226 replies to this topic

[RobbieG]

HighDesertWizard you asked: 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?

I believe there is evidence to support a relationship between these microbiome end-products (Indoxyl Sulfate and P-Cresyl Sulfate) and telomere length. Here is one article but there are others.  http://www.scienceda...31115093715.htm

 

"Researchers discovered after gastric bypass, certain patients' telomeres actually became longer. Preoperative patients with high levels of LDL cholesterol, the so called "bad cholesterol," and high levels of inflammation (CRP), not only saw these levels drop within a year of surgery, they also experienced significant lengthening of their telomeres, when compared to patients with initial low LDL and CRP levels."
 

For the record Gastric bypass surgery refers to a surgical procedure in which the stomach is essentially stapled shut at both ends and small intestine is rearranged to connect the digestive tract bypassing the old stomach all together. Obviously, bypassing the stomach also bypasses the effects of the microbiome.  The quote below is from the article you referenced earlier: 
 

"It is increasingly recognized that the microbiome may affect health and disease of the host, e.g. by modulating the immune system, by harvesting energy from the breakdown of otherwise difficult to digest plant glycans, by synthesizing vitamins, by metabolizing xenobiotics or by exposing the host to potentially toxic metabolites [4]. .............. Indoxyl sulfate and p-cresyl sulfate are the sulfate conjugates of indole and p-cresol, which are end-products of bacterial protein fermentation of respectively tryptophan and tyrosine in the colon [6], [7].  In vitro and ex vivo data show that indoxyl sulfate and p-cresyl sulfate may trigger or accelerate cardiovascular disease and progression of kidney failure [14]–[19]. Clinical observational studies also relate high levels of both metabolites with overall mortality [19]–[22] as well as cardiovascular disease [23], [24] and renal disease progression [25]."

 

I was unable to find any articles/research indicating that another type of surgery (ie non-bariatric) also increased telomere length.  

[HighDesertWizard]

In this post… an attempt to explain how recent science about gastric bypass, uremic toxins, "blood factors," heterochronic parabiosis, and NF-kB-Telomerase aligns...

 

 

I believe there is evidence to support a relationship between these microbiome end-products (Indoxyl Sulfate and P-Cresyl Sulfate) and telomere length. Here is one article but there are others. http://www.scienceda...31115093715.htm

 

"Researchers discovered after gastric bypass, certain patients' telomeres actually became longer. Preoperative patients with high levels of LDL cholesterol, the so called "bad cholesterol," and high levels of inflammation (CRP), not only saw these levels drop within a year of surgery, they also experienced significant lengthening of their telomeres, when compared to patients with initial low LDL and CRP levels."

 

For the record Gastric bypass surgery refers to a surgical procedure in which the stomach is essentially stapled shut at both ends and small intestine is rearranged to connect the digestive tract bypassing the old stomach all together. Obviously, bypassing the stomach also bypasses the effects of the microbiome. The quote below is from the article you referenced earlier:

 

Thanks much, Woody, for that reference... I take it as confirmation of a sort… Gastric bypass reduces Uremic Toxins in the Blood Circulation… Without providing study references now, I believe, but am not certain, the causal flow of evidence goes something like this...

 

Gastric Bypass -> Reduction in circulating Uremic Toxins in Blood Circulation ->

Reduced ROS -> Reduced NF-kB Activation in Blood and Tissues ->

Increased Telomerase -> Longer Telomeres

 

Speaking of "blood factors," well known Heterochronic Parabiosis (HP) studies are now focused on discovering factors strongly associated with aging and rejuvenation. (For an introduction to HP studies, I recommend Josh Mitteldorf's discussion here.) The factors discussed in recent studies include CCL11 (aka, eotaxin), B2M, and TGF-b1.

• ccl11, Villeda et al, 2011, The aging systemic milieu negatively regulates neurogenesis and cognitive function
• B2M, Villeda et al, 2015, β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis
• TGF-b1 and B2M, Conboy et al, 2015, Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal

 
Consider this… If the NF-kB-Telomerase-UremicToxins nexus of functions is as important for morbidity, mortality, and longevity as the science up thread suggests, these Blood Factors found important in HP must somehow implicate it.

 

So do they?

• TGF-b1… As noted up thread...

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.

