217 replies to this topic

[William Sterog]

Was this already mentioned?

The authors find that sulforaphane treatment increase levels of CHIP and HSP70.

https://onlinelibrar.../mnfr.201800240

Sulforaphane Activates Heat Shock Response and Enhances Proteasome Activity through Up-regulation of Hsp27*

https://www.ncbi.nlm...les/PMC2975177/

Sulforaphane allegedly improving autism in humans thanks to heat shock proteins.

https://www.ncbi.nlm...les/PMC4217462/

Edited by William Sterog, 12 February 2019 - 12:32 PM.

[HighDesertWizard]

On February 5th, Josh Mitteldorf published an important blog entitled, Rumors of Age Reversal: The Plasma Fraction Cure. It describes an experiment done by Dr Harold Katcher and an Indian partner, Akshay Sanghvi.

 

Dr Katcher has summarized the study results, not published in a journal, in an unpublished document entitled, Animal Data of Plasma fraction Treatment for Anti-Aging Effect on Rats, that I've copied to a public folder on OneDrive.

 

I won't summarize Mitteldorf's blog post or Katcher's study summary here. And there's another Longecity thread about it here.

 

I believe this is a very significant study and I believe the study profoundly implicates Heat Shock Proteins and said so in that Katcher thread.

 

I want to be sure that the flow of discussions about Heat Shock I'm engaged in make sense. So I've pasted in quotations from that Katcher thread below.

 

I'm very excited by what the content suggests can be done...

 

 

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

 

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

 

-------

 

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

 

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

 

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

 

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

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

1 - By Katcher

 

We have addressed several different problems:

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

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

 

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

 

 

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

 
All that said, I've spent some time investigating whether some experiment shows a relationship of each of the variables of Dr Katcher and his partner have written are important and Heat Shock Proteins. Info about that appears below...
 
 
Cholesterol
2002, Hyperlipidemia induced by high cholesterol diet inhibits heat shock response in rat hearts
 
Glutathione
2018, Glutathione modulates the expression of heat shock proteins via the transcription factors BZIP10 and MYB21 in Arabidopsis
 
Catalase
1999, Catalase activity is necessary for heat-shock recovery in Aspergillus nidulans germlings
2017, Anti-heat Shock 70 kDa Protein Antibody Induced Neuronal Cell Death
 
Nrf2
2018, NRF2 transcriptionally activates the heat shock factor 1 promoter under oxidative stress and affects survival and migration potential of MCF7 cells
 
Albumin
2007, Changes in albumin precursor and heat shock protein 70 expression and their potential role in response to corneal epithelial wound repair
 
Autophagy
2015, Heat shock response and autophagy--cooperation and control
 
Bilirubin
2013, The Effect of Different Doses of Aerobic Exercise Training on Total Bilirubin Levels
 
BUN
2011, Induction of stress response proteins and experimental renal ischemia/reperfusion
 
Creatinine
2016, Higher urine heat shock protein 70/creatinine ratio in type 1 diabetes mellitus
 
DNA Repair Systems
2017, Heat shock proteins and DNA repair mechanisms: an updated overview
 
Glucose
2018, Skeletal muscle‐specific overexpression of heat shock protein 72 improves skeletal muscle insulin‐stimulated glucose uptake but does not alter whole body metabolism
 
HDL
2016, Heat shock protein expression affects high-density lipoprotein function in atherosclerosis
 
IL-6
2010, Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3
 
Mental agility
2013, The α Crystallin Domain of Small Heat Shock Protein b8 (Hspb8) Acts as Survival and Differentiation Factor in Adult Hippocampal Neurogenesis
2011, Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1
 
Mitophagy
2018, Hsp70 participates in PINK1-mediated mitophagy by regulating the stability of PINK1
 
Physical strength
2018, Exercise, heat shock proteins and insulin resistance
 
SOD
2014, Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs
 
TNF
1993, Overexpression of major heat shock protein hsp70 inhibits tumor necrosis factor-induced activation of phospholipase A2
2009, Dynamic effect of heat shock pretreatment on apoptotic responses to TNF-alpha in liver cells
 
Triglycerides
 
Ubiquitin Proteasome System
2016, HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans

 

 

Edited by HighDesertWizard, 14 February 2019 - 06:46 PM.

[HighDesertWizard]

Follow the bouncing ball....  # 2....

• a7nAchR activation, associated with The Inflammatory Reflex, profoundly inhibits inflammation expression in multiple ways...
• Acetylcholine expression triggers increased NRF2 expression...
• NRF2 expression triggers increased Heat Shock Protein expression...

 

 

Follow the bouncing ball....  # 1....

• a7nAchR activation, associated with The Inflammatory Reflex, profoundly inhibits inflammation expression in multiple ways...
• Acetylcholine expression triggers increased NRF2 expression...

 

 

 

Ok... Now that I've set that context up... Check this out...

 

Anti-inflammatory effects of astroglial α7 nicotinic acetylcholine receptors are mediated by inhibition of the NF-κB pathway and activation of the Nrf2 pathway

 

<< SNIP >>

 

There are some other studies showing that acetylcholine expression increases NRF2 expression. Here's another one... You'll recall that the Muscarnic M1 Acetelcholine Receptor is among the primary triggers for activation of The Inflammatory Reflex...

 

The muscarinic M1 receptor activates Nrf2 through a signaling cascade that involves protein kinase C and inhibition of GSK‐3beta: connecting neurotransmission with neuroprotection

 

 

 

2011, The Nrf2-Keap1 cellular defense pathway and heat shock protein 70 (Hsp70) response. Role in protection against oxidative stress in early neonatal unilateral ureteral obstruction (UUO)

 

2015, Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection

Highlights

• Heat shock factor (Hsf)1 and nuclear factor-erythroid 2 p45-related factor (Nrf)2 orchestrate comprehensive cytoprotective transcriptional programs.
• Hsf1 and Nrf2 control overlapping target genes and may compensate for each other.
• Activation of Hsf1 and Nrf2 promotes reducing cellular environment.
• Lack of Hsf1 or Nrf2 is associated with impaired mitochondrial function.

2016, Protective Role of Nrf2 during the Adaptive Survival Response Induced by Mild Heat Stress at 40°C

 

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

 

 

 

Edited by HighDesertWizard, 16 February 2019 - 07:40 AM.

[HighDesertWizard]

Follow the bouncing ball....  # 3....

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

 

Follow the bouncing ball....  # 2....

• a7nAchR activation, associated with The Inflammatory Reflex, profoundly inhibits inflammation expression in multiple ways...
• Acetylcholine expression triggers increased NRF2 expression...
• NRF2 expression triggers increased Heat Shock Protein expression...

 

 

 

 

2011, The Nrf2-Keap1 cellular defense pathway and heat shock protein 70 (Hsp70) response. Role in protection against oxidative stress in early neonatal unilateral ureteral obstruction (UUO)

 

2015, Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection

Highlights

• Heat shock factor (Hsf)1 and nuclear factor-erythroid 2 p45-related factor (Nrf)2 orchestrate comprehensive cytoprotective transcriptional programs.
• Hsf1 and Nrf2 control overlapping target genes and may compensate for each other.
• Activation of Hsf1 and Nrf2 promotes reducing cellular environment.
• Lack of Hsf1 or Nrf2 is associated with impaired mitochondrial function.

