226 replies to this topic

[HighDesertWizard]

Hot off the press...

 

Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions

 

From Science Daily... October 15, 2015...

 

Scientists produce clearest-ever images of enzyme that plays key roles in aging, cancer

 

The telomerase enzyme is known to play a significant role in aging and most cancers. Scientists have discovered several major new insights about this enzyme and they are now able to see the complex enzyme's sub-units in much sharper resolution than ever before.

<< SNIP >>

Among the new insights the team reported:

<< SNIP >>

• Feigon's research team knew that the RNA strand interacts with the proteins, but not exactly where it interacted. The new study found that within the enzyme's "catalytic core," which is formed by the RNA and its partner proteins TERT and p65, the RNA forms a ring around the donut-shaped TERT protein.
• The researchers showed that a key protein called p50 interacts with several components of telomerase, including TERT, Teb1 and p75, and this network of interactions has important implications for telomerase's function.

Here's a pic from that study showing two views of the p50 and p65 proteins as part of the Tetrahymena telomerase holoenzyme.

 

 

 

 

But p50 and p65 have been known since at least 1993 to constitute NF-kB Subunits...

 

The p65 subunit of NF-KB regulates IKB by two distinct mechanisms, 1993

 

Abstract

 

Transcription factor NF-KB (p50/p65) is generally localized to the cytoplasm by its inhibitor IKB.... Overproduced IKB, free from NF-KB, is rapidly degraded. Overexpression of p65 increases endogenous IKB protein in both carcinoma and lymphoid cells by two mechanisms: protein stabilization and increased transcription of IKB mRNA. In contrast, p65zX, a naturally occurring splice variant, fails to markedly augment IKB protein levels. Both overexpressed p65 and coexpressed p50 are cytoplasmic, whereas p65~X is partly nuclear, indicating that the IKB induced by p65 can maintain NF-KB in the cytoplasm. Thus, p65 and IKB are linked in an autoregulatory loop, ensuring that NF-KB is held in the cytoplasm until cells are specifically induced to translocate it to the nucleus.

 

More recently, p50 and p65 have been understood to be 2 of 5 NF-kB Subunits...

 

 

 

In fact, that p50 and p65 are NF-kB Subunits is well known... So well known that a graphic figure illustrating NF-kB p50/p65 Activation/Translocation to the Nucleus is a part of some online Bio Science Flash Cards one can purchase to study for mid-terms...

 

 

 

The net of it... Two important proteins of the Telomerase Haloenzyme--whatever that is, I have no idea--are, in fact, Subunits of NF-kB...

 

FWIW, IMO, we're way past the point when Telomerase Expression Enthusiast "Thought Leaders" have credibility in talking about Telomerase Expression without capability to discuss the relationship to NF-Kb...

 

That's why Michael Fossel's new book, The Telomerase Revolution, published in October 2015, must be considered so, um, 2009-ish, already dated. There are Index entries for Resveratrol and c-Reactive Protein, but not for NF-kB... 'nuff said...

Edited by HighDesertWizard, 09 November 2015 - 12:59 AM.

[Steve H]

Of course a primary culprit in increased NF-KB and TGF-beta levels in aging is AGE (advanced Glycation end products)

 

http://www.ncbi.nlm..../pubmed/9287050

 

and the links Logic posted:

 

http://www.longecity...-cardiac-aging/

 

http://www.longecity...14857-obp-9195/
 

There are many more papers relating to this. So remove AGE and you can remove not only inflammation issues but also correct stem cell dysfunction and telomere dysfunction and mitochondrial issues downstream too. There is currently no way to remove AGE but we can inhibit ALK-5 that emulates this and shows us what we can get for "free" if we removed AGE. I am proposing to test this method in a mouse testing program and ideally combined with senlyotics and mTOR as a "trinity" of anti aging and in combinations of two. We can then test two SENS approaches in one experiment.

[Logic]

Of course a primary culprit in increased NF-KB and TGF-beta levels in aging is AGE (advanced Glycation end products)

 

http://www.ncbi.nlm..../pubmed/9287050

 

and the links Logic posted:

 

http://www.longecity...-cardiac-aging/

 

http://www.longecity...14857-obp-9195/
 

There are many more papers relating to this. So remove AGE and you can remove not only inflammation issues but also correct stem cell dysfunction and telomere dysfunction and mitochondrial issues downstream too. There is currently no way to remove AGE but we can inhibit ALK-5 that emulates this and shows us what we can get for "free" if we removed AGE. I am proposing to test this method in a mouse testing program and ideally combined with senlyotics and mTOR as a "trinity" of anti aging and in combinations of two. We can then test two SENS approaches in one experiment.

 

Plant-Derived Agents with Anti-Glycation Activity. Some stronger than Aminoguanidine

http://www.longecity...aminoguanidine/

[Steve H]

From the new conboy paper:
 

In addition to the changes in the biochemical cues from local and systemic niches or possibly due to these changes, some stem cells become less sensitive to activating stimuli with age, which might be due to the elevated activity of the molecular target of rapamycin, mTOR pathway [98]. Attenuation of mTOR with rapamycin is being explored as a multi-faceted anti-aging strategy for combatting senescence-associated permanent cell cycle arrest [99, 100] and enhancing tissue regeneration, and rapamycin was suggested to promote stem cell responses [98] and even increase life span in mice [101].

Exploring the secretome of hESCs as a more convenient and translational approach than young blood, a key age- specific role of MAPK has been uncovered; and several novel FGFs have been identified for their pro-regenerative activity on old tissue stem cells in part, by activating the Delta/Notch pathway, and this is conserved between mice and humans [13, 89]. The hESC-secreted pro-regenerative proteins can be isolated via heparin affinity; they enhance regenerative capacity of muscle and neuronal stem cells and are neuroprotec- tive in an in vitro model of Alzeimer's disease [13, 89]. A search for the physiologic MAPK agonist that has receptors on muscle stem cells and declines in circulation with aging has identified the FDA approved small peptide oxytocin as a novel anti-aging systemically acting molecule with positive effects on skeletal muscle and bone, mental well being and combating obesity [5, 7, 102-105].

Attenuating inflammatory chemokines and cytokines, including those produced at high levels by senescent cells (SASP), and ablating senescent cells (for example, via the use of their cell-surface markers) are expected to enhance tissue maintenance and regeneration, as well as diminish the risk of the age-related flare of cancers. In this regard, excellent mouse models reporting senescence in vivo and enabling selective ablation of p16^high cells in live animals have been recently described [106, 107].

These reports demonstrate rational strategies to attenuate and possibly reverse multi-tissue attrition, preventing a number of degenerative and metabolic diseases (sarcopenia, osteoporosis, obesity, diabetes, neuro-degeneration, etc.) as a class, instead of or in addition to approaching each disease individually, Figure 4.

 

ALK5 Senlyotics and mTOR as suggested here by the Conoys could be a potent aging therapy. 

Alone ALK5 could prevent and TGF-b1 running amok and leading to various aging decline including stem cell dysfunction. SENS proposes to start at the source of that underlying damage AGE (advanced glycation end products) but as such technology is not yet here we can see what the effect of removing AGE could be simply by using ALK 5 or similar. The only problem with such solutions is long term the AGE will still build up but we can prove SENS proof of concept now. TGF-beta can also antagonize NK-FB as there is crosstalk so we may see reduction of NK-FB using ALK 5 as well. 

Now if we remove AGE itself we can stop NK-FB and TGF-b1 running amok as AGE antagonizes both factors causing them to increase with age. So remove AGE we remove both problems at the root.

