about these results is that chronic, i.e. long term, elevated temperature is clearly a negative health and aging biomarker - as you might expect based on metabolic rate. But we also know from the Swedish Sauna study and others that acutely raising temperature for a short period is profoundly beneficial for lifespan, again as you might expect based on spurring regeneration. This is analogous to damaging a muscle through weight lifting in order to spur localized inflammation and rebuilding to leave it stronger than before, as opposed to a generalized raised inflammation level across the body, which may lead to autoimmunity and exhaustion of replacement cells and faster aging.

 
QuestforLife... I'm glad you've responded as you have. I'm uncertain about what the actual effect of chronic higher temperature is and I believe it would be useful to discuss, even argue, about it...
 
It's best, IMO, if we take opposing sides on what the evidence suggests. I'm happy to take either side of the argument because I think there is evidence for both.
 
But my hunch is that chronic higher temperature is healthier if it is triggered by exogenous means rather than endogenous inflammatory conditions.
 
:)
 
1 - My take on the data shown above is that it implies two very different things are true.

  • A higher temperature is unhealthy.
  • As we age, average temperature declines, even among those who survive into their 80s, hence, the implication that a higher temperature is healthier.

2 - These paradoxical implications of the data are consistent with other studies about Heat Shock Proteins.

  • They aren't a single thing. They're different substances by their molecular weight.
  • Some of them (HSP70 most prominently) are healthier than others (e.g., HSP90).
  • HSP70 can have both healthy and unhealthy effects.

3 - A central meme of this thread is that a reduction in Endogenous HSP (70?) expression triggered in our mid-20s is central to the aging process. I posted a diagram in the opening post that highlights the paradoxical impact of HSPs and it's always in the back of my mind so I'll repost it here.

  • The diagram highlights what appears to be a fact: that HSP70 inhibits NF-kB Inflammatory Cytokine Transcription and we know from other evidence that that is healthy.

4 - An observation about the evidence I think is important to keep in mind...

  • Endogenous HSP expression because of inflammatory states, like obesity, is unhealthy.
  • Exogenous triggering of HSP expression while NOT in an inflammatory state appears to be healthy.

5 - I'm not clear about what you believe the evidence is that supports the following statement given the two observations in #4 above.

  • "What is interesting about these results is that chronic, i.e. long term, elevated temperature is clearly a negative health and aging biomarker - as you might expect based on metabolic rate".
  • I posted a link to a study up thread that shows the opposite...
  • Notice in at least two studies referenced in this thread that healthy effects of HSP expression have to do with its impact on NF-kB...

As I mentioned in the opening post, I've been thinking about this topic a good while. I'd completely forgotten about this thread created back in May until this evening.
 
Hotter bodies fight infections and tumours better – researchers show how
 
Two big puzzle pieces are noted here, my friends, heat and NF-kB...

 
Let's figure this out!
 
:)
 
 
NUDt7TG.jpg


Edited by HighDesertWizard, 17 January 2019 - 03:54 PM.


#132 QuestforLife

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Posted 17 January 2019 - 03:52 PM

It could be that older people are failing to maintain temperature homeostasis and those that do it better are living on, even as their temperatures also fall - or it could be that hotter people are being weeded out. We'd need a study that followed individuals throughout their lifetimes to know for sure.

 

It's analogous to the 'older fathers have offspring with longer telomeres argument' - we don't know whether this is actually true, or whether succeeding generations are losing telomere length, because no one has actually followed individuals throughout their lifespans, they've only looked at a cross section of population at a given time.



#133 Engadin

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Posted 17 January 2019 - 08:44 PM

Just to get you informed about the last progress on OSKM genes research path, some today's Life Extension Advocacy Foundation news titled 'Hitting the Reset Button on Aging Cells':

 

"For the study, the researchers used a specially engineered progeric mouse designed to age more rapidly than normal as well as an engineered normally aging mouse strain. Both types of mice were engineered to express OSKM when they came into contact with the antibiotic doxycycline, which was given to them via their drinking water. They allowed the OSKM genes to be expressed by including doxycycline in the water for two days then removed it so that the OSKM genes were silenced again. The mice then had a five-day rest period before another two days of exposure to doxycycline; this cycle was repeated for the duration of the study.

