226 replies to this topic

[Steve H]

Very interesting and have passed on the information about nfkb

[Avatar of Horus]

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-?B 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. "

[DorianGrey]

One literature reference ( http://goo.gl/HZm6gN ) states NF-kB upregulation activates HTERT, so the inhibition theory isn't fully conclusive IMO. On the other hand, this was for cancer cells where anomalies may be easier to explain.

The HRV correlation with telomer length and for sure general health and mortality is interesting, I was planning on getting a monitor, any ideas what to get without spending a fortune? Some bluetooth device with a good Android app and data export would be best.

Edited by DorianGrey, 10 June 2015 - 02:24 AM.

[Steve H]

You might also find this interesting as it directly relates to Telomerase gene therapy which I am working to get tested. This is for skin which is the planned test target that bioviva plan to do a pilot study on. As well as replicative rejuvenation the interesting effect is restoration of Collagen 1 and 3 which fall with age and very interestingly restoration of the Dermal Matrix which is part of the ECM. I have heard various people state that Telomerase will not fix the ECM and yet here we are showing it does:

 

http://www.ncbi.nlm....pubmed/10896778

 

A similar result for Endothelial Cells which as a result of Telomerase activation (in this case via Nitrous oxide) continue working and do not enter senescence as soon.

 

http://circres.ahajo...t/87/7/540.full

 

Dr Michael Fossel firmly believes that Telomeres are a very good point of intervention for health and longevity and I agree. The evidence supporting Telomerase is growing all the time and no surprise as Telomeres control gene expression and thus epigenetic drift, they have a growth factor like function as well as controlling replication and aiding cellular stability. About time it got tested as it is clearly a major player in aging and whilst probably not the cause of aging as Dr Fossel says its a place to intervene against it.

 

[HighDesertWizard]

 

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-?B 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. "

 

 

Avatar... Thanks for this... The links provide interesting and useful data and perspective...

 

p50 is implicated in angiogenesis, for certain in cancer studies, but also in youthful development? Dunno... So does p50 blockade at a gene level lead to growth problems in young animals? Dunno... The study summary suggests that the p50 role in promoting senescence has something to do with tumors not appearing in the animals with p50 blockaded... But wouldn't the p50 role in angiogenesis address the lack of tumor appearance more directly? I just find it odd that the study summary doesn't raise the p50 role in angiogenesis... Are the authors in 2014 not familiar with the p50 literature of years earlier?

• Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interleukin-6 expression, 2008
• NF-KappaB expression correlates with apoptosis and angiogenesis in clear cell renal cell carcinoma tissues, 2008
• and there are more on the topic, many from years prior to 2014... And there's this from 2014...
• Involvement of the NF-кB/p50/Bcl-3 complex in response to antiangiogenic therapy in a mouse model of metastatic renal cell carcinoma

I'm not claiming to have serious expertise about these matters. I just have a lot of questions... :-)

FWIW, IMO, it's important, 1) to pay attention to these kinds of details and 2) not to get distracted by the details so much that one loses sight of the overwhelming evidence: NF-kB inhibition, by itself in the literature, and also via its surrogate marker, Higher HRV, is associated with increased longevity In Humans, and Lower HRV is associated, in hundreds of studies, with morbidity and mortality.

 

Thanks!

Edited by HighDesertWizard, 10 June 2015 - 03:30 PM.

[HighDesertWizard]

One literature reference ( http://goo.gl/HZm6gN ) states NF-kB upregulation activates HTERT, so the inhibition theory isn't fully conclusive IMO. On the other hand, this was for cancer cells where anomalies may be easier to explain.

The HRV correlation with telomer length and for sure general health and mortality is interesting, I was planning on getting a monitor, any ideas what to get without spending a fortune? Some bluetooth device with a good Android app and data export would be best.

 

Great point, yes...

 

The role of NF-kB expression vis-a-vis hTERT is paradoxical. But that shouldn't be surprising when controversy has existed about whether Telomerase is implicated in causing cancer. My view of this issue on 2015-06-10 is specific and also amorphous... :-)

 

A literature search for the two phrases, "NF-kB HMGB1" and "Telomerase HMGB1" reveals that HMGB1 related functions are profoundly related to both NF-kB and Telomerase expression. (I'll provide a bit about that later.) My hunch, today, is that the complex relationship between NF-kB and Telomerase is mediated to a significant degree by HMGB1...

 

So that would mean that HMGB1 functionality is, itself, paradoxical, right? And we see that it is...

 

 

I am in good company in believing that Telomerase expression is not the cause of tumors. Also, shouldn't we appreciate Bill Andrews more for supporting a Telomerase Management approach that is loaded with NF-kB Inhibitors that inhibit the probability of cancer? (http://tinyurl.com/ochm7ln)

 

For me, the same principle I mentioned above applies 1) to pay attention to seemingly negative kinds of details but 2) don't get distracted by them so much that I lose sight of the overwhelming evidence: NF-kB inhibition, by itself in the literature, and also via its surrogate marker, Higher HRV, is associated with increased longevity In Humans...

 

And for Avatar... The issue about p50 you raise is important. Also, HMGB1 functions appear to be even more complex and are at the heart of the NF-kB - Telomerase relationship. So I place a higher priority on it in terms of time spent in research... The point, of course, is to discover practical knowledge buried in that literature.

 

:-)

Edited by HighDesertWizard, 10 June 2015 - 03:39 PM.

[Avatar of Horus]

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. "

 

 

Avatar... Thanks for this... The links provide interesting and useful data and perspective...