[Logic]

A Review of Pterostilbene Antioxidant Activity and Disease Modification

...Zhang and colleagues have demonstrated that pterostilbene treatment induces autophagy in oxLDL-stimulated VECs through activation of AMP-activated protein kinase (AMPK), intracellular calcium (Ca2+), and mammalian target of rapamycin (mTOR) signaling...

 

...The authors concluded that the effects of pterostilbene were comparable to the experimental effects of 500 mg/kg oral metformin...

 

...Pterostilbene was also shown to exhibit comparable and synergistic effects when compared to medications used in the treatment of human disease, specifically clofibrate, metformin, Tamoxifen, and the chemotherapy regimen FOLFOX...

 

http://www.hindawi.c...cl/2013/575482/

 

A summary by yours truly (with bad English by  Tom Andre F. (ex shinobi)):
http://www.pterostilbene.com/

Edited by Logic, 09 November 2015 - 03:16 PM.

[Rocket]

This thread is over my head, not being a cell biologist.  But to ask a simple question, if GNRH inhibits NFKB, and there are GNRH peptides readily available, is there any benefit to using them.  Specifically, triptorelin comes to mind as one such peptide. Yes, I know it causes chemical castration, but suppose someone was already on TRT, or females who don't have to worry about testosterone.

 

 

[HighDesertWizard]

This thread is over my head, not being a cell biologist.  But to ask a simple question, if GNRH inhibits NFKB, and there are GNRH peptides readily available, is there any benefit to using them.  Specifically, triptorelin comes to mind as one such peptide. Yes, I know it causes chemical castration, but suppose someone was already on TRT, or females who don't have to worry about testosterone.

 

Given that there are many NF-kB inhibitors that have few, if any, side effects, it makes no sense to ingest one that does.

[HighDesertWizard]

We all look forward to future scientific advance that will further healthy longevity. I'm increasingly impressed with what we already could know is important about Longevity if we could but integrate the insight of already published studies.

 

Five months ago, Avator of Horus posted a couple study links up thread about the nfkb1 gene and the NF-kB Subunit p50 that were obviously important. At the time, Avatar clearly understood their meaning while I had no idea how to think about them...

 

I've been posting at Longecity about NF-kB and its role in aging for more than 3 years now. Every time I've thought that there is nothing more to learn about it, some new information pops up that provides more profound insight about aging and the potential for rejuvenation. Avatar's posts were the initial indication that there was much more for us to learn that WILL turn out to be of practical value...

 

The opportunity to learn from each other is the greatest thing about the Longecity Forum. I wanted to repost Avatar's posts and insight to thank him. Here are his posts...

 

 

 

The type of NFkB seems to matter, cf.:
from the topic:
Nfkb1-/- mice experience accelerated aging - BioscienceNews - LONGECITY
 

http://www.longecity...elerated-aging/

 

Posted 17 April 2015 - 02:50 PM

Nfkb1 knockout mice experience accelerated aging:

Nfkb1/p50 and mammalian aging
Bakhtiar Yamini
Oncotarget. 2015 Feb 28;6(6):3471-2.
PMID: 25704886

"In sum, we find that loss of p50/Nfkb1 leads to a decrease in cellular apoptosis and an increase in senescence that is associated with premature animal aging. Interestingly, the increase in aging is not associated with an increase in tumor formation possibly because the increased cellular senescence acts to suppress tumor formation. p50 is ideally situated to modulate the response to a universal process such as RS [replication stress] because it is not only constitutively produced and found in virtually all tissues, but because it is also the primary DNA-bound NF-kB subunit present at baseline. While it is difficult to definitively say whether the loss of p50 DNA binding with age is a cause, or consequence, of aging, our data nevertheless emphasize the importance of p50 to aging and indicate that further examination of this subunit is warranted."


Loss of Nfkb1 leads to early onset aging.
Bernal GM et al
Aging (Albany NY). 2014 Nov;6(11):931-43.
PMID: 25553648

" ... these data show that loss of Nfkb1 leads to early animal aging that is associated with reduced apoptosis and increased cellular senescence. Moreover, loss of p50 DNA binding is a prominent feature of aged mice relative to young. "

 

 

 

<< SNIP... I've snipped out my reply because it wasn't of much use...

 

 

IMO the point of the studies I cited is that:

the "young" NFkB type is the p50 dimer and the "old" is the p52, cf.:

from the first, the Yamini paper, Nfkb1/p50 and mammalian aging, PMID: 25704886

 

Aging is a progressive process that involves a
combination of genetic and acquired factors that ultimately
cause loss of tissue homeostasis and death. Among the
pathways that modulate aging, NF-kB has been shown to
play a central role [1]. Interestingly, the majority of studies
examining NF-kB and aging suggest that this transcription
factor promotes aging. However, as was shown with the
role of NF-kB in carcinogenesis and the response to DNA
damage, NF-kB proteins often have antagonistic effects
in the regulation of cellular processes. In this regard, we
recently demonstrated that the p50 (NF-kB1) subunit
actually attenuates mammalian aging [2]. These opposing
findings regarding NF-kB and aging are likely in part
explained by the subunit specific nature of the NF-kB
response.
The five NF-kB proteins, p50 (NF-kB1, p105), p52
(NF-kB2, p100), p65 (relA), c-rel, and relB modulate
gene expression as dimers.

...

The premature aging of Nfkb1-/- mice raised the
question of whether loss of this subunit is associated
with physiological aging. We therefore harvested tissue
from a series of young and old wildtype mice. While we
corroborated the well known finding that aging leads to an
increase in NF-кB DNA binding [1], we also noted that
in both aged tissue and serially passaged primary mouse
embryonic fibroblasts (MEFs), there is an increase in the
expression of p52 protein. Most remarkably, however, we
found that the DNA-bound NF-kB dimer composition
changes with age such that while p50/p65 makes up the
DNA-bound dimer in young tissue, in old tissue p52
replaces p50. This latter observation suggests that the NF-
kB dimer in physiologically aged tissue is similar to that
in Nfkb1-/- mice in that p50 is lost and replaced by p52 [6].
Despite the functional redundancy of NF-kB subunits, p52
does not mediate the response to RS in the same manner as
p50 resulting in an increase in cellular senescence [3, 7].
In sum, we find that loss of p50/Nfkb1 leads
to a decrease in cellular apoptosis and an increase in
senescence that is associated with premature animal aging.

 

 

[HighDesertWizard]

Here's a longer, chronologically sorted, list of the studies about the nfkb1 gene, the p50 and p52 NF-kB subunits, and the p50 relationship to Telomerase expression... And some survival curves from independent studies confirming that nfkb1 and p50 are important...

 

The p50-p50 NF-kB subunit has long been documented at the Boston University NF-kB site

 

Tetrahymena telomerase holoenzyme assembly, activation, and inhibition by domains of the p50 central hub, Aug 2013

• OMG, we've known for more than 2 years now that p50 plays an important role in both NF-kB and Telomerase

Noncanonical Functions of Telomerase: Implications in Telomerase-Targeted Cancer Therapies, Mar 2014

 

Chronic inflammation induces telomere dysfunction and accelerates ageing in mice, Jun 2014

• Knock out nfkb1/p50 and you get the survival curves and old mice pics we like to see... 