After just six weeks of this treatment, which steadily reprogrammed the cells of the mice, the researchers noticed improvements in their appearance, including reduced age-related spinal curvature. Some of the mice from both experiment and control groups were also euthanized at this point so that their skin, kidneys, stomachs, and spleens could be examined. The control mice showed a range of age-related changes compared to the treated mice, which had a number of aging signs halted or even reversed, including some epigenetic alterations. The treated mice also experienced a 50% increase in their mean survival time in comparison to untreated progeric control mice. It should be noted that not all aging signs were affected by partial reprogramming, and if treatment was halted, the aging signs returned.

Perhaps most importantly, while the partial reprogramming conducted in this periodic manner reset some epigenetic aging signs, it did not reset cell differentiation, which would cause the cell to revert to an embryonic state and forget what kind of cell it previously was; as you can imagine, this would be a bad thing in a living animal.

Finally, not only did OSKM expression at least partially rejuvenate cells and organs in progeric mice, but it also appeared to improve tissue regeneration in the engineered 12-month-old normally aging mouse group. The researchers observed that the partial reprogramming improved these mice’s ability to regenerate tissue in the pancreas, resulting in an increased proliferation of beta cells; additionally, there was an increase of satellite cells in skeletal muscle. Both types of cells typically decline during aging".

Source: https://www.leafscience.org/oskm/

Enjoy the read and the video.

 
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#134 HighDesertWizard

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Posted 18 January 2019 - 07:39 AM

2017, The Association of Hot Red Chili Pepper Consumption and Mortality: A Large Population-Based Cohort Study

 

The evidence base for the health effects of spice consumption is insufficient, with only one large population-based study and no reports from Europe or North America. Our objective was to analyze the association between consumption of hot red chili peppers and mortality, using a population-based prospective cohort from the National Health and Nutritional Examination Survey (NHANES) III, a representative sample of US noninstitutionalized adults, in which participants were surveyed from 1988 to 1994. The frequency of hot red chili pepper consumption was measured in 16,179 participants at least 18 years of age. Total and cause-specific mortality were the main outcome measures. During 273,877 person-years of follow-up (median 18.9 years), a total of 4,946 deaths were observed. Total mortality for participants who consumed hot red chili peppers was 21.6% compared to 33.6% for those who did not (absolute risk reduction of 12%; relative risk of 0.64). Adjusted for demographic, lifestyle, and clinical characteristics, the hazard ratio was 0.87 (P = 0.01; 95% Confidence Interval 0.77, 0.97). Consumption of hot red chili peppers was associated with a 13% reduction in the instantaneous hazard of death. Similar, but statistically nonsignificant trends were seen for deaths from vascular disease, but not from other causes. In this large population-based prospective study, the consumption of hot red chili pepper was associated with reduced mortality. Hot red chili peppers may be a beneficial component of the diet.

 

 

 

I've been experimenting with the Pain Bloc product I referenced in a post above recently. I'm not certain why I didn't see an https link the first time around but there is one now here...

 

I now have 2 friends with more than very positive anecdotal stories of their experience with it in reducing arthritic pain.

 

As I mentioned, I don't have much, if any, body pain, but I do have cardiovascular disease (had a 3x CABG 16+ years ago). For the last 3 to 4 months, I noticed reduced so-called "exercise tolerance". That's one of the reasons I've been "hot" in pursuit of a heat shock protein approach.

 

So after experimenting with applying the Pain Bloc product to my knees I felt comfortable applying it to my chest. I had the same experience my friends did. Up to 36 hours later, when taking a hot shower or eating a spicy soup I felt a completely tolerable, but certain burning sensation at the locations I had applied it. QuestforLife called it a synergistic effect and I think that's a good word for it.

 

Also, I had an increased average body temperature. These days, I have a thermometer with me all the time so I can take my temp at random moments during the day.