 

p50 is implicated in angiogenesis, for certain in cancer studies, but also in youthful development? Dunno... So does p50 blockade at a gene level lead to growth problems in young animals? Dunno... The study summary suggests that the p50 role in promoting senescence has something to do with tumors not appearing in the animals with p50 blockaded... But wouldn't the p50 role in angiogenesis address the lack of tumor appearance more directly? I just find it odd that the study summary doesn't raise the p50 role in angiogenesis... Are the authors in 2014 not familiar with the p50 literature of years earlier?

• Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interleukin-6 expression, 2008
• NF-KappaB expression correlates with apoptosis and angiogenesis in clear cell renal cell carcinoma tissues, 2008
• and there are more on the topic, many from years prior to 2014... And there's this from 2014...
• Involvement of the NF-кB/p50/Bcl-3 complex in response to antiangiogenic therapy in a mouse model of metastatic renal cell carcinoma

I'm not claiming to have serious expertise about these matters. I just have a lot of questions... :-)

FWIW, IMO, it's important, 1) to pay attention to these kinds of details and 2) not to get distracted by the details so much that one loses sight of the overwhelming evidence: NF-kB inhibition, by itself in the literature, and also via its surrogate marker, Higher HRV, is associated with increased longevity In Humans, and Lower HRV is associated, in hundreds of studies, with morbidity and mortality.

 

Thanks!

 

 

...

For me, the same principle I mentioned above applies 1) to pay attention to seemingly negative kinds of details but 2) don't get distracted by them so much that I lose sight of the overwhelming evidence: NF-kB inhibition, by itself in the literature, and also via its surrogate marker, Higher HRV, is associated with increased longevity In Humans...

 

And for Avatar... The issue about p50 you raise is important. Also, HMGB1 functions appear to be even more complex and are at the heart of the NF-kB - Telomerase relationship. So I place a higher priority on it in terms of time spent in research... The point, of course, is to discover practical knowledge buried in that literature.

 

:-)

 

 

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.

[Steve H]

Something I have also noticed is the effect of Androgens on TERT expression and digging deeper I am finding further correlation between Estrogen in particular and its ability to regulate and activate TERT leading to Telomerase and Telomere maintainance. I have barely begun collating the data but there seems a definite association between longevity, Estrogen and even Phytoestrogens occuring in food which work similar to Estrogen.

 

Given that Japan and in particular Okinawa tend to have on average longer lifespan and they eat diets containing a number of Phytoestrogen rich food eg, rice, tofu, ginseng, fennel, Mung beans etc.. there could be a link between Estorogen and Phytoestrogen helping maintain Telomeres and thus resisting disease and slowing aging as well as increasing cell division and delaying Senescence. Coincidence?

 

There also appears to be some indication that women who have considerably more Estrogen than men and who have children later in life often live longer.

 

http://journals.lww....hild_and.7.aspx

 

I have just started to sift papers and data to support this but the sheer amount of data relating to Estrogen and Phytoestrogen regulating and activating Telomerase is considerable. I have listed a few below, the basic idea is that this particular Androgen is activating Telomerase and thus effecting Telomere length with all the things that entails. It might be coincidence but I suspect it is important.

 

Too much Estrogen may lead to Cancer as some of the links suggest, not enough leads to short telomeres and the dysfunction and disease that brings. This suggests to me at least that Estrogen and Phytoestrogen may be playing a role in longevity in particular through their ability to effect Telomeres and slow their attrition. For me at least this confirms the work of Dr Michael Fossel who suggests Telomeres are a suitable point for aging intervention. Of course it may be a coincidence but maybe not.

 

 

Estrogen activates Telomerase

 

Kyo S1, Takakura M, Kanaya T, Zhuo W, Fujimoto K, Nishio Y, Orimo A, Inoue M. 1999

 

http://www.ncbi.nlm....pubmed/10606235

 

Estrogen regulates Telomerase

 

Chunxiao Zhou,1 Tara A. Steplowski,2 Hallum K. Dickens,1 Kimberly M. Malloy,1 Paola A. Gehrig,1 John F. Boggess,1and Victoria L. Bae-Jump1,* 2013

 

http://www.ncbi.nlm....les/PMC3567109/

 

Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice

 

Sharyn Bayne1, Margaret EE Jones2, He Li1, Alex R Pinto1, Evan R Simpson2 and Jun-Ping Liu1 2008

 

http://www.nature.co...cr2008291a.html

Induction of hTERT Expression and Telomerase Activity by Estrogens in Human Ovary Epithelium Cells

 

Silvia Misiti,1 Simona Nanni,1 Giulia Fontemaggi,1 Yu-Sheng Cong,2 Jianping Wen,2 Hal W. Hirte,3Giulia Piaggio,1 Ada Sacchi,1 Alfredo Pontecorvi,1,4 Silvia Bacchetti,2,* and Antonella Farsetti1,5,* 2011

 

http://europepmc.org/articles/PMC85692

 

Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells

 

Rodrigo T. Calado,1 William T. Yewdell,1 Keisha L. Wilkerson,1 Joshua A. Regal,1 Sachiko Kajigaya,1 Constantine A. Stratakis,2 and Neal S. Young1

 

http://www.bloodjour...so-checked=true

 

In vivo regulation of hTERT expression and telomerase activity by androgen.