 

 

Loss of Nfkb1 leads to early onset aging, Nov 2014

• More NFkb1 -/-, p50 knockout pics... It took me a while to absorb the meaning of the survival curve in this pic. Notice that the solid, bold line at the 1.0 mark is not merely delimiting the top of the chart. Not. It's the line depicting the survival ratio of the nfkb1 +/+ mice.   :-)

 

Nfkb1/p50 and mammalian aging, Jan 2015

• As noted in my last post, this is the study that Avatar of Horus posted text from. There is a transition from the p50 to the p52 NF-kB subunits during aging.

And, finally, the study I posted about yesterday...

 

Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions, Oct 2015

• Pictures of the Telomerase Holoenzyme from the study here, including ones showing p50 as a part of Telomerase

Edited by HighDesertWizard, 10 November 2015 - 04:42 AM.

[Rocket]

 

This thread is over my head, not being a cell biologist.  But to ask a simple question, if GNRH inhibits NFKB, and there are GNRH peptides readily available, is there any benefit to using them.  Specifically, triptorelin comes to mind as one such peptide. Yes, I know it causes chemical castration, but suppose someone was already on TRT, or females who don't have to worry about testosterone.

 

Given that there are many NF-kB inhibitors that have few, if any, side effects, it makes no sense to ingest one that does.

 

 

That's like saying why would anyone go on TRT when there are testosterone boosters as supplements. I would like to see the efficacy of curcumin compared to a GNRH in inhibiting NFKB.  In the experiments with mice, they used GNRH, not supplements with poor bioavailability, and poor efficacy.  To use the curcumin example, I doubt the researchers would have gotten the same results in the mice as with GNRH. 

 

Or are you saying there are compounds as potent as GNRH without side effects? Explain.  Because if you're talking the over the counter supplement route, that may as well be snake oil.

Edited by Rocket, 10 November 2015 - 02:00 PM.

[HighDesertWizard]

We reviewed evidence up thread demonstrating that some recent science about gastric bypass, uremic toxins, "blood factors" discovered in heterochronic parabiosis studies, and NF-kB-Telomerase aligns. We saw, more specifically, that some pro-aging blood factors discovered via heterochronic parabiosis were Uremic Toxin and NF-kB related...

 

There are other Heterochronic Parabiosis studies focused on Youthful Blood Factors. For example, here is a great 2014 note entitled Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice... The key finding...

 

... we examined phosphorylated Creb in the DG of aged animals systemically treated with plasma from young or aged mice by immunohistochemistry. Creb phosphorylation increased in the DG after administration of young plasma.

 

Taken together, our data demonstrate that exposure to young blood counteracts aging at the molecular, structural, functional and cognitive levels in the aged hippocampus. Mechanistically, we identified Creb as one member of the regulatory network underlying structural and cognitive enhancements by young blood.

 

Here’s a graphic depiction of the Mechanism from a study summary. Notice that both Creb and c-Fos are referenced in the figure...

 

 

 

 

Meanwhile, as described up thread, we know that the positive Longevity effects of High Heart Rate Variability in Humans are related to triggering of the Cholinergic Anti-inflammatory Pathway, primarily via Vagus Nerve Stimulation. And what is the more specific Mechanism driving NF-kB inhibition as it sets the Context of the blood of the circulatory system? Well, it turns out that the specific mechanism is phosphorylation of CREB and cfos expression, the same factors called Young Blood factors...

 

Here's Tracey about that question in his 2012 study summary...

 

The molecular signaling mechanism of α7 inhibition of TNF occurs through a physical interaction between α7 and adenylate cyclase 6, which generates increased levels of intracellular cAMP. This activates phosphorylation of CREB, which increases expression of cfos, a member of the immediate early gene family of transcription factors. Activation of cfos inhibits NF-κB activity, effectively shutting down the transcription of cytokines.

 

 

In short, the science of NF-kB Inhibition via the Vagus-HRV-CAIP nexus establishes a more complete Physiological/Biological Explanatory Context for that CREB -> c-fos Mechanism discovered important in the 2014 Heterochronic Parabiosis study.

Edited by HighDesertWizard, 15 November 2015 - 10:08 PM.

[ceridwen]

Parabiosis Clinical Trial recruiting next year
Dr Diblamean Maharaja
10301 Hagen Ranch Road Ste 600
Boynton Beach
FL33437

Phone 001 561 7525522

also based at Bethesda Hospital
2815 S Seacrest Boulevard
Boynton Beach
FL33435

[HighDesertWizard]

I'd been feeling a bit discouraged today, overwhelmed by the complexity of the NF-kB-Telomerase relationship, while still astonished by the simple meaning of the Survival Curves associated with that relationship and posted up thread... And then...

Hot off the press, from the lab of one of the three 2009 Telomerase Nobel Laureates. There has been a...

... New Enzyme Discovered for Sustaining Telomere Length. That's a study summary. Here is the complete text PDF...

... ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells

And what's the role of ATM? It regulates NF-kB signaling from the cell nucleus...

A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kB, 1998.

• From the abstract... These data provide support for a novel ionizing radiation-induced signaling pathway for activation of NF-kB and a molecular basis for the sensitivity of AT patients to oxidative stresses.

The ATM protein is required for sustained activation of NF-kB following DNA damage, 1999.

Nuclear initiated NF-κB signaling: NEMO and ATM take center stage, 2011.

ATM regulates NF-κB-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment, 2014.

ATM deficiency in absence of T cells promotes development of NF-kB-dependent murine B cell lymphomas that resemble human ABC DLBCL, 2015.

And there are a lot more....

:-)

Edited by HighDesertWizard, 17 November 2015 - 05:28 AM.

[Santi]

I'd been feeling a bit discouraged today, overwhelmed by the complexity of the NF-kB-Telomerase relationship, while still astonished by the simple meaning of the Survival Curves associated with that relationship and posted up thread... And then...

Hot off the press, from the lab of one of the three 2009 Telomerase Nobel Laureates. There has been a...

... New Enzyme Discovered for Sustaining Telomere Length. That's a study summary. Here is the complete text PDF...

... ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells

 

 

The article summary says "Additionally, the team also found that in normal mouse cells, a drug that blocks an enzyme called PARP1 would activate ATM kinase and spur telomere lengthening." 

 

ATM is recruited and activated by DNA double-strand breaks. PARP1 repairs single-strand breaks. PARP1 inhibition drugs increase double-strand breaks increasing ATM and lengthening telomere in the cells that are repaired. It increases cell death but those that are repaired are healthier. Interesting. 

 

 

[HighDesertWizard]

reason is a reasonable person and he restates the Longevity Science Conventional Wisdom about the last 200 year increase in human life expectancy quite well, even if the statement is--sorry but there's no other way to say it--nonsense and misleading...

... let us think beyond the box. Consider the small horde of children that you'll find playing and running in any junior schoolyard here and now. By the time the survivors of their cohorts reach a century of age, the 2100s will have arrived. If the current very slow trend in increasing adult life expectancy continues, adding a year of remaining life expectancy at 60 for every passing decade, then something like 25% of these present children will live to see that centenary. But I don't for one moment believe that this trend will continue as it has in the past. Past increases in life expectancy were an incidental side-effect of general improvements in medicine across the board, coupled with increasing wealth and all the benefits that brings. Across all of that time, no-one was seriously trying to intervene in the aging process, to address the causes of aging, or to bring aging under medical control. Times are changing, and now many groups aiming to build some of the foundations needed to create exactly this outcome. You may even have donated to support some of them, such as the SENS Research Foundation. The trend in longevity in an age in which researchers are trying to treat the causes of aging will be very different from the trend in longevity in an age in which no such efforts are taking place.

The trend of increase in average life span that reason attributes, like everyone does, to "General Improvements" is illustrated in this graphic figure...