2016, Protective Role of Nrf2 during the Adaptive Survival Response Induced by Mild Heat Stress at 40°C

 

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

 

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

 

2017, Nrf2 signaling pathway: Pivotal roles in inflammation

 

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

 

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

Edited by HighDesertWizard, 17 February 2019 - 10:52 PM.

[HighDesertWizard]

I haven't looked at the study referenced below in detail yet, but the abstract appears to support a major conjecture of this thread, so I thought I'd throw it into the knowledge mix...

 

2017, Mechanisms underlying longevity: A genetic switch model of aging

 

While the questions of "What causes aging?" and "Why do we age?" and "How can we stop it?" remain unanswered, recent advances in aging research have continued to increase our understanding of the aging process. Until the last couple of decades, aging was viewed as an inevitable process of damage accumulation and not a subject for scientific pursuit. This view changed when it was demonstrated that the aging process is in fact malleable and genetically determined: mutations in single genes can have dramatic effects on longevity. Despite the rapid advancement of our knowledge about aging, the cause of aging remains unclear. In this paper, experiments demonstrating the roles of genetics and epigenetics in modulating longevity are reviewed, concluding with a new model of aging. This genetic switch model of aging proposes that aging is caused by a genetically-programmed turning off of survival and maintenance pathways after reproduction finishes leading to a progressive functional decline. If this model is correct, it may be possible to extend lifespan and healthspan by identifying the molecular pathways involved and simply turning the switch back on.

 

The author references Morimoto, et al, 2015, but does not reference the Grant, 2017 study highlighted in this longecity forum thread in the opening post.

 

A Key Question...

 

Is the Grant-2017-study-"PSD-95-related-epigenetic-turn" found in mice and humans the Ortholog of the Morimoto, 2015, HSP-related aging switch found in c Elegans?

 

I believe the answer will turn out to be yes. This forum thread's title conjecture is intended to suggest the answer is yes. That said, it must also be said that, AFAIK, no falsification experiment has yet been performed to firmly establish this belief as one that has passed an attempt to falsify it.

 

In the meantime, I'll be pasting-in more evidence about this question from another thread I've been exploring it in soon.

Edited by HighDesertWizard, 20 February 2019 - 04:39 PM.

[VP.]

Seems related to the discussion:

 

Transplanting marrow from young lab mice to old mice preserves memory and learning skills

A new study has found that transplanting the bone marrow of young laboratory mice into old mice prevented cognitive decline in the old mice, preserving their memory and learning abilities. The findings support an emerging model that attributes cognitive decline, in part, to aging of blood cells, which are produced in bone marrow.

"While prior studies have shown that introducing blood from young mice can reverse cognitive decline in old mice, it is not well understood how this happens," said Helen Goodridge, PhD, associate professor of Medicine and Biomedical Sciences at Cedars-Sinai and co-senior author of the study. "Our research suggests one answer lies in specific properties of youthful blood cells."

In the study, published in the journal Communications Biology, 18-month-old laboratory mice received bone marrow transplants from either 4-month-old mice or mice their own age. Six months later, both transplanted groups underwent standard laboratory tests of activity level and learning, plus spatial and working memory. Mice that received young bone marrow outperformed mice that received old bone marrow. They also outperformed a control group of old mice that did not get transplants.

https://www.scienced...90220103341.htm

[QuestforLife]

Seems related to the discussion:

 

In the study, published in the journal Communications Biology, 18-month-old laboratory mice received bone marrow transplants from either 4-month-old mice or mice their own age. Six months later, both transplanted groups underwent standard laboratory tests of activity level and learning, plus spatial and working memory. Mice that received young bone marrow outperformed mice that received old bone marrow. They also outperformed a control group of old mice that did not get transplants.

https://www.scienced...90220103341.htm

 

A good find. Interesting that they draw a line of causality from bone marrow (mesenchymal stem cells) to microglia hyperfunction/senescence to over-pruning synaptic connections.

 

This approach is in agreement with that of Dr Michael Fossel, who is trying to get a telomerase gene therapy for Alzheimer's through the FDA approval process (let's hope he lives long enough). He has said many times that it is the senescence of brain immune cells that is the underlying cause of dementia.

 

http://www.michaelfossel.com/

Edited by QuestforLife, 21 February 2019 - 09:26 AM.

[HighDesertWizard]

I've found a study very important to understanding a dosing issue related to one of my personal approaches to increasing Heat Shock... 

 

I've recently emphasized the importance of Heat Shock and TNF Inhibition for increasing survival probability in several different threads, including the posting of survival probability study graphic figures. I won't make redundant posts here about it. I'll assume readers have already spent the time required to deeply grasp the significance of that science for achieving a higher probability of survival.

 

 

So... Question... Does PEMF inhibit TNF expression?

 

2017, Effect of a low-frequency pulsed electromagnetic field on expression and secretion of IL-1β and TNF-α in nucleus pulposus cells

 

Objective

To investigate changes in nucleus pulposus cell expression and secretion of interleukin (IL)-1β and tumour necrosis factor (TNF)-α following stimulation with a low-frequency (LF) pulsed electromagnetic field (PEMF).

 

Methods

< SNIP >

 

Results

Stimulation of nucleus pulposus cells with LF-PEMFs did not appear to affect cell morphology or nucleus pulposus cell IL-1β and TNF-α expression levels. LF-PEMFs did not significantly affect cell proliferation, however, levels of IL-1β and TNF-α secreted into the culture media were found to be significantly reduced in an intensity-dependent manner.

 

Conclusion

Low-frequency PEMF stimulation may inhibit secretion of IL-1β and TNF-α in cultured nucleus pulposus cells.

 

 

In the graphic figure below, "A/m" means Amperes per Meter.

 

 

 

Edited by HighDesertWizard, 26 February 2019 - 02:01 AM.

[HighDesertWizard]

A multi-part argument below...

 

 

The Cytokine Theory of Disease has been validated in mammals, including in Humans. And it is circulating TNF that is most intensively discussed when discussing cytokines.

 

The key point to consider here is a point first made by Kevin Tracey, the premier research scientist of The Inflammatory Reflex, in his 2014 essay, Approaching the Next Revolution? Evolutionary Integration of Neural and Immune Pathogen Sensing and Response.
 
 
 
<SNIP>

Until quite recently, however, the existence of regulatory reflexes exerting control over the immune system had evaded description. Immunological thinking had not viewed immunity as a reflexively regulated response.