Guo C1, Armbruster BN, Price DT, Counter CM. 2003

 

http://www.ncbi.nlm....pubmed/12853842

 

Human Telomerase and Its Regulation (talks about Estrogen controlling TERT)

Yu-Sheng Cong,* Woodring E. Wright, and Jerry W. Shay 2002

 

 

Modulation of longevity-associated genes by estrogens or phytoestrogens. (Estrogen or plant based equivelent regulate Telomerase)

Viña J1, Sastre J, Pallardó FV, Gambini J, Borrás C. 2008

 

http://www.ncbi.nlm....pubmed/18177268

 

In vivo regulation of hTERT expression and telomerase activity by androgen. (too much Androgen causes Cancer)

Guo C1, Armbruster BN, Price DT, Counter CM. 2003

 

http://www.ncbi.nlm....pubmed/12853842

 

 

[ceridwen]

Women of a certain age find taking oestrogen makes them worse not better. So if that is the case is telomerase harmful also?

[Steve H]

Ceridwen from what I have found out so far too much is bad and not enough is bad so maybe all about that balance? 

 

HRT seems to help Telomere length though and in general longevity:

 

http://www.ncbi.nlm....les/PMC2815830/

 

Wright and Shay also discuss Longevity in Women and Men and differences in Telomere mechanisms. This would include Estrogen.

 

http://sageke.scienc...ct/2005/23/pe16

 

Diets rich in Phytoestrogen also seem to correlate with longevity. It all has a common theme that they activate TERT which boosts Telomeres. Coincidence? I will continue to dig to build a more comprehensive understanding but it seems there is some association.

 

 

[HighDesertWizard]

 

 

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

 

 

Avatar... Sorry for being slow... I see the point... Please don't hesitate to hound me when I'm slow...  :-)

 

Have a few thoughts about this... First one appears below...

 

 

Something I have also noticed is the effect of Androgens on TERT expression and digging deeper I am finding further correlation between Estrogen in particular and its ability to regulate and activate TERT leading to Telomerase and Telomere maintainance. I have barely begun collating the data but there seems a definite association between longevity, Estrogen and even Phytoestrogens occuring in food which work similar to Estrogen.

 

So combining the p50 and estrogen related comments, is there any significance to the means Chang et al chose to block NF-kB expressionin Reversal of aging by NFkappaB blockade?

 

A quote from the article...

 

Because NFκB is important during animal development and RelA-/- mice are embronyic lethal (Fig. 1B) it was not possible to determine if a NFκB knockout animal could live longer. Instead, we focused on the tissue-specific role of increased NFκB activity in an aged animal. In particular, we determined the role of NFκB in aged mouse skin by utilizing a transgenic mouse system that allows induc- ible NFκB blockade.30 Dominant negative p50 protein was fused to a 4-hydroxytamoxifen (4-OHT)-responsive estrogen receptor (ΔSP-p50-ER) and expressed from a keratin 14 promoter, which drives expression in the basal layer of epidermal skin in a transgenic mouse. Consequently, the mutant protein normally remains inactive and localized in the cytoplasm; however, upon 4-OHT addition ΔSP-p50-ER translocates to the nucleus where it inhibits NFκB transcriptional activity in the skin.

 

To study the role of NFκB in regulating aged skin,18 we aged ΔSP-p50-ER transgenic mice 1.5–2 years in the absence of 4-OHT. The mice were then topically treated with 4-OHT (or ethanol as a control) for two weeks to block NFκB activity specifically in the skin. Global gene expression profiling of the control-treated old skin compared to young skin treated in parallel revealed a set of >400 genes that were robustly induced with age. Surprisingly, upon 4-OHT treatment to inhibit NFκB activity we found that more than half of these genes reversed their expression levels back to that observed in young mice. Consistently, unsupervised hierarchical clustering confirmed that the expression profile of NFκB-blocked old skin was globally more similar to that of young skin than that of the control-treated skin from the same aged animals. We next analyzed the histology of the aged skin, which is normally character- ized by atrophy and increased cellular senescence. NFκB blockade increased the proliferative capacity of the skin and reversed several markers of cellular senescence to levels observed in young animals.

 

 

The set of Chang studies became a part of the Kawahara dissertation about NF-kB...

Edited by HighDesertWizard, 10 June 2015 - 06:10 PM.

[HighDesertWizard]

@ Avatar... another nfkb1 -/- study... nfkb1 -/- has deleterious impacts on telomere function... Thanks for pointing in a great direction...

 

2014, Chronic inflammation induces telomere dysfunction and accelerates ageing in mice (that's the full text link)

 

From study text...

 

We hypothesize that chronic low-grade inflammation might enhance telomere dysfunction by increasing ROS-mediated DNA damage and thus accelerate accumulation of senescent cells, initiating a ‘circulus vitiosus’ in which cell senescence aggravates chronic inflammation, limits tissue regeneration and accelerates ageing.

 

To test this hypothesis, we utilized a mouse model of chronic low-level inflammation, the nfkb1−/−mouse that lacks expression of the p105 and p50 NF-κB proteins.

 

Abstract...

 

Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1−/− fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1−/− tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.

 

As mentioned up thread, in the last few years, the frequency of studies that specifically relate NF-kB related functions to Telomeres has increased...

Edited by HighDesertWizard, 10 June 2015 - 08:03 PM.

[Steve H]

nfkb1 can be regulated by Telomeres too at least in Cancer

 

http://www.nature.co...ll/ncb2621.html

 

nkfb1 induces Telomere dysfunction too suggesting the two form a feedback loop

 

http://www.nature.co...ncomms5172.html

 

So the question is if you increased Telomere length would that pull the other mechanism into line and regulate it at a youthful level?

[ceridwen]

It all depends on how long it has been since the menopause stopped. If it is 5 years or more the symptoms get worse not better and can exacerbate dementia and then of course if one already has it

[HighDesertWizard]

nfkb1 can be regulated by Telomeres too at least in Cancer

 

http://www.nature.co...ll/ncb2621.html

 

nkfb1 induces Telomere dysfunction too suggesting the two form a feedback loop

 

http://www.nature.co...ncomms5172.html

 

So the question is if you increased Telomere length would that pull the other mechanism into line and regulate it at a youthful level?