Is the statement nonsense? Let's see... Give me 20 minutes... I'm gonna search for a physiological/biological organ/substance/process within us, Homo Sapiens, called "General Improvements"...

Hmm... Back after 2 minutes... Well, it turns out that there is no Physiological/Biological organ/substance/process within us, Homo Sapiens, called "General Improvements"... So.. .reason must be speaking metaphorically... So what are we to do?

 
Caleb Finch is a Professor of the Neurobiology of Aging at USC and an Historian of (Human) Life Expectancy. He published a book in 2007 entitled The Biology of Human Longevity: Inflammation, Nutrition, and Aging in the Evolution of life Spans. In 2011, Dr. Finch spoke at a SENS Foundation Conference and in the course of introducing Dr. Finch, Dr. Aubrey de Grey, of the SENS Foundation, said that Dr. Finch was one of the 3 or 4 people who were the "Holy Grail" of people in the field...

So... What does Dr. Finch have to say about the causes of shorter life expectancy in previous centuries? His argument is in his book subtitle and it comes down to higher rates of infection and inflammation... My talking points follow...

• Another phrase often used about previous century death rates is that Sanitation wasn't as good as today so there were increased rates of infection... Now we know that better Sanitation mostly means we're not ingesting fecal matter in ways our ancestors did... So do you remember the Kevin Tracey study summary graphic figure I just recently posted that had 4 Survival Curves in it? The Survival Curves for animals having their intestines punctured?

In those studies, the study animals survived in dramatically greater numbers shown in two of the Curves when NF-kB was inhibited by Vagal Stimulation... So, yes, a century or two ago, we, Humans, decided to stop puncturing our intestines, i.e., we established better Sanitation methods, we prevented much NF-kB expression, whether we knew or not that's what we were doing, and we began to survive in dramatically greater numbers...

• I purchased Dr. Finch's book. I have great respect for him. But with all due respect to Dr. Finch, there has been enormous change in the science of Inflammation since he wrote it...So to say that shorter life expectancy was due to inflammation is to say that the shorter life expectancy is due to greater NF-kB Activation in previous centuries...

reason's postulating that our task, today, is fundamentally different than the task of our ancestors is unsupported by evidence.

Previous generations were, in fact, taking concrete steps to prevent NF-kB expression, even if they didn't comprehend what they were doing and even if we haven't, yet, given them credit for doing it.

Evolution, herself, god bless her, has established this fundamental mechanism for aging and rejuvenation within us, for NF-kB Activation Inhibition, and no amount of amorphous thinking about death rates of previous centuries demonstrates that we cannot hijack thIs NF-kB-Telomerase mechanism even further for longer and healthier lives.

Edited by HighDesertWizard, 18 November 2015 - 11:44 AM.

[corb]

we cannot hijack thIs NF-kB-Telomerase mechanism even further for longer and healthier lives.

 

If you cannot why are you making this large thread about it.
Is that a typo?
Or just a Freudian slip.
 

Edited by corb, 18 November 2015 - 10:43 AM.

[HighDesertWizard]

 

we cannot hijack thIs NF-kB-Telomerase mechanism even further for longer and healthier lives.

 

If you cannot why are you making this large thread about it.
Is that a typo?
Or just a Freudian slip.
 

 

 

What I actually wrote... "...no amount of amorphous thinking about death rates of previous centuries demonstrates that we cannot hijack thIs NF-kB-Telomerase mechanism even further for longer and healthier lives."

[HighDesertWizard]

There's a puzzle in the literature evidence reviewed thus far about the relationship of NF-kB Activation/Translocation Inhibition and Telomerase Expression. I won't take the time now to provide a link for the statements below. I believe literature references to each of them exists up thread. Let's recap the puzzle elements...

• NF-kB Activation/Translocation to the Nucleus is associated with shorter life spans. We know that via it's general measure, Lower Heart Rate Variability. But the translocation of one particular NF-kB Subunit to the nucleus, p50, appears associated with youth and declines during aging.
• Increased telomerase expression is associated with, both, longer survival in population studies and with tumor growth.
• It appears that the p50 protein plays a role of importance in both NF-kB and in Telomerase expression. It's an NF-kB Subunit as well as an element of the Telomerase HoloEnzyme.
• But for the p50 NF-kB Subunit to become an element of the Telomerase HoloEnzyme it must translocate to the nucleus. So not all NF-kB translocation to the nucleus is bad for health?
• It appears that all known substances that stimulate Telomerase Expression also are NF-kB inhibitors. But not all NF-kB inhibitors stimulate Telomerase expression. In fact, some known NF-kB inhibitors also inhibit Telomerase expression. (IMO, that fact(?) is the current best explanation for why all the Telomerase stimulating ingredients in the Telomerase Maintenance product associated with Bill Andrews work constitute 99% of the ingredient by volume.)

What are we to make of these puzzle pieces? I have no complete and satisfactory explanation, but I think there are some interesting leads we might pursue about this and I believe we can and will figure out the details of this puzzle. It's an important next objective for this forum thread...

 

 

Take a close look at the two graphic figures below. The first depicts how Curcumin (associated with Turmeric) inhibits NF-kB. The second figure is Kevin Tracey's 2012 view of how higher Vagal Tone (i.e., Vagus Nerve Stimulation resulting in Cholinergic Anti-Inflammatory Pathway Activation) inhibits NF-kB.

 

Notice that Curcumin inhibits NF-kB Activation within a cell's cytoplasm. On the other hand, Higher Vagal Tone inhibits the pro-inflammatory effects of NF-kB Activation/Translocation to the nucleus within the nucleus itself by means of Creb Phosphorylation and increased c-fos expression.

 

One thing is clear... I've been sloppy in my thinking and writing about NF-kB Activation/Translocation to the nucleus. I've been implying that all Activation/Translocation to the nucleus is bad for health. Evidently, not true. I apologize for that. I'll try to do better.

 

 

Here's the Tracey 2012 view of Vagal Tone inhibition of NF-kB within the nucleus in his 2012 study summary...

 

The molecular signaling mechanism of α7 inhibition of TNF occurs through a physical interaction between α7 and adenylate cyclase 6, which generates increased levels of intracellular cAMP. This activates phosphorylation of CREB, which increases expression of cfos, a member of the immediate early gene family of transcription factors. Activation of cfos inhibits NF-κB activity, effectively shutting down the transcription of cytokines.

Edited by HighDesertWizard, 23 November 2015 - 03:05 PM.

[HighDesertWizard]

At the risk of being redundant, I'll quote a few lines from the opening post made back in June 2015...

 

 

6 – Evidence about HRV, telomere length, telomerase, and NF-kB
Elissa Epel’s [and Elizabeth Blackburn's] life work asks the questions that lead, inexorably, to the conclusion that the larger Longevity Benefit Mechanism underlying NF-kB Inhibition, measured by its HRV surrogate marker, is the same as that for Telomerase Expression. Her work demonstrates at least two things…
— Meditation, among other Techniques Promoting “Positive Cognition,” increases, both, HRV and telomerase expression. (http://tinyurl.com/pqsh6ae)
— Chronic Stress (i.e., Autonomic Ill Health, aka Lower HRV) shortens Telomeres (http://tinyurl.com/nrawp9w).
— Meanwhile, Fredrickson has also found that Positive Emotions increase HRV (http://tinyurl.com/bxqwyym). And in another study, Fredrickson and Cole found that individuals with Eudaimonic Intent (aka, Noble Intent, a type of Positive Cognition (Emotion) that contrasts with Hedonic Intent) have reduced NF-kB expression in their peripheral blood (http://tinyurl.com/pzuupxu).