REFLEX REGULATION OF INNATE IMMUNITY
This began to change following the discovery that cytokines produced in response to infection and injury are necessary and sufficient mediators in disease pathogenesis. This provided experimental tools and strategies that enabled the illumination of neural circuits that regulate innate immunity. Termed “the cytokine theory of disease,” cytokines produced in response to infection and injury mediate cellular, metabolic, and pathological effects underlying the major physiological and clinical manifestations of illness (Tracey 2007). Restated, disease occurs when there is a loss of immunological homeostasis producing an unbalanced or excessive cytokine response. In such cases, inhibiting or modulating the cytokine response to restore immunological homeostasis can prevent or reverse disease, and it should be stressed that the cytokine theory does not state that all cytokines are “bad.” By analogy, the germ theory does not state that all microbes are pathogenic. Rather, the cytokine theory indicates that in some instances of cytokine imbalance or excess, treatment of diseases can be specifically accomplished with targeted therapeutics.
The cytokine theory of disease was validated in mammals, including humans, within a few years after early direct evidence became available that tumor necrosis factor (TNF) is a necessary and sufficient mediator of acute septic shock during infection (Tracey et al. 1986, 1987). The first principles for administering anti-TNF monoclonal antibodies as therapy were established in baboons infected withEscherichia coli (Tracey et al. 1987). Treated animals survived despite the presence of replicating bacteria in their bloodstream, proving that the disease (septic shock) required the activity of TNF. Disease was attributable to the activity of the cytokine, regardless of the status of the pathogen (Tracey et al. 1987). Today it is common to witness this principle being applied to patients receiving monoclonal anti-TNF for the treatment of rheumatoid arthritis, inflammatory bowel disease, and other conditions. From a practical point of view, the earliest underlying or inciting etiological agent can be dissociated from the disease. The physician standing at the patient’s bedside is witness to signs and symptoms of inflammation, organ damage, and toxicity mediated by the direct action of cytokines. In many, if not most, diseases, excessive cytokine activity can be considered as a failure of immunological homeostasis.

 

 

 

PEMF inhibits TNF Secretion on a dose-dependent basis, where the dose is Amperes per Meter at 2 Hz...

 

 

 

 

Dr Oz did a TV show about PEMF in 2014. At the beginning of the show, Dr Oz says the following... (I've pasted in the youtube transcript verbatim...)

 

a groundbreaking oz you don't have to live in agony anymore heal your chronic pain no pills no surgery today we are changing the practice of medicine the new invisible treatment your doctor hasn't heard of bill is a magnetic field around you going deep into your body is this the revolutionary cure you've been waiting for everything's for real this is new cutting-edge research dr. oz investigates this is how we're gonna change medicine together thank you very much I am more excited about the show that any other we have done this season because today we are changing the practice of medicine and you get the help

 

If you listen to Dr Oz's summary of the Mechanism of Action of PEMF, it's a disappointment. His explanation leaves a lot to be desired.

 

I post the video below to remind myself in this thread that PEMF has been making a difference for health in people, and now we know why!

 

 

 

Edited by HighDesertWizard, 26 February 2019 - 04:02 AM.

[HighDesertWizard]

I've come to the conclusion that NRF2 is intimately tied to the "Heat Shock", aka, Stress, Response...

 

I've tried to come up with a bolder, broader, harder-to-vary major conjecture statement for the title of this thread and have a first candidate new title...

 

The thread title before today was...

 

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

 

And now it is...

 

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

 

 

I believe the "These" that can be modulated are...

• the "Heat Shock" / NRF2 / Pluripotency Related Epigenetic Turn itself
  • I've provided evidence about both, the relationship of Heat Shock to NRF2 and Heat Shock to Pluripotency
  • I'll be posting evidence about the relationship of NRF2 to pluripotency soon
  • My hunch is that considering them as a set of elements impacted by The Turn will be a useful heuristic decision
• the effects of the accelerated aging state in Humans that results from The Turn having occurred

Edited by HighDesertWizard, 26 February 2019 - 03:23 AM.

[HighDesertWizard]

 

The thread title before today was...

 

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

 

And now it is...

 

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

 

 

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

 

Nuclear factor, erythroid 2-like 2 (Nrf2) is a master transcription factor for cellular defense against endogenous and exogenous stresses by regulating expression of many antioxidant and detoxification genes. Here, we show that Nrf2 acts as a key pluripotency gene and a regulator of proteasome activity in human embryonic stem cells (hESCs). Nrf2 expression is highly enriched in hESCs and dramatically decreases upon differentiation. Nrf2 inhibition impairs both the self-renewal ability of hESCs and reestablishment of pluripotency during cellular reprogramming. Nrf2 activation can delay differentiation. During early hESC differentiation, Nrf2 closely co-localizes with OCT4 and NANOG. As an underlying mechanism, our data show that Nrf2 regulates proteasome activity in hESCs partially through proteasome maturation protein (POMP), a proteasome chaperone, which in turn controls the proliferation of self-renewing hESCs, three germ layer differentiation and cellular reprogramming. Even modest proteasome inhibition skews the balance of early differentiation toward mesendoderm at the expense of an ectodermal fate by decreasing the protein level of cyclin D1 and delaying the degradation of OCT4 and NANOG proteins. Taken together, our findings suggest a new potential link between environmental stress and stemness with Nrf2 and the proteasome coordinately positioned as key mediators.

 

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

 

The potential of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts. We reveal early NF-κB, AP-1, and NRF2 transcription factor activation prior to a temporal peak in hypoxia inducible factor α (HIFα) activity. Mechanistically, we show that an early burst in oxidative phosphorylation and elevated reactive oxygen species generation mediates increased NRF2 activity, which in turn initiates the HIFα-mediated glycolytic shift and may modulate glucose redistribution to the pentose phosphate pathway. Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation.

Edited by HighDesertWizard, 26 February 2019 - 03:46 AM.

[HighDesertWizard]

I haven't fully digested the meaning of the studies I've posted today above nor the two studies below...

 

But my hunch is that they're important...

 

 

2014, Polyhydroxylated fullerene attenuates oxidative stress-induced apoptosis via a fortifying Nrf2-regulated cellular antioxidant defence system

 

Polyhydroxylated derivatives of fullerene C60, named fullerenols (C60[OH]n), have stimulated great interest because of their potent antioxidant properties in various chemical and biological systems, which enable them to be used as a new promising pharmaceutical for the future treatment of oxidative stress-related diseases, but the details remain unknown. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a principal transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element and plays a crucial role in cellular defence against oxidative stress. In this study we investigated whether activation of the Nrf2/antioxidant response element pathway contributes to the cytoprotective effects of C60(OH)24. Our results showed that C60(OH)24 enhanced nuclear translocation of Nrf2 and upregulated expression of phase II antioxidant enzymes, including heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1, and γ-glutamate cysteine ligase in A549 cells. Treatment with C60(OH)24 resulted in phosphorylation of p38 mitogen-activated protein kinases (p38 MAPK), extracellular signal-regulated kinases, and c-Jun-N-terminal kinases. By using inhibitors of cellular kinases, we showed that pretreatment of A549 cells with SB203580, a specific inhibitor of p38 MAPK, abolished nuclear translocation of Nrf2 and induction of HO-1 protein induced by C60(OH)24, indicating an involvement of p38 MAPK in Nrf2/HO-1 activation by C 60(OH)24. Furthermore, pretreatment with C60(OH)24 attenuated hydrogen peroxide-induced apoptotic cell death in A549 cells, and knockdown of Nrf2 by small interfering ribonucleic acid diminished C60(OH)24-mediated cytoprotection. Taken together, these findings demonstrate that C60(OH)24 may attenuate oxidative stress-induced apoptosis via augmentation of Nrf2-regulated cellular antioxidant capacity, thus providing insights into the mechanisms of the antioxidant properties of C60(OH)24.