 

And we already know from Uremic Toxin studies referenced up thread that Indoxyl Sulfate increases NF-kB.

• B2M

B2M is a component of MHC class I molecules and its expression varies with TGF-b1 level. As TGF-b1 level rises during aging so does B2M. From the 2015 Conboy study...

 

... B2M levels were extremely low in young brain and muscle, consistent with prior work, but increased significantly with aging... These results demonstrate that B2M becomes upregulated with aging in multiple tissues (suggesting an increase in inflammation) and that down-modulation of TGF-β signaling, which rejuvenates myogenesis and neurogenesis, normalizes B2M in myogenic and neurogenic regions to their young levels, suggesting attenuation of inflammation. As further support of this conclusion, the levels of B2M were also significantly reduced in regenerating regions of the old muscle administered with the dnTGFBR2, as compared to tissue administered with control GFP virus. Furthermore, addition of low concentrations of TGF-β1 (0–5 ng/mL) to immune cells, specifically BV2 cells – a microglia cell line – did not affect B2M levels, as assayed by pixel intensity and percent area staining of B2M. In contrast, high TGF-β1 (50 ng/mL) levels induced a significant increase in B2M expression. Thus, physiologically young levels TGF-β1 does not induce B2M, but increased TGF-β1 does.

 

From Villeda, 2015...

 

The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

 

So is B2M triggered in the same way TGF-b1 is, by a Uremic Toxin? Short Answer: No. B2M IS a Uremic Toxin. You’ll recall that Chronic Kidney Disease has been found to be an accelerated form of aging.

• B2-microglobulin, a uremic toxin with a double meaning

• Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients

Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients… B2M levels increased with CKD stage and thus were highest in hemodialysis patients… Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.

• Beta-2-microglobulin as a uremic toxin: the Japanese experience

β(2)-microglobulin (β(2)-MG) as the major constitutional protein of dialysis-related amyloidosis (DRA) a quarter of a century ago. Since then, β(2)-MG has been the most extensively studied low molecular weight protein in end-stage renal disease.

 

And how is MHC-1 (of which B2M is one component) regulated?

• Reprogramming of the MHC-I and its regulation by NFκB in human-induced pluripotent stem cells

… We show that, during their reprogramming, human-induced pluripotent stem (iPS) cells downregulate expression of human leukocyte antigen (HLA)-A/B/C and β2 microglobulin (β2M), the two components of major histocompatibility complex-I (MHC-I)... Our results show a significant positive correlation between MHC-I expression and expression of the nuclear factors, nuclear factor kappa B 1 (NFκB1) and RelA, at the levels of RNA, protein and was confirmed by chromatin binding... Overexpression of NFκB1 and RelA in undifferentiated pluripotent stem cells led to induction in expression of MHC-I, whereas silencing NFκB1 and RelA by small hairpin RNA decreased the expression of β2M after IFNγ treatment. Our data point to the critical role of NFκB proteins in regulating the MHC-I expression in human pluripotent stem cells.

• ccl11
  • Intestinal CCL11 and Eosinophilic Inflammation Is Regulated by Myeloid Cell–Specific RelA/p65 in Mice

In inflammatory bowel diseases (IBDs), particularly ulcerative colitis, intestinal macrophages (MΦs), eosinophils, and the eosinophil-selective chemokine CCL11, have been associated with disease pathogenesis. MΦs, a source of CCL11, have been reported to be of a mixed classical (NF-κB–mediated) and alternatively activated (STAT-6–mediated) phenotype… Our results indicate that myeloid cell–specific NF-κB–dependent pathways play an unexpected role in CCL11 expression and maintenance of eosinophilic inflammation in experimental colitis. These data indicate that targeting myeloid cells and NF-κB–dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation and histopathology in IBD.

• PKCbetaII augments NF-kappaB-dependent transcription at the CCL11 promoter via p300/CBP-associated factor recruitment and histone H4 acetylation

The transcription factor NF-kappaB plays a pivotal role in regulating inflammatory gene expression… In this study, we describe a novel role for protein kinase C (PKC) betaIotaIota in augmenting NF-kappaB-mediated TNF-alpha-induced transcription of the target gene CCL11 in human airway smooth muscle cells by phosphorylating the HAT p/CAF... These data suggest a novel important biological role for PKCbetaIotaIota in NF-kappaB-mediated CCL11 transcription by p/CAF activation and histone H4 acetylation.