 

 

 

For me, the most amazing potential implication of these last few posts is this...

• Evolution has been selecting for establishing a mechanism in Homo Sapiens that provides for Increasing Cognitive Control of Physical Health via Increased Vagal Tone and the Cholinergic Anti-inflammatory Pathway, via Creb Phosphorylation, and increased cfos expression..

Note that this proposition is consistent with the Blood-Factors work done by Villeda and Wyss-Corey noted a few posts ago along with a pic. Here's the study link again...

 

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice

 

:-)

Edited by HighDesertWizard, 23 November 2015 - 04:08 PM.

[HighDesertWizard]

An answer to a question I asked a while back in another thread, here, is "20"... "20 Hours, in mice..." I'm not certain of the meaning of the 20 hours... It's an important question...
 

How often and at what intensity, should either Vagus Nerve Stimulation and/or Acetylcholine Agonist "dosing"  take place?
 
I can't seem to find the full study of a study referenced by Kevin Tracey that sheds light on this question. It's this one...
 
Stimulated production of proinflammatory cytokines covaries inversely with heart rate variability
 
Can anyone help me out with this? Thx...

 

I'd put the question differently today...

 

How often and at what intensity, should either Vagus Nerve Stimulation and/or Acetylcholine Agonist dosing [to trigger pcreb/c-fos expression] take place?

 

I still haven't seen the full study text and it would be great to have it because it's a study in Humans... But a few months ago, Tracey himself was part of a study that is chock full of anatomical/biological insight and provides an answer to the question in mice. The study contains Survival Curves...

 

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. An early draft full study text PDF is here.

 

Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer's disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases.

 

Important study insights

• Peripheral administration of a "centrally acting" Cholinergic Anti-Inflammatory Pathway (CAIP) agonist, evidently, reaches the centrally acting receptor (i.e., M1 Muscarinic).
• Positive effects require "intact vagus nerve and splenic nerve signaling." This requirement is implicated also in that graphic figure with 4 Survival Curves I've posted multiple times, once very recently.
• The positive effect of the CAIP agonist against administration of "lethal murine endotoxemia," evidenced by increased Survival Ratios, has something to do with 20 hours in the study animals... I'll post again about this after I've fully digested the meaning of the 20 hours...

I confess that I am a big fan of Kevin Tracey but, I think, there is good reason for my enthusiasm... His work contains profound implications for Longevity Science Enthusiasts interested in Practice... His work takes on Substances, Anatomical/Biological Mechanism of Action, and, in this study, Dosing Schedule Analysis...

 

I haven't yet fully digested this study. There are more independent variables address in it than I'm referencing in this post... I don't yet have a handle on the meaning of 20 hours... But here are a few of the study Survival Curves highlighting how important the 20 hour answer to the question is ... Notice the difference in Survival between 20 and 30 hours in the snapshot...

 

Edited by HighDesertWizard, 26 November 2015 - 06:47 PM.

[HighDesertWizard]

<< SNIP >>

 

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. An early draft full study text PDF is here.

 

<< SNIP >>

 

Finally got around to reading the study from my last post... Well, it's a Kevin Tracey study... You know, he's not associated At All with the Longevity Science Movement. And yet, he's into what we Longevity Science Enthusiasts are into...

• The data about and the display of Survival Curves
• Experiments that get at the Anatomical/Biological Mechanisms of Action underlying those Survival Curves... It turns out, per Tracey, his collaborators, and the study link above, the Spleen is a Very Big Deal
• Substances that make a difference for Survival Curves
• Dosing Schedule Analysis

Send Mind a message... "Mind: When will you do a LongeCity.org podcast interview with Kevin Tracey? Don't all the Survival Curves he's published count for something?"

 

;-)

Edited by HighDesertWizard, 03 December 2015 - 01:17 AM.

[Logic]

Some insights and leads on NF-kappaB and p50 may be gleaned from this study?  I haven't yet read the whole study:

A glycine-rich region in NF-kappaB p105 functions as a processing signal for the generation of the p50 subunit.

Transcription factor NF-kappaB is generally considered to be a heterodimer with two subunits, p50 and p65. The p50 subunit has been suggested to be generated from its precursor, p105, via the ubiquitin-proteasome pathway. During processing, the C-terminal portion of p105 is rapidly degraded whereas the N-terminal portion (p50) is left intact. We report here that a 23-amino-acid, glycine-rich region (GRR) in p105 functions as a processing signal for the generation of p50. A GRR-dependent endoproteolytic cleavage downstream of the GRR releases p50 from p105, and this cleavage does not require any specific downstream sequences. p50 can be generated from chimeric precursor p105N-GRR-IkappaBalpha, while the C-terminal portion (IkappaBalpha) can also be recovered, suggesting that p105 processing includes two steps: a GRR-dependent endoproteolytic cleavage and the subsequent degradation of the C-terminal portion. We have also demonstrated that the GRR can direct a similar processing event when it is inserted into a protein unrelated to the NF-kappaB family and that it is therefore an independent signal for processing.

http://www.ncbi.nlm....cles/PMC231212/

[HighDesertWizard]

There's a puzzle in the literature evidence reviewed thus far about the relationship of NF-kB Activation/Translocation Inhibition and Telomerase Expression. I won't take the time now to provide a link for the statements below. I believe literature references to each of them exists up thread. Let's recap the puzzle elements...
 
<< SNIP >>

• The post referenced in the quotation above contained a couple graphic figures. To understand what follows below, you'll need to have digested what's going on in those pics. You will also need to have digested those posts about p50 and p65 awhile back. [Logic: Your post immediately above triggered great feeling. I feel often I'm posting into some void. It's a great feeling to know someone is paying attention! :-) ]
• I'm out on the edge of my current knowledge and capability here with this post. In this post, I'm thinking and asking questions I believe are important out loud and online. My questions may be stupid to ask. :-)
• Asking these questions will lead to answers but I have no idea what the answers will look like. That's what makes it fun...
• Some study, perhaps already published, or soon to be published, will speak to the issue highlighted in the table below.

Edited by HighDesertWizard, 04 December 2015 - 01:24 PM.

[HighDesertWizard]

Now... let's squeeze more Telomerase related evidence juice out of this pcreb / c-fos angle. There's a lot to squeeze out that is interesting and exciting. But first, at the risk of being redundant, a rehearsal of the context for exploration in this post...

• Our starting point is the Epel/Blackburn and Fredrickson/Cole body of work referenced up thread about stress, meditation, mindfulness, Positive Cognition (independent variables that impact Heart Rate Variability (HRV).
• I especially like the Epel/Blackburn body of work and findings because they enable us to make the assumption highlighted below that leads to new insight about the Mechanism of Action underlying Telomerase expression.

• From the Tracey led studies referenced up thread, we know that HRV is coincidentally increased upon Vagus Nerve Stimulation (VNS) resulting in NF-kB inhibition within the nucleus via pcreb and c-fos. I've posted the diagrams illustrating that evidence multiple times. By now, you're probably as bored with seeing them again as I am taking the time to post them...  :-)

Our Reasonable Assumption is this... Without specific evidence from Epel/Blackburn, Telomerase expression probably takes place via that intra-nucleus, pcreb and c-fos mechanism referenced by Tracey.

 

But wait, there are other Telomerase increasing independent variables besides the cognitive ones studied by Epel/Blackburn, right? Herbs, a number of them...