 

Here are a few ways to think about that question...

 

1 - About nomenclature… The opening post argument is that NF-kB and Telomerase expression (and associated reductions in Telomere Length) are Biologically Intimate processes within some larger Primary Mechanism of Aging and Rejuvenation… I strongly believe they are but I’m open to alternative evidence and argument. But there’s an awful lot of evidence that would have to be falsified to make that case, with only some of it appearing in the OP...

 

And if they are, increasing Telomerase Expression is an Intervention Technique to leverage that Mechanism, just as Inhibiting NF-kB Transcription Expression is also an Intervention Technique. And I think we need to get used to thinking and speaking clearly about that larger Mechanism...

 

I'm not qualified to give that Mechanism, theoretical at this point, a name... Anyone have thoughts about a name for it or what other major processes are a part of it?

 

2 - The opening post contains links to NF-kB inhibition capabilities of known activators of Telomerase (astragalus, Astragaloside IV, .4-OHT (Chang and DePinho), and Mindfulness/Positive Cognition). I couldn't find a study about Cycloastragenol (the active ingredient in TA-65?) and NF-kB. Any thoughts or links about it?

 

3 - Bill Andrews has spent a little time working on Telomerase Activators. And 38/42 ingredients of the product he’s associated with are NF-kB inhibitors. (See opening post for the spreadsheet link.) Anyone prepared to make a case that Bill Andrews doesn't know what he's doing?

 

So, imo, here’s a better question… Given the info above, can we come up with a Telomerase Activator that is Not also an NF-kB inhibitor? I can’t think of one...

Edited by HighDesertWizard, 19 June 2015 - 12:21 AM.

[Steve H]

No because Telomerase regulates NF-KB and suppress inflammation. Although interestingly NF-KB can compensate for lack of Telomerase in cancers suggesting there is a feedback loop here.

 

One of the best people to ask would be Dr Fossel who convinced Bill Williams that Telomeres are a place of intervention and part of Epigenetic aging. His new book "The Telomerase Revoluton" out October is apparently very informative as are his earlier books. I bet if anyone know the link between these two it is him.

 

Unless you can find an activator that is not an NFKB inhibitor it suggest to me that Telomerase and Telomeres actively inhibit it as part of their many functions. It suggests strongly to me that if Telomerase restoration alone does not inhibit NF-KB again one telomeres lengthen it is a prime target for direct inhibiting and probably the logical companion to accompany Telomerase gene therapy.

 

You might find this older thread here interesting:

 

http://www.longecity...life-extension/

 

We should hopefully know for sure what's going on as Bioviva is gearing up to test Telomerase therapy. They will be ready to deploy it within the next six weeks provided they can crowdfund the 20k to run the pilot test. I will ask them to measure levels of NK-FB expression as a result if measuring is easy.

 

 

[HighDesertWizard]

 

No because Telomerase regulates NF-KB and suppress inflammation. Although interestingly NF-KB can compensate for lack of Telomerase in cancers suggesting there is a feedback loop here.

 

IMO, it would be difficult to falsify the assertion that there is significant cross talk between Telomerase and NF-kB. Also, IMO, there are two kinds of evidence that biological regulation of Telomerase is mostly driven by NF-kB.

• There is a study entitled Inflammation, Telomere Length, and Grip Strength: A 10-year Longitudinal Study. The abstract below... Full study text link found here...

Telomere attrition has been associated with age-related diseases, although causality is unclear and controversial; low-grade systemic inflammation (inflammaging) has also been implicated in age-related pathogenesis. Unpicking the relationship between aging, telomere length (TL), and inflammaging is hence essential to the understanding of aging and management of age-related diseases. This longitudinal study explored whether telomere attrition is a cause or consequence of aging and whether inflammaging explains some of the associations between TL and one marker of aging, grip strength. ...

<< SNIP >>

We present evidence that inflammaging may be driving telomere attrition and in part explains the associations that have previously been reported between TL and grip strength. Thus, biomarkers of physical aging, such as inflammaging, may require greater exploration. Further work is now indicated.

• In addition, IMO, the evidence that evolution has established a flow of regulation from NF-kB to Telomerase is pretty clear...
  • Epel/Blackburn have shown that Mindfulness/Meditation/"Positive Cognition" promotes, both, Higher Heart Rate Variability (HRV) and Telomerase expression.  (tinyurl.com/pqsh6ae and tinyurl.com/nrawp9w)
  • Fredrickson/Cole have shown that Meditation/"Positive Emotions" promotes Higher HRV and NF-kB Inhibition. (tinyurl.com/bxqwyym and tinyurl.com/pzuupxu)
  • Kevin Tracey, and dozens of others, in many studies, have established the existence of a biological mechanism called the Cholinergic Anti-Inflammatory Pathway that specifically Inhibits NF-kB Cytokine Transcription via acetylcholine via Vagus Nerve Stimulation that simultaneously increases HRV. Tracey first depicted the "wiring" of this process in two graphic figures in his 2007 literature review. Those figures are shown below... Note that NF-kB inhibition inhibits HMGB1. That's a big deal re: Telomerase. I imagine we'll be discussing HMGB1 sometime in this forum thread...
  • AFAIK, there is no study establishing the existence of a biological mechanism linking increased Telomerase expression to vagal/acetylcholine/HRV increase independent of NF-kB inhibition. Epel/Blackburn have studiously avoided the question. IMO, it would be fantastic if Dr Fossel, or anyone, could point us to one.