• Rosmarinic acid as a downstream inhibitor of IKK-beta in TNF-alpha-induced upregulation of CCL11 and CCR3

Tumor necrosis factor (TNF)-alpha is known to induce the expression of CCL11 and CCR3 via the activation of NF-kappaB. … Our results show that rosmarinic acid inhibits the expression of CCL11 and CCR3 by suppressing the IKK-beta activity in NF-kappaB activation signaling. Further, these results suggest that rosmarinic acid might inhibit the expression of NF-kappaB promoter-related genes.

 

So... It turns out that

• Blood Factors recently found important in Aging by HP scientists confirm the findings from CKD studies
• Findings from CKD studies confirm the importance of the blood factors associated with aging in HP studies.

The studies referenced in this post constitute further confirmation that there is a (Metaphorical) Leak of Vagal Tone during aging... i.e., Increased NF-kB Activation and Expression and Lower HRV and Telomere Length...

Edited by HighDesertWizard, 03 August 2015 - 06:54 PM.

[HighDesertWizard]

My post above yesterday was timely. The Guardian has a story about Young Blood today. Most of the factors identified in my post are mentioned in the story...

Can we reverse the ageing process by putting young blood into older people?

Edited by HighDesertWizard, 04 August 2015 - 08:43 PM.

[RobbieG]

This article sheds some light on the relationship between inflammation (NF-kB) and Telomere Length.  Nothing earth shattering but it suggests that the level of inflammation determines telomere length.  

 

Medical Xpress: Inflammation, not telomere length, predicts healthy longevity of centenarians

[Steve H]

Of course if one restore telomere length using telomerase induction for example then the gene expression pattern in the cells would revert back to a younger profile thus inflammation pathways would again be down regulated, so yes inflammation is the key factor in aging after a point but then we are talking about reverting aging and restoring telomeres which is another matter. There is plenty of data to support that cells inducted would resume youthful gene expression, this would result in an overall reduction of inflamation anwyays. Key is not allowing our cells to reach that aged point where inflammation becomes the major issue. 

 

Inflammation is one reason I take Creatine as well.

[HighDesertWizard]

Of course if one restore telomere length using telomerase induction for example then the gene expression pattern in the cells would revert back to a younger profile thus inflammation pathways would again be down regulated, so yes inflammation is the key factor in aging after a point but then we are talking about reverting aging and restoring telomeres which is another matter. There is plenty of data to support that cells inducted would resume youthful gene expression, this would result in an overall reduction of inflamation anwyays. Key is not allowing our cells to reach that aged point where inflammation becomes the major issue. 

 

Inflammation is one reason I take Creatine as well.

 

I am a self-described Telomerase Expression Enthusiast (TEE). I am a big fan of Bill Andrews. I like what he says and I like what he's done. And, caveat emptor, I'm an IsaGenesis Product B user.

 

But I think many other TEEs oversimplify by insisting that increasing Telomere Length, by itself, will "revert aging."

 

As early as 2007/2008, Adler/Kawahara/Chang made an argument and provided evidence that a Motif module map reveals enforcement of aging by continual NF-κB activity, and that Reversal of aging [could be achieved] by NFkappaB blockade. They did some tinkering and used 4-OHT to achieve the rejuvenation effect.

 

Insisting that Telomerase induction would trigger reversion "back to a younger profile thus inflammation pathways would again be down regulated" doesn't get my attention.without a study reference. And the study reference to support the point cannot be DePinho's Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice because that team also used 4-OHT to achieve the rejuvenation effect. And the team didn't bother to reference the 2007/2008 Chang led studies noted above.

 

That's strange, right? Prove rejuvenation is possible, use the same substance as the Chang Team did but don't reference the study... Sloppy, IMO...

 

Is the suggestion that mere Telomerase induction would also address the Uremic Toxins impact on Vagal Tone that Epel/Blackburn have emphasized as important for Telomere Length stability?

 

But the most serious evidence that TEE single minded focus on Telomerase Expression is unjustified comes from the most Enthusiastic of us TEEs, namely, Bill Andrews. Dr. Andrews, of course, is closely associated with the Isagenesis Product B "Telomerase Support" product. And that product is composed of NF-kB Inhibiting ingredients that constitute 99% of the product, by weight. See my google spreadsheet for details.