 

But I haven't applied the Pain Bloc product for the last 3 days so I could asses what would happen to my average body temperature and, sure enough, my average temperature has dropped back to what it was before, around 97o F. (It had been close to or just above 98o F while doing Pain Bloc. I should say also that I'm now taking Cayenne capsules.

 

The good news is this... My "exercise tolerance" improved significantly enough for me to notice in the very short time I had been doing Pain Bloc.

 

Another thing... I noticed that if the Pain Bloc dosing took place within the last 24 hours, when I lay on the heat/PEMF mat I've discussed up thread, my temperature would increase rapidly within 10 to 15 minutes. But when I tried it just now, after not having done Pain Bloc for 3 days, it took two to three times as long to get the same temperature increase.

 

Seems to me that my anecdotal experience is a kind of confirmation of the findings at the top of this post. You'd be right if you imagine this is great news for me.

 

:)

 

My hunch is that the positive health effects are cumulative over time. I'll be experimenting with dosing strategies and will report on my experience from time to time...

 

Oh... before I forget... One more thing... I've noticed increased muscle growth in the time since I started frequent use of the heat mat. And with the capsaicin use, it's been even more pronounced. I couldn't figure out what the heck was triggering it. And then I came across this 14-minute video by the great Rhonda Patrick. It's a must see...

 

Enjoy!

 


Edited by HighDesertWizard, 18 January 2019 - 07:45 AM.

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#135 QuestforLife

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Posted 18 January 2019 - 10:24 AM

 

Oh... before I forget... One more thing... I've noticed increased muscle growth in the time since I started frequent use of the heat mat. And with the capsaicin use, it's been even more pronounced.

 

Interesting post. Have you been lifting weights as well?



#136 HighDesertWizard

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Posted 18 January 2019 - 04:49 PM

Interesting post. Have you been lifting weights as well?

 
Good question, because only in trying to answer it did I come up with a new insight. Thanks for asking,
 
I have not been lifting weights.
 
I am, what is called, barrel-chested and my upper body strength has been good without much effort. I'm also right-handed and for decades I've noticed that my right bicep is obviously larger than my left. I didn't care enough for myself and it wasn't obvious to others so I didn't try to even it out with left-bicep exercise.
 
And now just within the time since I began consistent and frequent use of my heated / PEMF mat, my left bicep has enlarged to become virtually equivalent in size to my right bicep. Only in thinking through what the explanation is, do I realize that my previous statement about new muscle development is incorrect. It's not that muscle development has increased throughout my body, that was an unconscious assumption based on an observation of my left bicep's increase in size.
 
Is there an explanation? I think there is and it's a function of the design of my PEMF mat and my use of it to maximize my temperature increase.
 

BK2TlVr.png

The pic is from a mat advertisement.

 

 

The mat has various types of small stones in it that are contained within sewn partitions you can see running perpendicular to the woman's body in the pic. Most of the mat surface is thick material but the two darker bands on the left side of the mat are plastic, I suppose, to expose the small stone content of the perpendicular running partitions.

 

When heated, the plastic is significantly hotter than the material of the mat, enough that I've been consciously placing my left palm on the plastic area to get my temperature higher and higher faster. Sometimes I have to reposition that palm for 10 seconds or so to reduce the bite of the heat. (The effect of doing that implicates additional useful information about triggering heat in ourselves.)

 

That's the only explanation I can think of to account for the increased size of my left bicep. And if you've watched the video in my last post featuring Rhonda Patrick you know why that explanation makes complete sense.
 

Oh my... A new idea about something to try: Suppose I applied Pain Bloc to both biceps as an additional test of the science Rhonda Patrick talks about in the video? I can measure the size of both biceps before and after regular intervals to see how well it works.

 

And what additional muscles might I try this idea out on?

 

I'm both foolish and stupid enough to actually want to try this. If you can think of a good reason for me not to, please speak up and tell me why I shouldn't.

 

:)  :unsure:  :)

 

And, QuestforLife, often when you ask a question, I get triggered and gain new insight. Please keep the questions coming!