 

 

 

Edited by HighDesertWizard, 19 June 2015 - 06:35 PM.

[Steve H]

GHK also appears to suppress NFKB in this study which may be of interest:

 

http://www.hindawi.c...ri/2014/151479/

 

It does suggest knocking down NF-KB would be a viable approach for a gene therapy coupled with TERT. One might even upregulate GHK to knock down NF-KB and gain the regenerative properties of GHK.

[Steve H]

I was wondering besides the work of Funk/Cal Harley in 2000 showing age reversal in-vivo of human skin fibroblasts is there any evidence that Telomerease activation reverses the aged phenotype?

 

http://www.ncbi.nlm....pubmed/10896778

 

There is also the Dephino experiment in null Telomerase mice where Telomerase was turned back on using an Estrogen like compound.

 

http://www.ncbi.nlm....les/PMC3057569/

 

Any other studies demonstrating reversal of aged Phenotype?

[Steve H]

HDW you might also find this topic relevant to NK-FB on Josh's blog:

 

http://joshmitteldor.../#comment-55704

 

NKFB seems a target or GnRH to inhibit it in the Hypothalamus. I could see that being coupled with a TERT gene therapy for robust rejuvenation.

[HighDesertWizard]

I feel hopeful about the near term prospects for Rejuvenation Science because we're getting clearer about how confused we are.

Is there a Primary Biological Mechanism for Rejuvenation, or not?

Really?

Because there are Multiple Points of Intervention that means there must be Multiple Biological Mechanisms?

 

Edited by HighDesertWizard, 25 June 2015 - 03:08 PM.

[Steve H]

Nice though in theory Telomeres would settle a number of these through correcting gene expression. Stem cell rejuvenation, Anti-oxidants, Mitochondria should hopefully all be somewhat addressed by that single intervention. All theory of course but Dr Fossel I think is on the right track and we will find out soon if Telomerase has the power. Bioviva for example has the funding to run a small test on TERT in a person and is looking at the next six weeks to begin testing. We should hopefully know more and the picture will be clearer by then.

 

[HighDesertWizard]

re: Finding and Plugging the Leak(s)…

 

Part 1 : Leak Concept Introduction...

 

Two graphic figures appear below. The first provides a view of Telomere Length (TL) slow decline over aging decades in humans. Josh Mitteldorf provides a great review of and link to the study the figure is based on here. The second figure provides a view of Heart Rate Variability (HRV) slow decline over aging decades. I've provided lots of links at LongeCity about HRV and its relationship to NF-kB, including in the opening post. Here's a link to a set of graphic figures about HRV and aging that contains a study reference link to the HRV figure below.

 

Given the study reference links and evidence provided in the opening post about TL and HRV…

• it’s not surprising these two graphic figures have a similar look. It would be surprising if they didn’t.
• A metaphor… The declines in TL and HRV are like slow Leaks in a balloon… The leaks are seemingly systemic and inexorable... I believe we ought to be able to identify their sources with more than statements like “it’s oxidative stress.”
• The evidence suggesting crosstalk between NF-kB and Telomerase expression is strong. Nevertheless, for reasons noted above referencing Epel/Blackburn and Fredrickson/Cole, I believe the evidence is mostly that the major flow of regulation runs from NF-kB over Telomerase. I hope someone (Steve H?) will argue with me about this. Are you Telomerase focused folks gonna concede this point? Really? :-)
• My hunch has been that the Slow Leak is a Leak of Vagal Tone resulting in decreasing HRV, increased ROS and NF-kB expression, and reduced Telomere Length during aging.

So, where do we look for the leak(s)?

 

Take a look at Tracey’s 2007 CAIP Wiring Diagram in a previous post. It clarifies that the Leaks are systemic: Notice they impact both NF-kB Inhibition and Higher HRV stimulation. The Leaks profoundly degrade Vagal Tone…
 

I now believe a set of Substances already described in the literature constitute a non-trivial proportion of this systemic vagal tone leak. I confess… I hadn’t heard of these substances until I began the leak search a few weeks ago...
 

The Independent Leaks Evidence I’ve found shows that these substances are already

• discussed in dozens of studies
• associated with degradation of Vagal Tone
• associated with reduced Acetylcholine Signaling
• associated with Lower HRV
• associated with increased NF-kB Expression
• associated with increased ROS and TNF expression
• associated with shorter telomeres
• associated with aging related epigenetic change
• associated with accelerated aging in advanced disorder cases

The problem isn't that the evidence doesn't exist. The problem is that we haven't yet put the Evidence Puzzle Pieces together...

 

My next post will identify these Vagal Tone, NF-kB Inhibition, and Telomere Length Leak Sources and include at least a couple dozen study reference links that drive the point home. Sorry for not including all the info quickly in back to back posts. It takes time to put an argument together that addresses and leverages the evidence in a way I feel comfortable about having to defend later...

 

:-)

 

Here are the two graphic figures referenced above...

 

Edited by HighDesertWizard, 01 July 2015 - 06:10 PM.

[Steve H]

Well Steve you may be happy to learn that Bioviva is going to be testing on half of your theory in a just a few weeks. A TERT test is going ahead on a person very soon followed by some even bigger news. The Epigenetic clock is about to be tested, then we shall see what we shall see...

[HighDesertWizard]

In my last post, metaphorically speaking, we discussed the existence of a growing "Leak" of Vagal Tone during Aging. This Leak is evidenced in the previous post's graphic figures by an increase in NF-kB Activation and reductions in HRV and Telomere Length. (The increase in NF-kB during aging is a process coincident with a decline in HRV per the mechanism referenced in the opening post.) We'd like to be able to Explain the source(s) of those Leaks as much as possible and I believe, via the literature of the last 5 years, we can now do that...