 

And so one way to confirm our assumption is to ask... Do the herbs that increase Telomerase expression act via increased pcreb and c-fos expression?

 

 

Astragalus and Cycloastragenol

 

Study on neuroprotective effects of astragalan in rats with ischemic brain injury and its mechanisms, 2012

 

OBJECTIVE:

To study the effects of astragalan (AG) on the expression of the neural cell adhesion molecule(NCAM) and c-fos of hippocampus CA1 region after the ischemic brain injury in rats.

METHODS:

<< SNIP >>

RESULTS:

<< SNIP >>

CONCLUSION:

Astragalan could improve significantly neural function of ischemia brain injury in rats,the mechanism concerned probably with blocking or reversing apoptosis of hippocampus by promoting the expression of the NCAM and c-fos of hippocampus CA1 region.

 

 

Cycloastragenol is a potent telomerase activator in neuronal cells: implications for depression management, 2014

 

Cycloastragenol (CAG) is an aglycone of astragaloside IV. It was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. The present study demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, CAG induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression-like behavior in experimental mice. In conclusion, CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression.

 

 

But there are also studies that contradict our assumption... For example...

 

Effects of astragalus on apoptosis and c-fos,Bcl-2 expression after focal ischemia-reperfusion injury in rats

 

[You'll appreciate this next one Logic per the great post you made here about Purslane and Telomerase expression... Did you create a thread about Purslane and Telomerase or perhaps it was about gingko and Telomerase?]

 

Purslane Suppresses Osteoclast Differentiation and Bone Resorbing Activity via Inhibition of Akt/GSK3β-c-Fos-NFATc1 Signaling in Vitro and Prevents Lipopolysaccharide-Induced Bone Loss in Vivo

 

Edited by HighDesertWizard, 04 December 2015 - 03:15 PM.

[HighDesertWizard]

From a post I made in another thread...
 

alc... The link you provide is a great find about Alzheimer's.
 

Our preclinical findings for ANAVEX 3-71 demonstrate its significant potential to enhance neuroprotection and cognition via concomitant activation of sigma-1 receptor and M1 muscarinic acetylcholine receptor (M1R), which could be a therapeutic advantage in treating Alzheimer’s and other related protein-aggregation diseases,” said study author Abraham Fisher, PhD. “Specifically, the study results reveal that ANAVEX 3-71 effects a strong reversal of synaptic loss in hippocampal neurons. At very low doses, it mitigates cognitive deficits and normalizes major pathological hallmarks in Alzheimer’s disease models indicating that ANAVEX 3-71 exerts a comprehensive disease-modifying effect. This data adds to the strong foundation of preclinical evidence to support the potential use of ANAVEX 3-71 in Alzheimer’s disease and a wide array of other central nervous system diseases.

 
Is there a larger physiological/biological significance to the findings supporting the use of ANAVEX 3-71?
 
I've said it before and I'm happy to say it again. To this date, Longevity Science Movement Thought Leaders are generally uninformed about the importance of the Vagus Nerve, Heart Rate Variability (HRV), and the Cholinergic Anti-Inflammatory Pathway (CAIP). CAIP activation has a profound impact on NF-kB Nucleus Translocation and Transcription of Inflammatory Cytokines. This pathway has implications for Survival in Humans as shown in the graphic figure pasted in below.
 
We understand a lot about the Mechanism of Action. Specifically, we know that...

• Activation of the M1 Muscarinic Acetylcholine Receptor by Vagus Nerve Stimulation and/or pharmachological means triggers the CAIP. Last week, I posted about another M1 Muscarinic Acetylcholine Receptor agonist, a drug, Xanomeline, that also has positive benefit for Allzheimer's Disease and for Schizophrenia. It also has implications for Survival--see the Survival Curves at the link--and we understand something about dosing schedule (see link in this bullet paragraph).
• Heterochronic Parabiosis scholars Villeda and Wyss-Corey have found that pCREB and c-fos activation are the immediate mechanism for rejuvenating cognition in mice. This confirms the importance of the M1 Muscarinic CAIP mechanism that Kevin Tracey has been writing about for 15 years. Details and graphic figure summaries can be found here.
• The Physiological Science of the CAIP provides an explanation about why even a very small dose of ANAVEX 3-71 could "mitigate cognitive deficits and normalize major pathological hallmarks in Alzheimer's disease models..." Per the work of Tracey and others, M1 Muscarinic Acetylcholine Receptor agonists trigger a CAIP Mechanism that Requires Intact Vagus Nerve and Splenic nerve processing. My hunch is that NF-kB Inhibition within the Spleen by this Vagus-Acetylcholine mechanism is The Primary Physiological Means by which Rejuvenation of Blood Factors within the Circulation takes place. Here are two simple graphic figure from Tracey's great 2007 state of the knowledge summary. Tracey had nailed the importance of the M1 Muscarinic Nicotinic Acetylcholine Receptor by 2007...

 

 

Here's the Human Survival Curve I promised above. It appears in the opening post of this thread.

 

Here’s the study context... Take a known Surrogate Marker for Health, it’s a Computed Statistic... Measure this marker for 24 hours in old, wild-type Humans, 65 years old and up with a mean of 73 years… Wait 10 years… 53% of the 347 study animals are now dead... Do some statistical analysis of that surrogate marker data and plot the two survival curves below… That marker, Heart Rate Variability (HRV), has profound implications for human health and longevity... Here’s a link to this study from 1998...

 

 

Edited by HighDesertWizard, 08 December 2015 - 03:01 PM.

[HighDesertWizard]

I want the key evidence about the importance of NF-kB Transcription Inhibition, per se, for healthy longevity to appear here...

 

This is my reply a few days ago to a post made by reason in the Bioscience News category. The thread is entitled... Zero Gravity Orbital Habitation Causes Changes that are at Least Superficially Similar to Accelerated Aging...

 

reason... As always, a great and informative article...

 

But I believe a statement you make doesn't fit the evidence... You write that "the root causes have yet to be pinned down, since very few people are actually researching this topic..." In fact, a good amount of science has been done about accelerated aging in space and the conclusions of that science fit with facts we already know about accelerated aging on earth. About what we already know and as just one example, I suggest a look at the graphic figure in this thread's opening post.

 

The bottom line... NF-kB Translocation and Cytokine Transcription is implicated in micro-gravity accelerated aging... A few studies highlighting the details of this emerging truth follow below...

 

Capacity of omega-3 fatty acids or eicosapentaenoic acid to counteract weightlessness-induced bone loss by inhibiting NF-kappaB activation: from cells to bed rest to astronauts, 2010

 

... We report here cellular, ground analogue, and spaceflight findings. We investigated the effects of EPA on differentiation of RAW264.7 monocyte/macrophage cells induced by receptor activator of NF-kappaB ligand (RANKL) and on activation of NF-kappaB by tumor necrosis factor alpha (TNF-alpha) or exposure to modeled weightlessness... In human studies, we evaluated whether NF-kappaB activation was altered after short-duration spaceflight and determined the relationship between intake of omega-3 fatty acids and markers of bone resorption during bed rest and the relationship between fish intake and bone mineral density after long-duration spaceflight. NF-kappaB was elevated in crew members after short-duration spaceflight, and higher consumption of fish (a rich source of omega-3 fatty acids) was associated with reduced loss of bone mineral density after flight (p < .05)...