Edited by HighDesertWizard, 18 January 2019 - 04:56 PM.

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#137 QuestforLife

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Posted 18 January 2019 - 05:06 PM

I think you should try and make your left bicep larger than your right, just to be sure (because it would be the kind of funny result you'd know wasn't placebo!)



#138 HighDesertWizard

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Posted 18 January 2019 - 06:43 PM

I think you should try and make your left bicep larger than your right, just to be sure (because it would be the kind of funny result you'd know wasn't placebo!)

 

Great idea. That's what I'll do.


Edited by HighDesertWizard, 18 January 2019 - 06:44 PM.


#139 HighDesertWizard

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Posted 19 January 2019 - 08:19 PM

I've spent too much time on this post today. But I want to get the key point posted even if the post doesn't yet have all the evidence I hope to include later. I'll be back later to work on it...

 

 

 

Thanks for this find, Bryan_S!
 

Here's a research twist, and food for thought, think about this, reprogramming somatic cells in the absence of exogenous biochemical factors. This approach is a complete 180 from the OSKM method used in the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" project.
 
See: "Laterally confined growth of cells induces nuclear reprogramming in the absence of exogenous biochemical factors
 
What's the significance? You don't need OSKM factors. Environmental physical constraints were used in this example, not exogenous biochemical factors. Reprogramming gene promoters were progressively acetylated, while mesenchymal promoters were deacetylated by 10 days without exogenous biochemical factors.  In vivo, cells transdifferentiate into different lineages in the absence of exogenous factors, indicating that the local mechanochemical factors could be important elements and are sufficient for inducing such transitions. WHO KNEW? This opens up insight into areas of regenerative medicine. It appears somatic cells have more plasticity than previously thought given the proper environment.
 
What is promoting the epigenetic reprogramming? It appears the cells in contact with a designed physical substrate undergo cytoskeletal reorganization, which changes nuclear shape and facilitates nuclear orientation along the growth axis. From this the epigenetic landscape of the chromatin, particularly the levels of H3K9Ac, H3K4Me3, and H3K27Me3, changes with time. The increase in nuclear plasticity along with the reorganization of epigenetic and chromosome packing within the nucleus, with time leads to the rewiring of the nuclear architecture in a manner that primes the nucleus for reprogramming.
 
<SNIP>

 
I believe if we find the right epigenetic targets we can regress a cell without installing an OSKM polycystronic cassette in each cell of a host organism we wish to regress in age.

 
[hr|
 
The question of this post...

  • A central conjecture of this thread is that Heat Shock Protein expression is implicated in epigenetic reprogramming.
     
  • The study Bryan_S posted above highlights describes a context of mechanical stress (environmental physical constraints) and some associated gene expression changes (including in H3K4Me3, and H3K27Me3) that led to "the progressive erasure of lineage specific[/size] characteristics and incorporation of pluripotency".

Do the descriptions of the context, discovery features, and findings of the study Bryan_S posted suggest that Heat Shock Protein expression was likely implicated, even if not noted in the study?
 
I believe the answer to that question is Yes. I've posted study links with some explanatory text in support of that answer.
 
 
 
Assumption: "environmental physical constraints" constitute a kind of mechanical stress.
 
Is Heat Shock Protein expression implicated in contexts of mechanical stress.
 
2018, Heat Shock Proteins as Sensors for Mechanical Stress
 

Heat shock proteins (HSP) are highly responsive to stresses including temperature and oxidative stress. Some heat shock proteins bind to improperly or unfolded protein substrates and directly promote refolding in an ATP-dependent manner. Others can act as nucleotide-exchange factors while small HSP can hold unfolded proteins, prevent their aggregation, maintain them in a folding competent state, and pass them on to the ATP-dependent chaperone networks. It is now clear that HSP are also very responsive to mechanical stresses such as compression, shear, and tensile forces and new roles in modulating inflammation and cytoskeletal reorganization have been attributed to these proteins following such mechanical stress. This chapter will summarize findings within the stress protein field demonstrating HSP are sensors for mechanical forces in many tissues.