 

 

2018, C60 Fullerene Prevents Restraint Stress-Induced Oxidative Disorders in Rat Tissues: Possible Involvement of the Nrf2/ARE-Antioxidant Pathway

 

The effects of C60FAS (50 and 500 μg/kg) supplementation, in a normal physiological state and after restraint stress exposure, on prooxidant/antioxidant balance in rat tissues were explored and compared with the effects of the known exogenous antioxidant N-acetylcysteine. Oxidative stress biomarkers (ROS, O2⋅−, H2O2, and lipid peroxidation) and indices of antioxidant status (MnSOD, catalase, GPx, GST, γ-GCL, GR activities, and GSH level) were measured in the brain and the heart. In addition, protein expression of Nrf2 in the nuclear and cytosol fractions as well as the protein level of antiradical enzyme MnSOD and GSH-related enzymes γ-GCLC, GPx, and GSTP as downstream targets of Nrf2 was evaluated by western blot analysis. Under a stress condition, C60FAS attenuates ROS generation and O2⋅− and H2O2 releases and thus decreases lipid peroxidation as well as increases rat tissue antioxidant capacity. We have shown that C60FAS supplementation has dose-dependent and tissue-specific effects. C60FAS strengthened the antiradical defense through the upregulation of MnSOD in brain cells and maintained MnSOD protein content at the control level in the myocardium. Moreover, C60FAS enhanced the GSH level and the activity/protein expression of GSH-related enzymes. Correlation of these changes with Nrf2 protein content suggests that under stress exposure, along with other mechanisms, the Nrf2/ARE-antioxidant pathway may be involved in regulation of glutathione homeostasis. In our study, in an in vivo model, when C60FAS (50 and 500 μg/kg) was applied alone, no significant changes in Nrf2 protein expression as well as in activity/protein levels of MnSOD and GSH-related enzymes in both tissues types were observed. All these facts allow us to assume that in the in vivo model, C60FAS affects on the brain and heart endogenous antioxidative statuses only during the oxidative stress condition.

Edited by HighDesertWizard, 26 February 2019 - 04:05 AM.

[HighDesertWizard]

 

The thread title before today was...

 

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

 

And now it is...

 

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

 

A question and potential criticism of considering NRF2 to be a part of the set of factors implicated in and/or associated with the 2017 Epigenetic Turn study of Grant and Skene is this...

 

Question: Is there a comparable study for NRF2 to the 2015 Morimoto study for Heat Shock Protein showing the existence of a switch or a decline during aging that exists both in human (c.f., Grant/Skene) and non-human organisms?

 

Answer: Yes.

 

2018, Aging-related decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells

 

Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE) cells from subjects of young adult (21–29 years) and older (60–69 years) non-smokers, and explored factors affecting expresion. The basal expression of three representative Nrf2-regulated genes, the catalytic and modulator subunits of glutamate cysteine ligase (GCLC and GCLM, respectively), and NAD(P)H quinone oxidoreductase 1 (NQO1), was higher in cells from the older donors compared with cells from the young adult donors. Upon exposure to the Nrf2 activator, sulforaphane (SF), the expression of these antioxidant genes was increased in cells from both the young adults and the older donors; however, the induction by SF in older donor cells was significantly less than that seen in young adult cells. In addition, the activation of an EpRE-driven reporter by SF was lower in cells from older donors compared to cells from young adults. The basal expression of Nrf2 protein was also lower in cells from older donors than cells from young adults. Furthermore, we found that the basal expression of both Bach1 and c-Myc, two Nrf2 suppressors, was higher in cells from older adults than from young adult donors. In summary, our data suggest that, as in other species, basal expression of Nrf2-regulated genes increases with aging, while inducibility declines with aging. The increased expression of Nrf2 suppressors such as Bach1 and c-Myc may contribute to the impaired inducibility of the Nrf2-regulated antioxidant genes with aging in human bronchial epithelial cells.

 

From the discussion section of the study...

 

The current study demonstrates that both Nrf2 signaling, and induction of Nrf2-regulated antioxidant genes, are impaired in primary HBE cells from older human donors, as evidenced by the significant decrease in gene induction and EpRE-driven reporter activation upon SF exposure (Fig. 2, Fig. 4respectively). To our knowledge, this is the first evidence based on human primary cells showing aging-related decline of Nrf2 signaling. These data confirmed previous studies based on animals including mice, Drosophila melanogaster flies, and Caenorhabditis elegans worms, that Nrf2 (orthologue) signaling is disrupted during aging and leads to a decreased endogenous antioxidant response.

 

I won't bother to post the 4 study links appending that last sentence above. They can easily be found if you're interested.

[QuestforLife]

 

2018, C60 Fullerene Prevents Restraint Stress-Induced Oxidative Disorders in Rat Tissues: Possible Involvement of the Nrf2/ARE-Antioxidant Pathway

 

The effects of C60FAS (50 and 500 μg/kg) supplementation, in a normal physiological state and after restraint stress exposure, on prooxidant/antioxidant balance in rat tissues were explored and compared with the effects of the known exogenous antioxidant N-acetylcysteine. Oxidative stress biomarkers (ROS, O2⋅−, H2O2, and lipid peroxidation) and indices of antioxidant status (MnSOD, catalase, GPx, GST, γ-GCL, GR activities, and GSH level) were measured in the brain and the heart. In addition, protein expression of Nrf2 in the nuclear and cytosol fractions as well as the protein level of antiradical enzyme MnSOD and GSH-related enzymes γ-GCLC, GPx, and GSTP as downstream targets of Nrf2 was evaluated by western blot analysis. Under a stress condition, C60FAS attenuates ROS generation and O2⋅− and H2O2 releases and thus decreases lipid peroxidation as well as increases rat tissue antioxidant capacity. We have shown that C60FAS supplementation has dose-dependent and tissue-specific effects. C60FAS strengthened the antiradical defense through the upregulation of MnSOD in brain cells and maintained MnSOD protein content at the control level in the myocardium. Moreover, C60FAS enhanced the GSH level and the activity/protein expression of GSH-related enzymes. Correlation of these changes with Nrf2 protein content suggests that under stress exposure, along with other mechanisms, the Nrf2/ARE-antioxidant pathway may be involved in regulation of glutathione homeostasis. In our study, in an in vivo model, when C60FAS (50 and 500 μg/kg) was applied alone, no significant changes in Nrf2 protein expression as well as in activity/protein levels of MnSOD and GSH-related enzymes in both tissues types were observed. All these facts allow us to assume that in the in vivo model, C60FAS affects on the brain and heart endogenous antioxidative statuses only during the oxidative stress condition.