 

Spaceflight alters expression of microRNA during T cell activation, 2011

 

Returning astronauts have experienced altered immune function and increased vulnerability to infection during spaceflights dating back to Apollo and Skylab suggesting that immune-suppression is a major barrier to safe, long-term human space habitation and travel. We present definitive evidence that early signal transduction events are inhibited by the microgravity (ug) environment of spaceflight. Human leukocytes were stimulated with T cell mitogens onboard the International Space Station using a 1g centrifuge as the Earth’s 1g control. Microarray analysis demonstrated significant (p< .05) differential expression of 54 genes in ug vs 1g conditions. Fifty percent of the genes most significantly inhibited in ug as compared to 1g showed marked over-representation of NFKB binding sites in their promoter regions. Qrtpcr confirmed that upregulation of key genes in the NFKB pathway were inhibited in ug. Inhibition of the NFKB pathway leads to activation dysfunction during spaceflight. Lack of immune response in microgravity occurs at the cellular level. In our recent spaceflight studies of early T cell activation, we have discovered that the expression of miRNAs in both man and mouse require gravity for appropriate regulation. MiRNAs expressed during activation in normal gravity (g), were down regulated in spaceflight. These data suggest that gravity may regulate T-cell activation by two separate mechanisms; promoter regions and microRNA.

 

The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity, 2012

 

This study tested the hypothesis that transcription of immediate early genes is inhibited in T cells activated in μg. Immunosuppression during spaceflight is a major barrier to safe, long-term human space habitation and travel. The goals of these experiments were to prove that μg was the cause of impaired T cell activation during spaceflight, as well as understand the mechanisms controlling early T cell activation. T cells from four human donors were stimulated with Con A and anti-CD28 on board the ISS. An on-board centrifuge was used to generate a 1g simultaneous control to isolate the effects of μg from other variables of spaceflight. Microarray expression analysis after 1.5 h of activation demonstrated that μg- and 1g-activated T cells had distinct patterns of global gene expression and identified 47 genes that were significantly, differentially down-regulated in μg. Importantly, several key immediate early genes were inhibited in μg. In particular, transactivation of Rel/NF-κB, CREB, and SRF gene targets were down-regulated. Expression of cREL gene targets were significantly inhibited, and transcription of cREL itself was reduced significantly in μg and upon anti-CD3/anti-CD28 stimulation in simulated μg. Analysis of gene connectivity indicated that the TNF pathway is a major early downstream effector pathway inhibited in μg and may lead to ineffective proinflammatory host defenses against infectious pathogens during spaceflight. Results from these experiments indicate that μg was the causative factor for impaired T cell activation during spaceflight by inhibiting transactivation of key immediate early genes.

 

About this study...

• What is SRF? Here's a study title, among many, that highlights it... Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element.
• The c-fos mRNA and protein is generally among the first to be expressed and hence referred to as an immediate early gene.
• Recent posts elsewhere at LongeCity provide evidence that pCREB and c-fos are implicated in the specific mechanism for NF-kB Cytokine Transcription Inhibition within the nucleus of cells.

Radiation induced nuclear factor kappa-B signaling cascade study in mammalian cells by improved detection systems, 2014

 

To enable long-term human space flight cellular radiation response to densely ionizing radiation needs to be better understood for developing appropriate countermeasures to mitigate acute effects and late radiation risks for the astronaut. The biological effectiveness of accelerated heavy ions with high linear energy transfer (LET) for effecting DNA damage response pathways as a gateway to cell death or survival is of major concern, not only for tumor radiotherapy but also for new regimes of space missions. Ionizing radiation modulates several signaling pathways resulting in transcription factor activation. NF-kappaB is one of the important transcription factors that respond to changes in the environment of a mammalian cell and plays a key role in many biological processes relevant to radiation response, such as apoptosis, inflammation and carcinogenesis.

 

Edited by HighDesertWizard, 08 December 2015 - 03:13 PM.

[HighDesertWizard]

This thread has recently focused on the significance of NF-kB Translocation and Cytokine Transcription for lifespan. This recent focus led to another study in which UVA related damage to DNA was apparently prevented by NF-kB Translocation and Cytokine Transcription Inhibition. The study abstract appears below. The full study text, including graphic figure snapshots related to NF-kB Translocation, can be found here.

 

Fullerene-polyvinylpyrrolidone clathrate localizes in the cytoplasm to prevent Ultraviolet-A ray-induced DNA-fragmentation and activation of the transcriptional factor NF-kappaB

 

By Western blot and immunostaining we proved that polyvinylpyrrolidone (PVP)-wrapped fullerene molecules (PVP-fullerene) could combine the 8- and 53-kb proteins which localize in the membrane of human skin keratinocytes HaCaT. Only fullerene molecules are able to cross the lipid membrane and conjugate 53-kb proteins in the cytosol. There are no fullerene molecules detectable in the nucleus or cytoskeleton. Ultraviolet-A (UVA)-irradiation on HaCaT or normal human epidermal melanocytes (NHEM) caused nuclear fragmentations, lowering of intracellular DNA-contents below diploidy, concurrently with the repressed DNA synthesis and the increased DNA-3'OH cleavage terminals, all of which were repressed by PVP-fullerene, as shown by flow cytometry and PI- or TUNEL-stain fluorography. Translocation of the transcriptional factor NF-kappaB in the cytoplasm to the nucleus of the keratinocytes was caused with UVA and repressed by PVP-fullerene with cytoprotective effects. Thus, the PVP-fullerene may be developed as a UV-protective agent with DNA-preservative effects owing to its combinative ability to molecules in the cytoplasm and cytomembrane, and then represses cellular oxidative stress and blocks abnormal signal pathways.

 

 

In the survival curves posted up thread, study objectives were a lot about isolating the effects of NF-kB Manipulation on LIfespan via NF-kB genetic defects or via doses of toxin. The study referenced above shows decreased UVA-related DNA damage via NF-kB Translocation Inhibition via administration of Fullerene C60 (F-C60).

 

The study above is interesting because, in 2012, a different study showed The prolongation of the lifespan of rats by repeated oral administration of [60]fullerene. Full text here.

 

AFAIK, at this date, 2015-12-19, the lifespan prolongation benefit mechanism of action of F-C60 in Olive Oil (F-C60-OO) has not been definitively determined. At a minimum, for those following the Lifespan / NF-kB Inhibition literature, it's interesting that (1) the survival curves shown in the F-C60-OO study resemble those we've seen up thread, and (2) we now know that F-C60 administration is capable of Inhibiting NF-kB Translocation.

 

Here's the survival curve shown in the F-C60-OO study.

 

 

 

This 2012 F-C60-OO study is interesting also for another reason. A key learning is documented up thread: Intact Splenic functions are Required for a significant Survival Benefit to be achieved by NF-kB Inhibition. And it turns out, the 2012 F-C60-OO is terribly confused about F-C60 accumulation in the spleen. I've previously posted a bit about that confusion here.

Edited by HighDesertWizard, 19 December 2015 - 03:24 PM.

[sensei]

I think that NF-kB inhibition may play a part.

 

Lycium Barbarum (Goji) is identified with anti-aging benefits

 

 

"We showed that the levels of HSP60, NF-κB and TNF-α are decreased by LBPs. Combined with the data of our previous studies, our results indicate that LBPs may act through the inhibition of NF-κB to prevent the over-activation of microglia."

 

http://www.spandidos...6/1977/download

 

LBPs = lycium barbarum polysaccharides

Edited by sensei, 19 December 2015 - 04:48 PM.

[Kirito]

Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo

 

http://onlinelibrary....12558/abstract

 

 

 

Also, Purslane yet again:

 

Portulaca oleracea L. aids calcipotriol in reversing keratinocyte differentiation and skin barrier dysfunction in psoriasis through inhibition of the nuclear factor κB signaling pathway

 

http://www.spandidos...com/etm/9/2/303

 

[HighDesertWizard]

selection pressure... Selection Pressure... SELECTION PRESSURE...