 
2000, Mechanical Stress–Induced Heat Shock Protein 70 Expression in Vascular Smooth Muscle Cells Is Regulated by Rac and Ras Small G Proteins but Not Mitogen-Activated Protein Kinases
 

Previous studies have documented that acute elevation in blood pressure results in heat shock protein (hsp) 70-mRNA expression followed by hsp70-protein production in rat aortas. In this article, we provide evidence that mechanical forces evoke rapid activation of heat shock transcription factor (HSF) and hsp70 accumulation. In our study, Western blot analysis demonstrated that hsp70-protein induction peaked between 6 and 12 hours after treatment with cyclic stain stress (60 cycles/minute, up to 30% elongation). Elevated protein levels were preceded by hsp70-mRNA transcription, which was associated with HSF1 phosphorylation and activation stimulated by mechanical forces, suggesting that the response was regulated at the transcriptional level. Conditioned medium from cyclic strain-stressed vascular smooth muscle cells (VSMCs) did not result in HSF-DNA-binding activation. Furthermore, mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases or stress-activated protein kinases, and p38 MAPKs, were also highly activated in response to cyclic strain stress. Inhibition of extracellular signal-regulated kinase and p38-MAPK activation by their specific inhibitors (PD 98059 and SB 202190) did not influence HSF1 activation. Interestingly, VSMC lines stably expressing dominant-negative rac (rac N17) abolished hsp-protein production and HSF1 activation induced by cyclic strain stress, whereas a significant reduction of hsp70 expression was seen in ras N17-transfected VSMC lines. Thus, our findings demonstrate that cyclic strain stress-induced hsp70 expression is mediated by HSF1 activation and regulated by rac and ras GTP-binding proteins. Induction of hsp70 could be important in maintaining VSMC homeostasis during vascular remodeling in response to hemodynamic stimulation.

 
[hr]
 
In the study, Bryan_S posted, expression levels of two genes underwent change and were related to the transformation toward pluripotency.
 
Do the H3K4Me3 and H3K27Me3 genes have anything to do with Heat Shock Protein expression?

 

 

 

H3K27Me3... 

From the opening post of this thread, a study from 2015...
 

  • 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

 

 
The abstract


The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 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. The removal of germ line stem cells preserves jmjd-3.1 expression, suppresses the accumulation of H3K27me3 at stress gene loci and maintains the HSR. These findings suggest that competing requirements of the germ line and soma dictate organismal stress resistance as animals begin reproduction.
 

And from the same year as the study above, 2015, there is this...

 

2015, Shockingly Early: Chromatin-Mediated Loss of the Heat Shock Response

yxiih2fl.png

 

 

 

H3K4Me3 is implicated also... 

 

2018, Distinct heat shock factors and chromatin modifications mediate the organ‐autonomous transcriptional memory of heat stress

 

Plants can be primed by a stress cue to mount a faster or stronger activation of defense mechanisms upon subsequent stress. A crucial component of such stress priming is the modified reactivation of genes upon recurring stress; however, the underlying mechanisms of this are poorly understood. Here, we report that dozens of Arabidopsis thaliana genes display transcriptional memory, i.e. stronger upregulation after a recurring heat stress, that lasts for at least 3 days. We define a set of transcription factors involved in this memory response and show that the transcriptional memory results in enhanced transcriptional activation within minutes of the onset of a heat stress cue. Further, we show that the transcriptional memory is active in all tissues. It may last for up to a week, and is associated during this time with histone H3 lysine 4 hypermethylation. This transcriptional memory is cis‐encoded, as we identify a promoter fragment that confers memory onto a heterologous gene. In summary, heat‐induced transcriptional memory is a widespread and sustained response, and our study provides a framework for future mechanistic studies of somatic stress memory in higher plants.

 

Histone H3 lysine 4 trimethylation regulates cotranscriptional H2A variant exchange by Tip60 complexes to maximize gene expression


Edited by HighDesertWizard, 19 January 2019 - 08:21 PM.