 

This post provides an overview of some significant portion of those Leak Sources, how large a portion, is unclear...

 

Compare the two graphic figures from my last post above to the increases in two Uremic Toxins (Indoxyl Sulfate and P-Cresyl Sulfate) in Wild Type Humans over decades of life below...

 

 

Indoxyl sulfate and p-cresyl sulfate according to age

 

From Heritability and Clinical Determinants of Serum Indoxyl Sulfate and p-Cresyl Sulfate, Candidate Biomarkers of the Human Microbiome Enterotype

 

The increases of these two Uremic Toxins appear to be inversely associated with the reductions in HRV and Telomere Length during aging. I don’t have the data from these studies to calculate correlation, but even calculating correlation will not get us what we want to know, namely…

 

Is there a causal relationship between the increases in Indoxyl Sulfate and P-Cresyl Sulfate on the one hand, and reductions in HRV and Telomere Length on the other?

 

There is an enormous literature about these two Uremic Toxins. In this post, we’ll briefly just skim the surface of that literature with a view toward understanding their relationship during aging with increases in NF-kB and reductions in Telomere Length...

 

 Background

• Indoxyl Sulfate and P-Cresyl Sulfate as Candidate Human Microbiome Enterotype Biomarkers

The human intestinal tract is colonized by hundreds of trillions of microbes, which collectively possess hundreds of times as many genes as coded for by the human genome. The combined genetic potential of the endogenous flora is referred to as the ‘microbiome’ [1]. The dissimilarity in gut bacterial composition between individuals is huge [2]. Recent findings demonstrate that the variation in the microbiome of individuals is not continuous, but stratified [3], indicating that one's individual gut flora are not a randomly composed set of bacteria but one of several possible well-balanced ecosystems. The microbiome can be classified into just three broad “enterotypes” dominated by three different genera: Bacteroides, Prevotella and Ruminococcus [3].

The association between the serum concentrations of indoxyl sulfate and p-cresyl sulfate and age is remarkable and intriguing and confirms previous observations in chronic kidney disease patients [23]. These observations support the hypothesis that aging goes along with a trend towards the Bacteroides enterotype and thus more prominent proteolytic fermentation and essentially concur with data from previous “classical” microbiology studies [34], [35].

• An important 2011 overview of the three Enterotypes of the human gut microbiome, including the Bacteroides enterotype...

• This discussion of The Role of Uremic Toxins in Chronic Kidney Disease Progression is also useful

• The Physiological Flow Overview… Notice that IS and PSC exist in the Systemic Circulation

from The gut–kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression
The colon is responsible for salvage of energy and possibly nitrogen from carbohydrate (CHO) and protein not digested in the upper gastrointestinal tract. Fermentation of the amino acids tyrosine and tryptophan by intestinal microbiota generates p-cresyl and indole, respectively. After absorption, these are further metabolized to generate p-cresyl sulfate and p-indoxyl sulfate. Indoxyl sulfate and p-cresyl sulfate circulate in equilibrium between a free solute fraction and a fraction bound to serum proteins. The best-characterized binding site is albumin Sudlow site II, for which indoxyl sulfate and p-cresyl sulfate are competitive binding inhibitors.

 

 

 Chronic Kidney Disease is a model of Premature Aging...

• Aging and Chronic Kidney Disease: The Impact on Physical Function and Cognition
  • Evidence has recently been building that the presence of chronic kidney disease (CKD) is an independent contributor to decline in physical and cognitive functions in older adults. CKD affects 45% of persons older than 70 years of age and can double the risk for physical impairment, cognitive dysfunction, and frailty.
• The Uremic Toxins… p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease
• p-Cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease:
  • Patients with advanced CKD had higher serum indoxyl sulfate, p-cresyl sulfate based on ANOVA test.
• The Gut as a Source of Inflammation in Chronic Kidney Disease
• Out of control: accelerated aging in uremia
• Chronic Kidney Disease is a Clinical Model of Premature Aging
  • The Klotho longevity gene decline is associated with Kidney disease
  • Downregulation of klotho gene expression by uremic toxins and subsequent gene hypermethylation... implies that epigenetic dysregulation may cause some of the physiologic changes associated with aging. Moreover, the fact that inflammation downregulates klotho expression through NF- KB confirms the observed relationship between inflammation and accelerated organ aging.
  • Klotho implicated in phosphate increase
  • Higher Phosphate levels correlated with shorter lifespans…
• Aging and uremia: Is there cellular and molecular crossover?

 

 

 The relationship to NF-kB expression...

• Indoxyl Sulfate Downregulates Renal Expression of Klotho through Production of ROS and Activation of Nuclear Factor-ĸB
• NF-κB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells
• The Uremic Toxin Indoxyl Sulphate Enhances Macrophage Response to LPS...Mechanistic studies revealed that IS increased LPS-induced NF-kB nuclear translocation, ROS release and altered calcium concentrations
• Protein traffic activates NF-kB gene signaling and promotes MCP-1–dependent interstitial inflammation

 The relationship to Telomere Length...

• Is there a connection between inflammation, telomerase activity and the transcriptional status of telomerase reverse transcriptase in renal failure?