 

NF-kB and Telomerase expression have a complex relationship that involves significant cross-talk. So insisting that one of them is more important than the other makes no sense. But if TEEs do want to insist on that, their argument isn't with me. It is, instead, with Bill Andrews... Go get him to explain why he and Isagenix' John Anderson felt a need to create a Telomerase induction product that is composed almost entirely of NF-kB inhibitors...

 

:-)

Edited by HighDesertWizard, 06 August 2015 - 02:49 AM.

[HighDesertWizard]

By the way... I got a full text pdf of the following study... It's masterful... I'm hoping the study author who provided it to me will post to this thread...

 

Telomerase directly regulates NF-B-dependent transcription

 

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.

 

 

Edited by HighDesertWizard, 06 August 2015 - 02:54 AM.

[HighDesertWizard]

An update about research for this forum thread...

 

I'm currently doing research and post drafting on two Content Batches related to the NF-kB - Telomerase relationship... (Previous Content Batch Examples: (1) The posts on Uremic Toxins as a kind of (metaphorical) Leak of Vagal Tone during aging. (2) Tying in the science of Heterochronic Parabiosis study Blood Factors to Chronic Kidney Disease and Uremic Toxins.)

 

What follows below is a high-level description of what I'd like to do next. And I could use some help doing it...

• One of the great things about Bill Andrews being associated with the Isagenix Product B IsaGenesis product is that we have a list of ingredients we can do research about that we know are related to NF-kB and/or Telomerase. As I noted in the previous post, Product B ingredients that inhibit NF-kB constitute 99% of the product by weight. And there is a link to one study demonstrating the NF-kB relationship for each ingredient when it exists in the spreadsheet I created.
• The next step for that spreadsheet is to determine, for each ingredient, whether 1 or more studies exist showing an impact of the ingredient on Telomerase expression.
• And there are two additional substances to do research about that appear to be important.
• You'll note that I've added three columns to the right side of the spreadsheet to enter url links for these 3 substances if a relationship exists in 1 or more studies.
• To save myself time, I'd appreciate the help of 3 persons who would commit to doing google scholar searches for these 3 substances.
• I would expect that 5 to 8 hours is all it ought to take for each substance.
• If you've got time and interest in participating, hit me with a LongeCity private message and I'll set you up to help.

Thanks.

Edited by HighDesertWizard, 07 August 2015 - 09:47 PM.

[mpe]

So, TA-65 and Product B should make a pretty good combination then or would they ?

 

Mike

[HighDesertWizard]

An August issue of Current Aging Science is focused on the theme, Is Aging a Failure or a Conquest of Natural Selection? It contains several interesting articles, including one by Dr. Aubrey de Grey entitled, Do We Have Genes that Exist to Hasten Aging? New Data, New Arguments, But the Answer is Still No.

 

It also contains an important literature summary article by Dr. Harold Katcher entitled, Towards an Evidence-based Model of Aging. All the articles referenced are available as PDFs.

 

The modern synthesis or evolutionary theory of aging assumes that aging results from the accumulation of errors or damages at the cellular level through the inadequacies of an organism's repair and maintenance machinery. The demonstration of cellular and organic rejuvenation requires the hypothesis that aging is the result of irreparable damage to be rejected. I will propose basic principles of mammalian aging based only on experimental data, without imposing the constraints of evolutionary theory. Consideration of the results of experiment suggests that fundamental assumptions about cell and organ aging being autonomous process, and about the centrality of cellular aging in organismic aging are wrong. The derived principles indicate that exogenous control of age-phenotype at cellular and higher levels of biological organization is possible.

 

I'm interested at first to discuss the eleven Principles of Aging as Determined by Experimental Studies that Katcher sketches and provides evidence for. I believe some of these have practical implications and it would be useful to discuss them in detail. I prefer that the discussion focus on evidence for and against these principles and whether additional principles can be identified. I prefer that the discussion not become a debate about the larger question of Programmed Aging vs. Non-Programmed Aging. I think a forum thread focused on Dr. de Grey's article is more appropriate for that debate.