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#140 QuestforLife

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Posted 21 January 2019 - 12:19 PM

Yes, cyctoskeleton manipulation seems to be THE way to determine cell fate, it can even de-differentiate cells. Hence my approach of using ROCK inhibitors, I.e. statins, here: https://www.longecit...es/#entry865161

 

Interesting that heat shock also seems to be feeding into the same pathway. Maybe all roads to eventually lead to Rome...



#141 HighDesertWizard

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Posted 22 January 2019 - 09:32 AM

Yes, cyctoskeleton manipulation seems to be THE way to determine cell fate, it can even de-differentiate cells. Hence my approach of using ROCK inhibitors, I.e. statins, here: https://www.longecit...es/#entry865161

 

Interesting that heat shock also seems to be feeding into the same pathway. Maybe all roads to eventually lead to Rome...

 

Thanks for this point, QuestforList. I hadn't run into the concept of "cytoskeleton reorganization/manipulation" much. Seems like conscious manipulation of it might be helpful to our achieving our longevity-related goals. It's on my To-Investigate list.



#142 HighDesertWizard

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Posted 22 January 2019 - 09:45 AM

Reflecting on the fact that, in a very short time, we can digest some new science and/or technique that can quickly become a central part of our regimens...

 

Such is the case for me these days, having begun focusing on understanding and triggering Heat Shock, first having been triggered to establish this thread, then, getting the heat/PEMF mat, and now learning to use a Capsaicin topical to increase my average body temperature. One cool thing about the Capsaicin topical: we can target specific body locations as loci for increased HSP (mostly 70?) expression. More about that later...

 

 

I thought it important to get a handle on the biological mechanism through which Capsaicin triggers increased heat. Found the following study and pic in a study. I'm putting this study on the table as background for discussion in the future about a set of receptors: TRPV1 through TRPV6...

 

2016, The Role of the Membrane-Initiated Heat Shock Response in Cancer

 

The heat shock response (HSR) is a cellular response to diverse environmental and physiological stressors resulting in the induction of genes encoding molecular chaperones, proteases, and other proteins that are essential for protection and recovery from cellular damage. Since different perturbations cause accumulation of misfolded proteins, cells frequently encounter fluctuations in the environment which alter proteostasis. Since tumor cells use their natural adaptive mechanism of coping with stress and misfolded proteins, in recent years, the proteostasis network became a promising target for anti-tumor therapy. The membrane is the first to be affected by heat shock and therefore may be the first one to sense heat shock. The membrane also connects between the extracellular and the intracellular signals. Hence, there is a “cross talk” between the HSR and the membranes since heat shock can induce changes in the fluidity of membranes, leading to membrane lipid remodeling that occurs in several diseases such as cancer. During the last decade, a new possible therapy has emerged in which an external molecule is used that could induce membrane lipid re-organization. Since at the moment there are very few substances that regulate the HSR effectively, an alternative way has been searched to modulate chaperone activities through the plasma membrane. Recently, we suggested that the use of the membrane Transient Receptor Potential Vanilloid-1 (TRPV1) modulators regulated the HSR in cancer cells. However, the primary targets of the signal transduction pathway are yet unknown. This review provides an overview of the current literature regarding the role of HSR in membrane remodeling in cancer since a deep understanding of the membrane biology in cancer and the membrane heat sensing pathway is essential to design novel efficient therapies.

 
mKZ29JAh.png
 

Edited by HighDesertWizard, 22 January 2019 - 09:46 AM.


#143 HighDesertWizard

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Posted 22 January 2019 - 09:58 AM

I'm investigating the long term use of Capsaicin for the same, conscious reason I talked up PEMF and a heat mat. I'm finding that there is a synergistic effect in using both.

 

Use of topical Capsaicin definitely increases my average body temperature. And I've found as high as a 48-hour residual sensitivity to heat at the body locations I've applied the Capsaicin to, however much reduced.

 

I can lay on my mat any time. Capsaicin dosing with a high-dose Capsaicin topical has to be thought through more carefully. And hand washing is essential after application if you don't want it in your eyes later.