 

The strong winds of accelerated aging in (micro-gravity) space referenced in the last post are attention grabbing. We're more accustomed to the light, persistent breezes of NF-kB cytokine expression that we experience every day. But cytokine storms also take place and have Selected many of us, homo sapien persons, Out of the game of life... 

 

From Wikipedia ... the 1918 flu pandemic

 

The 1918 flu pandemic (January 1918 – December 1920) was an unusually deadly influenza pandemic, the first of the two pandemics involving H1N1 influenza virus.^[1] It infected 500 million people across the world,^[2] including remote Pacific islands and the Arctic, and resulted in the deaths of 50 to 100 million (three to five percent of the world's population^[3]), making it one of the deadliest natural disasters in human history.^[2][4][5][6]

Most influenza outbreaks disproportionately kill juvenile, elderly, or already weakened patients; in contrast, the 1918 pandemic predominantly killed previously healthy young adults. Modern research, using virus taken from the bodies of frozen victims, has concluded that the virus kills through a cytokine storm (overreaction of the body's immune system). The strong immune reactions of young adults ravaged the body, whereas the weaker immune systems of children and middle-aged adults resulted in fewer deaths among those groups.^[7]

 

What is a Cytokine Storm?

 

Nature published a two part review of the concept and its adoption in 2007. The advent of the cytokine storm is the title of part 1.

 

For me, and many others, the difficult thing at first to digest is this... Our Immune Systems, themselves, can wreck havoc on our physical health, sometimes even to the death. These deaths in a short time during the 1918 flu pandemic from Cytokine Storms might even be imagined to be a normal lifespan wave of cytokine expression, but in a short time.

 

https://en.wikipedia.../Cytokine_storm

 

How Ebola Kills You: It's Not The Virus

 

[EDIT] : I confess that I have not investigated the science around the Ebola virus article to be confident that Ebola also kills via a cytokine storm. It does make sense to me, however, that, what makes the Ebola virus unique and deadly is that it has evolved in a way that makes halting the cytokine storm more difficult. Apologies, in advance, if my hunch is incorrect.

 

A few study references among many from your friendly neighborhood NF-kB Inhibition enthusiast... :-)

 

Active NF-kappaB signalling is a prerequisite for influenza virus infection

 

... it has been shown here that an active NF-kappaB signalling pathway is a general prerequisite for influenza virus infection of human cells. Cells with low NF-kappaB activity were resistant to influenza virus infection, but became susceptible upon activation of NF-kappaB. In addition, blocking of NF-kappaB activation severely impaired influenza virus infection of otherwise highly susceptible cells, including the human lung carcinoma cell lines A549 and U1752 and primary human cells. On the other hand, infection with vaccinia virus was not dependent on an active NF-kappaB signalling pathway, demonstrating the specificity of this pathway [NF-kB] for influenza virus infection.

 

Influenza viruses and the NF-kappaB signaling pathway - towards a novel concept of antiviral therapy

 

Influenza A virus remains a major public health concern, both in its annual toll in death and debilitation and its potential to cause devastating pandemics. Like any other virus, influenza A viruses are strongly dependent on cellular factors for replication. One of the hallmark signaling factors activated by viral pathogens is the transcription factor NF-kappaB. Activation of NF-kappaB leads to the up-regulation of a variety of antiviral genes. Thus, the factor is commonly regarded as a major regulator of the innate immune defense to infection. However, several recent studies indicate that influenza viruses have acquired the capability to reprogram this [NF-kB] antiviral activity and to exploit the factor for efficient replication. These data provide novel insights into the pathophysiological function of NF-kappaB in the special environment of a virus-infected cell. Furthermore, the unexpected viral dependency on a cellular signaling factor may pave the path for novel antiviral approaches targeting essential cellular components rather than viral factors.

 

From the study immediately above, I take it that the following statement is likely true... Thoughts?

 

Aggressive NF-kB Activation Inhibition is a potent means for disarming the harm influenza viruses can do before they get started.

  

 

From Wikipedia about the Black Death...

 

The Black Death was one of the most devastating pandemics in human history, resulting in the deaths of an estimated 75 to 200 million people and peaking in Europe in the years 1346–53.[1][2][3] Although there were several competing theories as to the etiology of the Black Death, analysis of DNA from victims in northern and southern Europe published in 2010 and 2011 indicates that the pathogen responsible was the Yersinia pestis bacterium, probably causing several forms of plague.[4][5]

 

 

So still another of the most devastating pandemics in human history implicates a bacterium schooled in manipulating homo sapiens' innate immune systems. Apparently, Plague lethality itself is driven by a Cytokine Storm...

 

Early Host Cell Targets of Yersinia pestis during Primary Pneumonic Plague, 2013

 

Abstract

Inhalation of Yersinia pestis causes primary pneumonic plague, a highly lethal syndrome with mortality rates approaching 100%. Pneumonic plague progression is biphasic, with an initial pre-inflammatory phase facilitating bacterial growth in the absence of host inflammation, followed by a pro-inflammatory phase marked by extensive neutrophil influx, an inflammatory cytokine storm, and severe tissue destruction. Using a FRET-based probe to quantitate injection of effector proteins by the Y. pestis type III secretion system, we show that these bacteria target alveolar macrophages early during infection of mice, followed by a switch in host cell preference to neutrophils. We also demonstrate that neutrophil influx is unable to limit bacterial growth in the lung and is ultimately responsible for the severe inflammation during the lethal pro-inflammatory phase.

 

From the Wikipedia reference link

 

Spread of the Black Death in Europe (1346–53)

 

 

 

 

 

 

<< SNIP >>

 

How Ebola Kills You: It's Not The Virus

 

[EDIT] : I confess that I have not investigated the science around the Ebola virus article to be confident that Ebola also kills via a cytokine storm. It does make sense to me, however, that, what makes the Ebola virus unique and deadly is that it has evolved in a way that makes halting the cytokine storm more difficult. Apologies, in advance, if my hunch is incorrect.

 

Per this 2010 study, an especially lethal species of the Ebola Virus is associated with a Cytokine Storm...

 

Human Fatal Zaire Ebola Virus Infection Is Associated with an Aberrant Innate Immunity and with Massive Lymphocyte Apoptosis

 

Abstract

 

Background

 

Ebolavirus species Zaire (ZEBOV) causes highly lethal hemorrhagic fever, resulting in the death of 90% of patients within days. Most information on immune responses to ZEBOV comes from in vitro studies and animal models. The paucity of data on human immune responses to this virus is mainly due to the fact that most outbreaks occur in remote areas. Published studies in this setting, based on small numbers of samples and limited panels of immunological markers, have given somewhat different results.

 

<< SNIP >>

 

Conclusions/Significance

 

This work, the largest study to be conducted to date in humans, showed that fatal outcome is associated with aberrant innate immune responses and with global suppression of adaptive immunity. The innate immune reaction was characterized by a “cytokine storm,” with hypersecretion of numerous proinflammatory cytokines, chemokines and growth factors, and by the noteworthy absence of antiviral IFNα2. Immunosuppression was characterized by very low levels of circulating cytokines produced by T lymphocytes and by massive loss of peripheral CD4 and CD8 lymphocytes, probably through Fas/FasL-mediated apoptosis.

 

 

 

Edited by HighDesertWizard, 29 December 2015 - 04:08 AM.