• The Age-phenotype of a Cell or Organ Depends on its Environment and Not its History
• Cellular Aging Changes are Reversible
• Aging Manifestations that Have Hitherto Been Proposed as the Causes of Aging are the consequences of Aging
• Post-adult Changes in Transcription, Translation and Splicing are Non-random, Life-stage-specific and Determined by Factors in the Bloodstream
• Post-adult, Life-stage-specific Changes in Transcription/Translation and RNA Splicing are Responsible for the Manifestations Seen as Aging at the Cellular Level and Beyond
• Cellular Aging Changes Cause Aging Changes in Organs and Organ Systems, Reciprocally, Changes in Organs and Organ Systems Effect Cellular Aging Changes
• Cells and Organs Both Signal their Age Status and Receive Age-status Information Via the Bloodstream
• The Age-Phenotype of Cells and Organs Depend on the Concentrations Rather Than the Presence or Absence of Blood-borne Factors
• The Factors that Determine Cellular Age-phenotype are Different for Different Cell Types
• Several Factors ‘Conspire’ to Promote Inflammation in Old Mammalian Bodies, Inflammation Leads to Several Diseases of Aging and Perhaps to Aging Itself
• The Combined Effects of the Body's Various Aging Clocks Result in a 'Body-clock' that Regulates the Age phenotypes of Cells and Organs, this "Body Clock" is Largely Read Through the Bloodstream

I'll be taking a few days to digest it. I have a principle or two I believe should be added to Dr. Katcher's list. I look forward to the discussion.

Edited by Mind, 06 January 2016 - 10:57 PM.
moderated by threadstarter

[niner]

2. Cellular Aging Changes are Reversible

 

Some cellular aging changes may be reversible, but not all of them.  If there is an endogenous way to reverse a lysosome swollen with indigestible junk, or a way to cleave glucosepane crosslinks in long-lived tissue, I don't think it's ever been demonstrated.

 

I prefer that the discussion not become a debate about the larger question of Programmed Aging vs. Non-Programmed Aging.

 

That might be difficult, given that the paper is specifically about that.

[Antonio2014]

An August issue of Current Aging Science is focused on the theme, Is Aging a Failure or a Conquest of Natural Selection? It contains several interesting articles, including one by Dr. Aubrey de Grey entitled, Do We Have Genes that Exist to Hasten Aging? New Data, New Arguments, But the Answer is Still No.

 

Oh, nice to see that it's now freely available! I'm reading it.

[Steve H]

Whilst TEEs claim it will solve most of aging there is good suggestion it can and does revert gene expression profiles to a youthful state. I have some papers showing some very interesting changes to gene expression patterns, so in a sense yes ectopic telomerase expression can and does revert cell age/function. Telomerase also has interaction with the wnt pathway which is responsible for growth and repair and short telomeres lead directly to production of P53 which inhibits PCG-1a/b leading to mitochondrial dysfunction and changes to metabolism and insulin processing and ultimately loss of stem cell mobility and function. 

 

Sure restoring or maintaining telomeres is not the full answer but the work of Michael Fossel shows that it could be very wide ranging in it's effects. Bearing in mind short telomeres are now being increasingly implicated in most major pathology. 

[Rocket]

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.
 

 

I think there is a lot purposeful misinformation about anti/reverse-aging therapies.  When it comes to telomerase, their argument goes as, "Cancer cells express telomerase, and therefore telomerase causes cancer."  Yet in all of the experiments in which telomerase was activated, and it was recently done in human skin cells with remarkable positive effects, cancer has never developed. 

 

This entire anti-telomerase argument is about as logical as claiming that because the ocean is blue and wet, if something is wet it is also blue.

[Steve H]

Telomerase obviously plays a key role in rate of many aspects of ageing the evidence is everywhere. NF-KB and telomerase is related strongly and another possibly important mechanism I have noticed below:

I recently read this new paper that shows how ALA induced up-regulation of PCG-1a modulates telomerase:

 

http://www.cell.com/...(15)00825-6.pdf

 

This carried a host of benefits and was tested on a range of phenotypes which is good and builds on previous papers by the same group. In short:

1: PGC-1a disruption promotes vascular aging and
atherosclerosis
2: PGC-1a modulates telomere function and length as well as
DNA damage
3: High-fat diet reduces PGC-1a-TERT signaling to drive
vascular aging and arteriopathy
4: Enabling PGC-1a-modulated TERT and ARE/ERE signaling
obviates age-related pathology

 

What is interesting is that increased PCG-1a protects against Oxidative stress and ROS, Mitochondrial dysfunction, telomere dysfunctionm vascular ageing and stem cell decline. It also appears to keep P53 in check and encourages its pro-longevity side rather than its pro-ageing effects which occur when P53 increases in the face of falling PCG-1a and TERT. I am aware this pathway also interacts with the SIRT side of things too so that's a lot of bang for your buck especially if increased PCG-1a helps resist ROS/oxidative stress slowing down damage to the telomeres via ERE/ARE increase.