 

Also, every person who has tried Pain Bloc after I've recommended it comes back with a positive story of pain reduction. I'm not using it for pain. I don't really experience much body pain. I'm using it strictly as a means to trigger heat shock protein to reduce inflammation and increase longevity.

 

 

 

This study caught my attention...

 

2015, Capsaicin may have important potential for promoting vascular and metabolic health

 

Capsaicin, the phytochemical responsible for the spiciness of peppers, has the potential to modulate metabolism via activation of transient receptor potential vanilloid 1 (TRPV1) receptors, which are found not only on nociceptive sensory neurons, but also in a range of other tissues. TRPV1 activation induces calcium influx, and in certain tissues this is associated with increased activation or expression of key proteins such as endothelial nitric oxide synthase (eNOS), uncoupling protein 2 (UCP2), KLF2, PPARdelta, PPARgamma, and LXRα. The calcium influx triggered by TRPV1 activation in endothelial cells mimics the impact of shear stress in this regard, activating and increasing the expression of eNOS-but also increasing expression of cox-2, thrombomodulin, and nrf2-responsive antioxidant enzymes, while decreasing expression of proinflammatory proteins. Hence, dietary capsaicin has favourably impacted endothelium-dependent vasodilation in rodents. TRPV1-mediated induction of LXRα in foam cells promotes cholesterol export, antagonising plaque formation. Capsaicin-mediated activation of TRPV1-expressing neurons in the gastrointestinal tract promotes sympathetically mediated stimulation of brown fat, raising metabolic rate. The increased expression of UCP2 induced by TRPV1 activation exerts a protective antioxidant effect on the liver in non-alcoholic fatty liver disease, and on vascular endothelium in the context of hyperglycaemia. In rodent studies, capsaicin-rich diets have shown favourable effects on atherosclerosis, metabolic syndrome, diabetes, obesity, non-alcoholic fatty liver, cardiac hypertrophy, hypertension and stroke risk. Clinically, ingestion of capsaicin-or its less stable non-pungent analogue capsiate-has been shown to boost metabolic rate modestly. Topical application of capsaicin via patch was found to increase exercise time to ischaemic threshold in patients with angina. Further clinical studies with capsaicin administered in food, capsules, or via patch, are needed to establish protocols that are tolerable for most patients, and to evaluate the potential of capsaicin for promoting vascular and metabolic health.

 

So the info in the table below provides a view of what heat shock protein triggering can do.

 

Notice that Capsaicin "improves endothelium-dependent vasodilation of coronary arteries".

 

So, yes, I'm applying Pain Bloc to my chest. Evidently, Capsaicin can permeate tissues close to the application location.

 

And, yes, I continue to notice a significant increase in exercise tolerance that Rhonda Patrick mentioned in her video about studies a few posts above...

 

 

up6CRx5h.png

 

My only dissent from the above list is that my appetite can sometimes go into overdrive in some contexts I don't yet have a handle on when doing heat shock triggering.


Edited by HighDesertWizard, 22 January 2019 - 10:08 AM.


#144 QuestforLife

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Posted 22 January 2019 - 03:36 PM

 

My only dissent from the above list is that my appetite can sometimes go into overdrive in some contexts I don't yet have a handle on when doing heat shock triggering.

 

Probably secondary to increased metabolic rate due to mitochondrial uncoupling. Any weight loss to report?



#145 Nate-2004

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Posted 02 February 2019 - 04:36 PM

So I did the cold thermogenesis thing the other night and measured my temperature at about 65 minutes in. It was 99.6 F

 

I also read last night that trying to reduce a fever by cold water or bath for kids is a bad idea because it can make a fever worse. Just things to note here.


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#146 xEva

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Posted 03 February 2019 - 06:43 PM

I don't know what's the most important aspect of sauna, but I'm certain you cannot extract/separate sweating from it. If you get your body hot enough, it will happen.