Telomerase is involved in the elongation of telomeres. It remains active in very few types of cell in mature organisms. One such cell type is the lymphocytes. In this study, we investigated the activity and expression of telomerase in lymphocytes from renal failure patients and compared it to that for normal controls. Inflammation status was determined at the same time. The enzyme activity was measured using PCR-ELISA with peripheral blood mononuclear cells (PBMCs) from three groups: 53 healthy individuals, 50 patients with chronic kidney disease (CKD) and 50 dialysis patients. In the same cell populations, the expression of the reverse transcriptase of the human telomerase gene (hTERT) was measured via real-time PCR. The inflammation status of these individuals was determined by calculating the interleukin 6 (IL-6), IL-10, C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-a) serum concentrations via ELISA. The lowest levels of telomerase activity were detected in CKD, and this group had the highest IL-6 and CRP values and the lowest hTERT expression. The dialysis group showed significant differences in comparison to the normal subjects and to the CKD patients. Further studies are warranted in order to explore the way inflammation influences telomerase activity and hTERT expression.

• Klotho Prevents NFκB Translocation and Protects Endothelial Cell From Senescence Induced by Uremia

 Summary...

It's important that we try to Explain the "Leak" of Vagal Tone that is evidenced by an increase in NF-kB and reductions in HRV and Telomere Length.

It would be extremely difficult to falsify an Explanation of that Leak as being, at least in part, a function of relative increases in Indoxyl Sulfate and P-Cresyl Sulfate within the gut via various Microbiome Enterotypes. The Bacteroides Microbiome Enterotype appears to trigger greater increases in Indoxyl Sulfate and P-Cresyl Sulfate than others, "supporting the hypothesis that aging goes along with a trend towards the Bacteroides enterotype."

 

At some point, I'll establish a thread for discussion of gut Enterotypes and what we can do to improve them if such a thread doesn't already exist.

 

While exploring the profound effects of the gut Microbiome Enterotype for aging, it's important that we not lose focus on the bigger picture of the primary mechanism of aging and longevity this thread is purposed to get at.

Edited by HighDesertWizard, 25 July 2015 - 05:02 PM.

[HighDesertWizard]

"Telomerase activity is linked to cellular proliferation, and its activation seems to be a mandatory step in carcinogenesis. In contrast to mammals, indeterminately growing multicellular organisms, like fish and crustaceae, maintain unlimited growth potential or 'immortality' in all somatic tissues throughout their entire life. Also this cell immortalization is brought about by maintaining telomerase expression..."   From Telomerase, immortality and cancer

 

Do studies now exist that explain a/the mechanism for the continuous expression of Telomerase in cancer cells? 

 

Telomerase directly regulates NF-B-dependent transcription

 

Abstract

 

Although elongation of telomeres is thought to be the prime function of reactivated telomerase in cancers, this activity alone does not account for all of the properties that telomerase reactivation attributes to human cancer cells. Here, we uncover a link between telomerase and NF-κB, a master regulator of inflammation. We observe that while blocking NF-κB signalling can inhibit effects of telomerase overexpression on processes relevant to transformation, increasing NF-κB activity can functionally substitute for reduced telomerase activity. Telomerase directly regulates NF-κB-dependent gene expression by binding to the NF-κB p65 subunit and recruitment to a subset of NF-κB promoters such as those of IL-6 and TNF-α, cytokines that are critical for inflammation and cancer progression. As NF-κB can transcriptionally upregulate telomerase levels, our findings suggest that a feed-forward regulation between them could be the key mechanistic basis for the coexistence of chronic inflammation and sustained telomerase activity in human cancers.

[Steve H]

Not all Cancer uses Telomerase but it is a required step in the majority of Cancers. However telomerase is not an oncogene and its activation in somatic cells has been proven not to increase cancer. It used to be thought commonly that short telomeres and senescence was an anti Cancer tactic however this is becoming increasingly unlikely, if anything having telomeres that are the correct length relative to starting length are beneficial. Simply making telomeres very long is however not a good idea as the important factor in telomere biology is its length relative to the starting length not simply just long. 

 

I believe in most Cancer stem cells the TERT gene is expressed leading to constant expression of telomerase and rampant replication, this is likely because the TERT receptor is Methylated and thus silenced in healthy cells. Healthy stem cells turn on telomerase as and when it is required.

 

I do wish to stress again though that telomerase expression whilst a step in Cancer does not cause Cancer and optimal telomeres do seem to impart a level of Genomic stability that protects from Cancer. Telomerase is also vital for stem cell rejuvenation as not only does it lengthen telomeres and maintain them in SCs it also interacts with the wnt pathway promoting mobilization of the stem cell and as a result regeneration of tissue. It is possible this also happens in Cancer stem cells and telomerase interacts with the wnt pathway and allows it to regenerate. 

 

I have a library of telomerase related data should you be interested in further reading.

 

Also of interest is TGF-beta 1, this inhibits telomerase expression and increases with age. So this is one reason stem cells become more dysfunctional with age as TGF levels rise. TGF-b1 is also an antagonist of B2M which directly impairs regeneration and has recently been in the news here:

http://www.ucsf.edu/...system-molecule

 

I have spoken with Irina Conboy about this and as noted in her 2015 paper she shows that TGF-b1 rises with age and causes B2M to rise too leading to inflamation and impaired regeneration. She confirms in her recent paper that B2M rises once TGF-b1 reaches a "tipping point" but does not when young. If you inhibit TGF-b1 it causes B2M levels to fall to youthful levels along with TGF-b1 after a short treatment with the inhibitor. This proves that stem cells can be rejuvenated and inflammation can be reversed. 

 

 

Edited by Steve H, 25 July 2015 - 06:45 PM.

[HighDesertWizard]

Not all Cancer uses Telomerase but it is a required step in the majority of Cancers. However telomerase is not an oncogene and its activation in somatic cells has been proven not to increase cancer. It used to be thought commonly that short telomeres and senescence was an anti Cancer tactic however this is becoming increasingly unlikely, if anything having telomeres that are the correct length relative to starting length are beneficial. Simply making telomeres very long is however not a good idea as the important factor in telomere biology is its length relative to the starting length not simply just long. 