 

This is a very interesting paper. It suggests that C60 (in this case pristine, in an aqueous solution) actually upregulates the Nrf2 response, but only when under stress. Normally you'd expect a powerful antioxidant to reduce Nrf2 because it reduces the effect of ROS on breaking the nrf2-KEAP association in the cytosol, but there are clearly other pathways going on here. The authors speculate it may have something to do with a separate suppression of NF-kB (by C60), which would otherwise bind to the nuclear NRF2 promoter and inhibit it.

Edited by QuestforLife, 26 February 2019 - 01:14 PM.

[QuestforLife]

 

 

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

 

The potential of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts. We reveal early NF-κB, AP-1, and NRF2 transcription factor activation prior to a temporal peak in hypoxia inducible factor α (HIFα) activity. Mechanistically, we show that an early burst in oxidative phosphorylation and elevated reactive oxygen species generation mediates increased NRF2 activity, which in turn initiates the HIFα-mediated glycolytic shift and may modulate glucose redistribution to the pentose phosphate pathway. Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation.

 

Another great paper. Will take some effort to mentally digest, but on first inspection it appears to show that reprogramming somatic cells into pluripotent ones is via ROS induced NRF2 induction, which eventually leads to a shift to glycolysis and away from oxidative phosphorylation.

[HighDesertWizard]

I'm posting to other threads about Heat Shock and its importance and when I do I'll try to remember to repost here so that the path and progression of learning I'm on are clear...

 

 

 

 

 
 

I made the post above solely on the basis of an educated hunch that Heat Shock had to be involved in this process of "cells cheating death..."
 
Also, it turns out...

• The authors of the study referenced in the opening post created a set of terrific study graphic images to illustrate the process.
• They established these images as an Infographic that is very cool.
• In image #2, they graphically depict their view of the evidence which suggests that Heat Shock Protein expression is key to this cell-cheating-death process.

 
 

 

Edited by HighDesertWizard, 27 February 2019 - 03:34 AM.

[HighDesertWizard]

The study below provides...

• findings about the NRF2 / Heat Shock Protein 70 relationship
   
• the knowledge trigger I've needed to post a first hunch about what one (or the) independent variable is that determines whether HSP 70 expression promotes healthy longevity or not.

 

 

2016, The antioxidant transcription factor Nrf2 contributes to the protective effect of mild thermotolerance (40°C) against heat shock-induced apoptosis (full text at sci-hub)

 

Note: I've reformated the abstract to assist myself (and perhaps you) to grasp the details and the larger meaning. HDW

 

The exposure of cells to low doses of stress induces adaptive survival responses that protect cells against subsequent exposure to toxic stress. The ability of cells to resist subsequent toxic stress following exposure to low dose heat stress at 40°C is known as mild thermotolerance. Mild thermotolerance involves increased expression of heat shock proteins and antioxidants, but the initiating factors in this response are not understood. This study aims to understand the role of the Nrf2 antioxidant pathway in acquisition of mild thermotolerance at 40°C, and secondly, whether the Nrf2 pathway could be involved in the protective effect of thermotolerance against heat-shock (42°C)-induced apoptosis. 

• During cell preconditioning at 40°C, protein expression of the Nrf2 transcription factor increased after 15-60min.
   
• In addition, levels of the Nrf2 targets MnSOD, catalase, heme oxygenase-1 [ increasing glutathione, HDW ], glutamate cysteine ligase, and Hsp70 increased at 40°C.  Levels of these Nrf2 targets were enhanced by Nrf2 activator oltipraz and decreased by shRNA targeting Nrf2.
   
• Levels of pro-oxidants increased after 30-60min at 40°C. Pro-oxidant levels were decreased by oltipraz and increased by knockdown of Nrf2.
   
• Increased Nrf2 expression and catalase activity at 40°C were inhibited by the antioxidant PEG-catalase and by p53 inhibitor pifithrin-α.

These results suggest that

• mild thermotolerance (40°C) increases cellular pro-oxidant levels, which in turn activate Nrf2 and its target genes.
• Moreover, Nrf2 contributes to the protective effect of thermotolerance against heat-shock (42°C)-induced apoptosis, because Nrf2 activation by oltipraz enhanced thermotolerance, whereas Nrf2 knockdown partly reversed thermotolerance.

Improved knowledge about the different protective mechanisms that mild thermotolerance can activate is crucial for the potential use of this adaptive survival response to treat stress-related diseases.

 

 

I'll post an explanation of the first hunch at some point soon...

Edited by HighDesertWizard, 28 February 2019 - 06:16 AM.

[QuestforLife]

I think you're onto something with the Nrf2-HSP link.

Astaxanthin induces nrf2

https://www.ncbi.nlm...ubmed/29381356/

Astaxanthin locates to mitochondria and protects embryonic cells from repeated bouts of heat stress

https://www.ncbi.nlm...les/PMC3663973/

Astaxanthin also increases the proliferation of neural stem cells via stemness signals

https://www.ncbi.nlm...les/PMC3100832/

[Nate-2004]

Astaxanthin is also in the Viva Naturals krill oil I buy and take in pretty sufficient and natural amounts. Phospholipid based DHA/EPA is far better than other fish oil in terms of bioavailability.

Edited by Nate-2004, 28 February 2019 - 10:02 PM.

[HighDesertWizard]

About the opening post conjecture... An Ancient "Heat Shock"/NRF2/Pluripotency Related Epigenetic Turn* Accelerates Human Aging** and These can be Modulated...

 

How Ancient is the "Heat Shock"/NRF2/Pluripotency Related Epigenetic Turn*? From the 2015 Morimoto study, we know that it is almost certainly as old as the common ancestor of c Elegans and Humans.

 

Question: How long ago did c Elegans and Humans have a common ancestor?

 

Answer: 638 million years

 

See the interactive  Tree of Life Explorer ...

 

 

 

 

Massive content is easily accessible from the graphically displayed Tree of Life Explorer. Time spent reflecting on the information it contains is highly recommended.

 

 

 

Question 2: How Ancient is the Heat Shock Protein, say the HSP 70, response? Do Humans have a common ancestor with some kind of existing life that is More Ancient than the common ancestor it has with c Elegans?

 

Answer 2: Yes, with King Bolete Mushrooms, 1 billion years ago.

 

That's pretty ancient, right?