 

But I'm sure you're gonna try. Find some sweat inhibitors?

am curious to read about your experiences

 

 

re sweating inhibition, surprisingly, it could be  a moisturizing lotion. I had eucerin on, applied on legs arms and torso the day before, and, for a long time I could not sweat and quickly felt much hotter than usual.
 


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#147 xEva

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Posted 03 February 2019 - 06:57 PM

So I did the cold thermogenesis thing the other night and measured my temperature at about 65 minutes in. It was 99.6 F

 

in what form? a cold bath or shower?

 

That's the thing about the cold water, it makes you feel hotter afterwards. I remember, back in Russia I often had trouble with my feet getting cold. One winter I had to stay in an apartment that did not have hot water, so every night, in lieu of shower, I washed my face and feet under the faucet, and it was cold! Turned out, I never suffered with cold feet again. Though I never had to do it again, the effect lasted many years.


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#148 Nate-2004

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Posted 05 February 2019 - 11:46 PM

In the form of cold vest in the AC drinking ice water.



#149 HighDesertWizard

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Posted 10 February 2019 - 05:23 AM

It appears there is a good reason right now to to review the status of a major conjecture of this thread...
 

It’s worthwhile to review the status of the 4 sub-conjectures of the thread title conjecture in more detail.
 
“Heat Shock” Expression Declines in Humans During Aging but can be Modulated for Benefit
 
< SNIP >
 
“Heat Shock”, OSKM, iPSC, and Epigenetic Reprogramming are Related Biological Processes
 
< SNIP >
 
An Epigenetic Turn Initiates an Aging Process in Humans
 
< SNIP >
 
See the Seth Grant video in the opening post for what this is asbout...
 
An Ancient, Non-Mammalian “Heat Shock” Related Epigenetic Turn Exists in Mammals
 
This sub-conjecture is that the ancient, heat shock-related gene expression turn in c. elegans Richard Morimoto wrote about in 2015 is an evolutionarily conserved analog to the epigenetic turn mechanism identified by the Grant/Skene/Roy team.. (I'm uncertain that the phrase "evolutionarily conserved analog to the epigenetic turn mechanism" is the right way to phrase what I mean here. If you know the right way to phrase it, please post it.)

 

The opening post contained the following study reference links as a kind of support for this conjecture. Now's the time to check out the video featuring a lecture by Seth Grant in the opening post if you haven't seen it already. I won't try here to summarize the meaning of this conjecture. What follows below assumes you're familiar with it or that you'll review it to become familiar... 
 

HSPs and PSD-95

 

I now believe this conjecture is almost certainly true. If you're caught up with the meaning of this conjecture, you know this is a big deal...

 

Two study pics below from the studies above highlight some evidence...

 

The point I want to make with these is that there is a causal relationship between HSP expression and Post-Synaptic Density expression...

 

-->> There is evidently a relationship between Heat Shock Protein expression and a fundamental epigenetic turn related to aging...

 

I'm not familiar in detail with this science, but I'll be referencing this general notion soon in another post...

 

I'll be getting back to this at some point... 

 

fqMs8kCh.png

 

 

fSrODulh.png


Edited by HighDesertWizard, 10 February 2019 - 06:25 AM.

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#150 albedo

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Posted 10 February 2019 - 12:03 PM

....

Two study pics below from the studies above highlight some evidence...

 

The point I want to make with these is that there is a causal relationship between HSP expression and Post-Synaptic Density expression...

 

-->> There is evidently a relationship between Heat Shock Protein expression and a fundamental epigenetic turn related to aging...

 

...

 

 

Hi HDW! You last post is very interesting as it also relates to the brain health.  I did not but wonder if you ever studied the relations between HSP with microbiota (sorry if I overlooked this in your posts). There is a clear gut-brain link. Recently I have spoken to a scientist who points to epigenetics (again!) and SCFA, particularly butyrate, which I know you also looked at. There are gut bacteria fermentation products traveling in the blood, crossing the blood-brain-barrier (BBB) and impacting gene expression in the brain. This might looks to me coherent with possibly HSP peptides as a therapeutic agent possibly being mediated by inflammation signaling. Looks to me like a good research path to investigate.







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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