 

I believe in some Cancers the TERT gene is expressed leading to constant expression of telomerase and rampant replication, this is likely because the TERT receptor is Methylated and thus silenced in healthy cells.

 

I do wish to stress again though that telomerase expression whilst a step in Cancer does not cause Cancer and optimal telomeres do seem to impart a level of Genomic stability that protects from Cancer. Telomerase is also vital for stem cell rejuvenation as not only does it lengthen telomeres and maintain them in SCs it also interacts with the wnt pathway promoting mobilization of the stem cell and as a result regeneration of tissue. 

 

I have a library of telomerase related data should you be interested in further reading.

 

Thank you, Steve, for your post. In my last post, it was not my intention to suggest that Telomerase caused Cancer and I didn't imply that it did. Still, your clarification is important and a useful one.

 

Still, I'm puzzled by why those in the Telomerase is Important Camp feel a need to explain rampant replication of Telomerase in Cancer in terms of some Telomere gene (like TERT) itself. In fact, the study I linked to in my last post demonstrated that the "feed forward" mechanism of rampant Telomerase expression involves NF-kB expression.

 

I believe the study evidence presented in this thread makes it clear that processes related to NF-kB and Telomerase expression are intimately linked, even if we don't understand the details. But...

• Will Michael Fossel's new book mention NF-kB?
• I've seen many youtube videos of Bill Andrews talking about Telomeres and Telomerase. And I like Bill Andrews a lot. But why doesn't Bill Ever mention NF-kB, especially seeing as how the Telomere Support product he's associated with, Isagenix Product B Isagenesis, contains ingredients shown to inhibit NF-kB that constitute 99% of the product by weight?

As a believer in the Rejuvenation promise of Telomere Lengthening products, I'm troubled by the fact thought leaders in that camp never mention (or are unaware of?) the importance of NF-kB.

 

A link to your library of telomerase related data would be much appreciated.

Edited by HighDesertWizard, 25 July 2015 - 07:09 PM.

[Steve H]

I can say with almost 100% certainty that Dr Fossel's new book does not mention NK-FB, I have a review copy and whilst it is an excellent book and gives a good idea to the layman of what telomeres and telomerase can achieve it is not a technical book compared to say cells and aging he wrote a few years back. He says in an interview on inspired insider recently that the book is aimed at people who are interested but are not researchers or specialists:

 

http://www.inspiredi...view/#more-1680

 

It might be a case that NF-KB being a downstream consequence of telomere shortening and changes in gene expression that it is not mentioned as it is part of the cascade of things that go wrong eg, rising B2M, rising NF-KB, rising levels of TGF-b1 and so on. I would be happy to ask Michael about it if you think it would be helpful?

 

NF-KB can indeed regulate TERT so the two are connected beyond a doubt. There appears to be a feedback loop between the two. 

 

http://www.sciencedi...014299911011988

I think the reason for the knee jerk reaction about telomerase for those in the camp is because for over a decade it was "common knowledge" that activating telomerase caused cancer, a claim that had absolutely no merit, no proof and no data. In fact some of the very people who urged caution about using it and Cancer like Dr Blasco have since reversed their opinion on the matter. It is very unfortunate that people made the original assumption because it has perpetuated the cancer myth which persists even today, despite numerous studies and data showing it to be false. I tend to be a little defensive about telomeres personally as I see the huge potential it has and the actions it has beyond simply being a replicative clock that some people tend to dismiss it as, it has interaction with regeneration pathways as well as controlling a slew of gene expression through TPE. It is amazing how some people in the field ignore this or do not know about it.
 

[HighDesertWizard]

<< SNIP >>

 

Also of interest is TGF-beta 1, this inhibits telomerase expression and increases with age. So this is one reason stem cells become more dysfunctional with age as TGF levels rise. TGF-b1 is also an antagonist of B2M which directly impairs regeneration and has recently been in the news here:

http://www.ucsf.edu/...system-molecule

 

I have spoken with Irina Conboy about this and as noted in her 2015 paper she shows that TGF-b1 rises with age and causes B2M to rise too leading to inflamation and impaired regeneration. She confirms in her recent paper that B2M rises once TGF-b1 reaches a "tipping point" but does not when young. If you inhibit TGF-b1 it causes B2M levels to fall to youthful levels along with TGF-b1 after a short treatment with the inhibitor. This proves that stem cells can be rejuvenated and inflammation can be reversed. 

 

Speak of the devil... TGF-b1...

 

It's especially great, Steve, that you posted Conboy's view of TGF-b1 immediately after my earlier post today...   :-)

 

I had never heard of Indoxyl Sulfate and P-Cresyl Sulfate, the subjects of my post earlier today, until about 4 weeks ago... Turns out, they're a big deal--two important Vagal Tone "Leak" Sources--and we can, even now, do something about reducing their presence in circulation... I'll post practical info about that soon, though there is a hint about what we can do below...

 

Indoxyl sulfate increases the gene expressions of TGF-β1, TIMP-1 and pro-α1(I) collagen in uremic rat kidneys

 

No need to paste in abstract text, the study title says it all.

 

An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys

 

AST-120 reduces the gene expression of TGF-beta1, TIMP-1 and pro-alpha1(I)collagen in the kidneys, and delays the progression of CRF, at least in part, by alleviating the overload of indoxyl sulphate on remnant proximal tubular epithelial cells.

 

Edited by HighDesertWizard, 25 July 2015 - 11:22 PM.