 

2005, Molecular defense systems are expressed in the king bolete (Boletus edulis) growing near metal smelters

 

The induction of defense systems against metal exposure was investigated in 48 wild-growing fruiting bodies of the king bolete (Boletus edulis) from two areas polluted with several transition metals from smelters, as well as five reference areas. To determine the degree of metal exposure, cadmium (Cd), zinc (Zn), and copper (Cu) were determined in caps of fruiting bodies by atomic absorption spectrophotometry (AAS), whereas mercury (Hg) was determined by cold vapor atomic fluorescence spectrometry (CVAFS). Caps were analyzed further with respect to relative activities of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), as well as concentrations of total glutathione (GSHTOT = GSH + GSSG) and relative concentrations of heat shock protein 70 kDa (HSP70). The results showed that concentrations of the four metals, as well as SOD, CAT and HSP70, were significantly elevated in the exposed group (Mann-Whitney, P < or = 0.001). In contrast, GSHTOT was significantly lowered in the exposed group (P < or = 0.05). Significant positive correlations were established between concentrations of Cd, Zn, Hg, or Cu and activities of SOD (Spearman's P < or = 0.01 for the association between SOD and Cd, P < or = 0.001 for all other metal exposure parameters), CAT (P < or = 0.001 for all exposure parameters), or expression of HSP70 (P < or = 0.001 for all exposure parameters). Significant negative correlations were found between total GSH and Cd (P < or = 0.001), Zn (P < or = 0.001), or Hg (P < or = 0.05). We conclude that antioxidant enzymes are induced in wild-growing B. edulis exposed to environmentally relevant concentrations of potentially toxic transition metals; whereas the net consumption of GSH that occurs with increasing metal exposure may reflect GSH consumption by mechanisms of metal detoxification. Finally, the induction of HSP70 suggests that the antioxidant response and the mechanisms in which GSH is consumed are insufficient for protection against the harmful effects of severe metal stress.

 

 

 

 

 

 

Edited by HighDesertWizard, 02 March 2019 - 05:11 PM.

[Nate-2004]

You mention and reference Dr. Oz earlier, well known for his quackery and deceit on several occasions over the years. Every time I look for anything PEMF on Amazon or Google I always end up on some gimmicky website making wild claims or some PEMF device with low or fake ratings. I can't seem to trust anything sold out there right now to put my money into it. All I know is this, PEMF is just an electromagnetic wave of very low frequency, like 25 hz. How hard is it really to just build something myself that does the job? Why does it have to be heated? I have a gym with a sauna that I use 4 times a week but no PEMF. 

[HighDesertWizard]

You mention and reference [1] Dr. Oz earlier, well known for his quackery and deceit on several occasions over the years. [2] Every time I look for anything PEMF on Amazon or Google I always end up on some gimmicky website making wild claims or some PEMF device with low or fake ratings. [3] I can't seem to trust anything sold out there right now to put my money into it. [4] All I know is this, PEMF is just an electromagnetic wave of very low frequency, like 25 hz. [5] How hard is it really to just build something myself that does the job? [6] Why does it have to be heated? [7] I have a gym with a sauna that I use 4 times a week but no PEMF. 

 

Nate... I've appreciated many of your posts about your anecdotal experience, but this isn't among them.

 

About the Dr Oz video, it includes interviews with people who do know something about PEMF and it features a quality PEMF product. Your post makes claims without supporting evidence links [1] (but take the chat about Dr Oz elsewhere please) and uses exaggerated language (highlighted in red) it's easy to falsify in 5 minutes [2] and [3].

 

About [4] and [5], if build your own, then do it and let us know how you do. About [6], it doesn't have to be heated, I bought one that does both heat and PEMF because it was cheaper than many others and there were multiple paths to benefit in it.

 

About [7], if you've kept up with the content of this thread, you know that Heat Shock provides a 24 to 48 hours of increased protection from inflammation, so the benefit you'd get from PEMF would be minimal if you're doing sauna 4 times a week.

 

In short, you don't need to do PEMF but blast it in your post for no good reasons backed by evidence and without regard to evidence (and products) that are contrary to your expressed feeling.

 

I posted a study image just a few days ago showing that PEMF reduced TNF expression in the serum in a dose-dependent manner. I've posted multiple times in different places at Longecity about the importance of what that means. If you're going to knock PEMF, you'll need to take that study evidence head-on.

 

I am the person who clicked the Ill-Informed icon on your post.

 

If you're going to post to threads I've created, please keep the quality of your posts high or don't post at all.

 

Thanks.

 

Edited by HighDesertWizard, 04 March 2019 - 02:35 AM.

[Nate-2004]

HDW, I strongly appreciate the concerted effort you put into every one of your posts, all the detail, sources, links, assessments and I think they've been really invaluable and have contributed considerably to the board and cause as a whole. This thread is one of the few remaining reasons I come to this board.

 

I apologize for the low quality of my earlier post, I shouldn't have posted in such a hurry without thinking. I was put off by the Dr. Oz video link as I wouldn't expect you to post something with him in it. Ignoring the well known, widespread facts and media talk about Dr. Oz for a moment, there is no mention of any specific brand of PEMF device in that video, perhaps it's later in some unposted video recording of the episode. What I should have done was just ask you how things were going with the PEMF pad you got, and also if there was anything like it that isn't heated and costs a lot less than what you got yours for.

 

 

I did see your referenced image from the in-vitro study on PEMF earlier and it was interesting and it, among your other posts on TNFa inhibition, was why I began looking around some more on Google and Amazon. I don't know if I'm blind or am missing the link to the origin of this image or if you just forgot to post it, or what. I also don't know what kind of study it was, in vitro, in vivo, animals, humans, etc. 

Edited by Nate-2004, 04 March 2019 - 04:42 AM.

[Ducky-001]

I have no clue if this is in any way related to what you are investigating, but at least it involves heat and people:

 

Unique research: Exercise in heat gives you better endurance

 

For the first time, it has been shown that exercising in high heat gives the same effect as height training

 

https://translate.go...arme-1.14503420

 

 

[HighDesertWizard]

2014, A Controlled Trial to Determine the Efficacy of Red and Near-Infrared Light Treatment in Patient Satisfaction, Reduction of Fine Lines, Wrinkles, Skin Roughness, and Intradermal Collagen Density Increase

 

Objective: The purpose of this study was to investigate the safety and efficacy of two novel light sources for large area and full body application, providing polychromatic, non-thermal photobiomodulation (PBM) for improving skin feeling and appearance. Background data: For non-thermal photorejuvenation, laser and LED light sources have been demonstrated to be safe and effective. However, lasers and LEDs may offer some disadvantages because of dot-shaped (punctiform) emission characteristics and their narrow spectral bandwidths. Because the action spectra for tissue regeneration and repair consist of more than one wavelength, we investigated if it is favorable to apply a polychromatic spectrum covering a broader spectral region for skin rejuvenation and repair.

 

Materials and methods: A total of 136 volunteers participated in this prospective, randomized, and controlled study. Of these volunteers, 113 subjects randomly assigned into four treatment groups were treated twice a week with either 611–650 or 570–850 nm polychromatic light (normalized to ∼9 J/cm2 in the range of 611–650 nm) and were compared with controls (n=23). Irradiances and treatment durations varied in all treatment groups. The data collected at baseline and after 30 sessions included blinded evaluations of clinical photography, ultrasonographic collagen density measurements, computerized digital profilometry, and an assessment of patient satisfaction.

 

Results: The treated subjects experienced significantly improved skin complexion and skin feeling, profilometrically assessed skin roughness, and ultrasonographically measured collagen density. The blinded clinical evaluation of photographs confirmed significant improvement in the intervention groups compared with the control.

 

Conclusions: Broadband polychromatic PBM showed no advantage over the red-light-only spectrum. However, both novel light sources that have not been previously used for PBM have demonstrated efficacy and safety for skin rejuvenation and intradermal collagen increase when compared with controls.

 

 

 

 

 

2008, Repeat mild heat shock increases dermal fibroblast activity and collagen production

 

Repeat mild heat shock (RMHS) has been shown to have anti-aging effects on cellular and biological processes within human dermal fibroblasts. We have investigated the potential of an abridged mild heat shock regime to impact upon the functional properties of human dermal fibroblasts derived from three donors (male, 12 years; female, 22 years; female, 65 years). For each donor mild heat shock increased the rate of contraction of fibroblast-containing collagen gels and increased the de novo synthesis of collagen. Thus, hormetic mechanisms are proposed to provide functional anti-aging benefits to skin cells.

 

 

2014, Far red/near infrared light-induced protection against cardiac ischemia and reperfusion injury remains intact under diabetic conditions and is independent of nitric oxide synthase

 

Far red/near-infrared light (NIR) promotes a wide range of biological effects including tissue protection but whether and how NIR is capable of acutely protecting myocardium against ischemia and reperfusion injury in vivo is not fully elucidated. Our previous work indicates that NIR exposure immediately before and during early reperfusion protects the myocardium against infarction through mechanisms that are nitric oxide (NO)-dependent. Here we tested the hypothesis that NIR elicits protection in a diabetic mouse model where other cardioprotective interventions such as pre- and postconditioning fail, and that the protection is independent of nitric oxide synthase (NOS). NIR reduced infarct size dose dependently. Importantly, NIR-induced protection was preserved in a diabetic mouse model (db/db) and during acute hyperglycemia, as well as in endothelial NOS−/− mice and in wild type mice treated with NOS inhibitor L-NAME. In in vitro experiments NIR light liberates NO from nitrosyl hemoglobin (HbNO) and nitrosyl myoglobin (MbNO) in a wavelength-(660-830 nm) and dose-dependent manner. Irradiation at 660 nm yields the highest release of NO, while at longer wavelengths a dramatic decrease of NO release can be observed. Similar wavelength dependence was observed for the protection of mice against cardiac ischemia and reperfusion injury in vivo. NIR-induced NO release from deoxymyoglobin in the presence of nitrite mildly inhibits respiration of isolated mitochondria after hypoxia. In summary, NIR applied during reperfusion protects the myocardium against infarction in an NO-dependent, but NOS-independent mechanisms, whereby mitochondria may be a target of NO released by NIR, leading to reduced reactive oxygen species generation during reperfusion. This unique mechanism preserves protection even during diabetes where other protective strategies fail.

 

From the study text...

 

Irradiation with NIR after myocardial infarction in rats resulted in a significant improved mitochondrial bioenergetics, and an increase in an inducible heat shock protein (HSP70), vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) expression (Yaakobi et al., 2001). This was paralleled by a significant elevation in angiogenesis (Tuby et al., 2006). 

 

 

2016, Heat shock protein 70-1A is a novel angiogenic regulator

 

Heat shock protein 70-1A (HSP70-1A) is a stress-inducible protein that provides an essential intracellular molecular chaperone function; however, the mechanism of HSP70-1A in angiogenesis has not been clarified. Herein, HSP70-1A gene silencing implicated this protein in angiogenesis. Additionally, recombinant human HSP70-1A (rhHSP70-1A) was able to stimulate human umbilical vein endothelial cell (HUVEC) migration and tube formation in vitro and microvessel formation in vivo similarly to recombinant human vascular endothelial growth factor (rhVEGF). Furthermore, rhHSP70-1A was tightly bound to the surface of HUVECs and participated in extracellular signal-related kinase (ERK)-dependent angiogenesis. Together, these results implicate HSP70-1A as a novel angiogenic regulator.

 

 

 

[HighDesertWizard]

I'm seriously thinking about buying this device at Amazon to add another arrow to my quiver of Heat Shock intervention techniques...

 

I'm continuing to use all the techniques I stated that I'm using above... PEMF Heat Mat, Pain Bloc, Cayenne Pepper on everything, as well as supplement capsules, and the red light I already have. Pain Bloc is fantastic. I have no body pain to speak of, but I do have CAD, so I apply Pain Bloc to my upper torso and it keeps my core temp higher.

 

Using these techniques in synergistic ways makes for a difference in exercise performance and endurance for me.

 

I'm imagining to use the Red Light device below on my face and my chest especially.

 

 

Edited by HighDesertWizard, 13 April 2019 - 07:46 PM.

[HighDesertWizard]

 

 

Nope. Ain't buying that one after all. I'm virtually convinced that it's a great device. And you can get it for $100 at Amazon. if that currency-value amount is what fits your budget, BUY THAT DEVICE!

 

But after some reflection, and with, regrettably, only recently knowledge I believe is that Red-Light-Related devices trigger Heat Shock Protein, I've been reflecting on this Question...

 

What are the Essential Requirements for Red Light-related Devices for the Serious Longevity Science Enthusiast?

 

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

 

Answer

 

After some reflection, I'm thinking that the thing to do is to purchase 2 different Types of devices that do at least 2 different wavelengths of light.

 

Device Types

• Whole (Half) Body Devices
   
• Spot Devices

Wavelengths

• Red Light (generally 630 to 680 nm) provides shallower benefit penetration
   
• Near Infrared (NIR) - (700 to 1000 nm) provides deeper tissue benefit penetration

 

I've already purchased a spot Red Light Device (650 nm). I purchased this spot NIR Infrared bulb this week.

 

I also purchased this book at Amazon. It recommends this half body device that does both Red and NIR light.

 

Not certain about what I'll do about a whole/half body device yet.

[HighDesertWizard]

2008, Short-duration-focused ultrasound stimulation of Hsp70 expression in vivo

 

The development of transgenic reporter mice and advances in in vivo optical imaging have created unique opportunities to assess and analyze biological responses to thermal therapy directly in living tissues. Reporter mice incorporating the regulatory regions from the genes encoding the 70 kDa heat-shock proteins (Hsp70) and firefly luciferase (luc) as reporter genes can be used to non-invasively reveal gene activation in living tissues in response to thermal stress. High-intensity-focused ultrasound (HIFU) can deliver measured doses of acoustic energy to highly localized regions of tissue at intensities that are sufficient to stimulate Hsp70 expression. We report activation of Hsp70-luc expression using 1 s duration HIFU heating to stimulate gene expression in the skin of the transgenic reporter mouse. Hsp70 expression was tracked for 96 h following the application of 1.5 MHz continuous-wave ultrasound with spatial peak intensities ranging from 53 W cm−2 up to 352 W cm−2. The results indicated that peak Hsp70 expression is observed 6–48 h post-heating, with significant activity remaining at 96 h. Exposure durations were simulated using a finite-element model, and the predicted temperatures were found to be consistent with the observed Hsp70 expression patterns. Histological evaluation revealed that the thermal damage starts at the stratum corneum and extends deeper with increasing intensity. These results indicated that short-duration HIFU may be useful for inducing heat-shock expression, and that the period between treatments needs to be greater than 96 h due to the protective properties of Hsp70.

 

[HighDesertWizard]

More fascinating info about the biological mechanism of Infrared light and its biological impact. But first a reminder about the mechanism of action of Cayenne Pepper, Capsaicin, and the receptors they touch, TRPVs...

 

 

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.

 

 

 

 

So it turns out that infrared light has a biological impact through the same set of Transient Receptor Potential Vanilloid receptors (TRPV1 and TRPV4) that Capsaicin does.

 

2017, Red (660 nm) or near-infrared (810 nm) photobiomodulation stimulates, while blue (415 nm), green (540 nm) light inhibits proliferation in human adipose-derived stem cells

 

We previously showed that blue (415 nm) and green (540 nm) wavelengths were more effective in stimulating osteoblast differentiation of human adipose-derived stem cells (hASC), compared to red (660 nm) and near-infrared (NIR, 810 nm). Intracellular calcium was higher after blue/green, and could be inhibited by the ion channel blocker, capsazepine. In the present study we asked what was the effect of these four wavelengths on proliferation of the hASC? When cultured in proliferation medium there was a clear difference between blue/green which inhibited proliferation and red/NIR which stimulated proliferation, all at 3 J/cm2. Blue/green reduced cellular ATP, while red/NIR increased ATP in a biphasic manner. Blue/green produced a bigger increase in intracellular calcium and reactive oxygen species (ROS). Blue/green reduced mitochondrial membrane potential (MMP) and lowered intracellular pH, while red/NIR had the opposite effect. Transient receptor potential vanilloid 1 (TRPV1) ion channel was expressed in hADSC, and the TRPV1 ligand capsaicin (5uM) stimulated proliferation, which could be abrogated by capsazepine. The inhibition of proliferation caused by blue/green could also be abrogated by capsazepine, and by the antioxidant, N-acetylcysteine. The data suggest that blue/green light inhibits proliferation by activating TRPV1, and increasing calcium and ROS.

 

 

2018, Theoretical Study on Gold-Nanorod-Enhanced Near-Infrared Neural Stimulation

 

Over the past decade, optical methods have emerged for modulating brain functions as an alternative to electrical stimulation. Among various optical techniques, infrared neural stimulation has been effective via a thermal mechanism enabling focused and noninvasive stimulation without any genetic manipulation, but it results in bulk heating of neural tissue. Recently, it has been shown that neural cells can be activated more efficiently by pulsed near-infrared (NIR) light delivered to gold nanorods (GNRs) near the neural cells. Despite its potential, however, the biophysical mechanism underlying this GNR-enhanced NIR stimulation has not been clearly explained yet. Here, we propose an integrative and quantitative model to elucidate the mechanism by modeling heat generated from interaction between NIR light and GNRs, the temperature-dependent ion channels (transient receptor potential vanilloid 1; TRPV1) in the neuronal membrane, and a heat-induced capacitive current through the membrane. Our results show that NIR pulses induce abrupt temperature elevation near the neuronal membrane and lead to both the TRPV1-channel and capacitive currents. Both current sources synergistically increase the membrane potential and elicit an action potential, and which mechanism is dominant depends on conditions such as the laser pulse duration and TRPV1 channel density. Although the TRPV1 mechanism dominates in most cases we tested, the capacitive current makes a larger contribution when a very short laser pulse is illuminated on neural cells with relatively low TRPV1 channel densities.

 

 

 

Edited by HighDesertWizard, 01 May 2019 - 04:05 PM.

[HighDesertWizard]

I'm focused, always, on theory, science details, and practical application, at the same time... Hence this forum thread...
 
---------
 
I've mentioned either up thread or some other place at Longecity that I have non-trivial cardiovascular disease. It's been on my mind a lot lately. And my focus on HSPs and means to trigger it is driven in large measure by this fact. Recently, I've been rewarded with study finds confirming that my hunch about the importance of HSPs is a good one...
 
---------
 
2018, Turning Up the Heat on Cholesterol
 

One of the early steps in atherosclerosis is the formation of foam cells in the arteries, which can lead to plaque formation. An important signaling pathway to prevent foam cell formation includes the activation of the thermally sensitive calcium channel TRPV1. Capsaicin, the active component of chili peppers, has been found to activate TRPV1, but its general administration causes toxic side effects.

Bo Tang, Shangdong Normal University, Jinan, China, and colleagues have used antibodies against TRPV1 to localize copper sulfide nanoparticles at the site of plaque formation. These nanoparticles can increase the local temperature when activated by harmless near-infrared (NIR) light. Increasing the temperature near TRPV1 channels activates the signaling pathway and leads to an inhibition of foam cell formation.

The technique was first validated in cell culture, showing that the antibody-bound nanoparticles can indeed induce downstream signaling of TRPV1 and provide a similar response to the application of capsaicin. It was shown that, in a test tube, the application of NIR light increases the temperature of the nanoparticle solution from room temperature to more than 65 °C in only three minutes.

The antibody-nanoparticle conjugates were then injected into mice susceptible to atherosclerosis. The team found that under NIR light, TRPV1 was activated in the arterial walls. The nanoparticle conjugates have a low toxicity and could also be used to image the arteries to screen for plaque formation. This could lead to the development of a new way of monitoring and treating those known to be at risk for atherosclerosis.

 

Here's the referenced study...
 
2018, Copper sulfide nanoparticles as a photothermal switch for TRPV1 signaling to attenuate atherosclerosis
 

Atherosclerosis is characterized by the accumulation of lipids within the arterial wall. Although activation of TRPV1 cation channels by capsaicin may reduce lipid storage and the formation of atherosclerotic lesions, a clinical use for capsaicin has been limited by its chronic toxicity. Here we show that coupling of copper sulfide (CuS) nanoparticles to antibodies targeting TRPV1 act as a photothermal switch for TRPV1 signaling in vascular smooth muscle cells (VSMCs) using near-infrared light. Upon irradiation, local increases of temperature open thermo-sensitive TRPV1 channels and cause Ca2+influx. The increase in intracellular Ca2+ activates autophagy and impedes foam cell formation in VSMCs treated with oxidized low-density lipoprotein. In vivo, CuS-TRPV1 allows photoacoustic imaging of the cardiac vasculature and reduces lipid storage and plaque formation in ApoE−/− mice fed a high-fat diet, with no obvious long-term toxicity. Together, this suggests CuS-TRPV1 may represent a therapeutic tool to locally and temporally attenuate atherosclerosis.

 

 

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The acronym "NIR" in the photo above and below stands for Near InfraRed...

 

OMG... Is this science Hot or what?       

 

Edited by HighDesertWizard, 01 May 2019 - 02:27 PM.