 

The diagram here shows the benefits well:

 

 

It seems to link in with the work of Dephino and his Ageing Axis (telomeres - PCG1a - P53) that links directly to mitochondria. The diagram below shows the relationship well:

The Dephino paper from 2012, later papers demonstrate this in other organs and tissues:
http://www.nature.co...ll/nrm3352.html

 

But something I noticed was how the two pictures might relate to each other. I put them together and noticed that PCG-1a appears in two places in the pathway, it appears above TERT at the top modulating TERT and appears again after dysfunctional telomeres and increased P53 which increases to inhibit it leading to cell decline etc... I might be off base here but am I looking at a feedback loop that increasingly reduces available PCG-1a with each "cycle" leading increasingly  to a dysfunctional system with each pass and ever decreasing reserves of available PCG-1a further reducing TERT and increasing telomere loss?

 

I also note that this paper links ROS and NF-KB with the former leading to the later. PCG-1a helps to mitigate ROS so clearly this is all interlinked. Could PCG-1a be an intervention point to halt all manner of issues by reducing ROS (and thus NF-KB), telomere loss (genomic stability), reduced DNA damage and mitochondrial protection?

http://www.ncbi.nlm....les/PMC3922784/

"In contrast, numerous reports have implicated ROS in the activation of NF-κB . Both DNA binding and transactivation by NF-κB have been shown to be strongly activated by H2O2. Mechanistically, evidence suggests that ROS are both cause and consequence of NF-κB pathway activation during senescence, making it challenging to establish which process occurs first. Further work is needed in order to understand the kinetics of activation of these pathways during senescence."

 

In addition to its previously documented role as a tumour suppressive mechanism, recent evidence strongly implicates cellular senescence in ageing and age-related diseases. Both telomeric and non-telomeric DNA damage has been shown to contribute to the phenotype, with ROS playing an important role in both the induction and stabilisation of senescence. Moreover, the activation of the DDR, and the MAPK and NF-κB pathways has been shown to contribute to the regulation of both ROS and the SASP. Despite accumulating evidence suggesting that ROS and the SASP cooperate to induce and stabilise the senescent phenotype, further research is necessary to mechanistically delineate their interactions in regulating their response, and their contributions to modulating the surrounding tissue micro-environment.

 

[alc]

Seems like telomeres/telomerase is just a part of the story, but quite an important one. I believe we have to look more in detail here, as there are very good things coming out of this path. Most likely will not be the total rejuvenation, but even we get couple things will be very good.

 

One thing that says a lot is that CNIO, lead by Maria Blasco, has an entire department dedicated to studying  telomeres ... and I do not think they just want to burn the budget on a dead end without seeing the potential.

 

https://www.cnio.es/...?grupo=50004259

 

just look at their publications and see how many things appear there

 

https://www.cnio.es/...ones.asp?pag=38

 

Also another very important thing that we found out from the article in Technology Review, is that now George Church believes that telomerase is a way to go.

 

And we know at what level is George Church and his team!

 

"Church, the Harvard professor, says he thinks targeted DNA changes could in fact extend the normal human life span, which has a maximum length of about 120 years. Earlier this month, at a meeting of the National Academy of Sciences organized to weigh policy on genetic interventions, Church proposed telomerase as one bearing serious consideration. “I think we are very close. I think the world is close, so long as we don’t have a setback,” he says. “The extension of life span is quite dramatic in model organisms … it would be amazing in humans.”"

 

http://www.technolog...f-gene-therapy/

 

I have doubts that George Church is speaking without having any serious prior work/tests done to support the telomerase argument.

 

So, all in all. I'm sure we'll be seeing soon nice and promising developments in this area.

 

 

[ceridwen]

I don't think anyone I know could afford TA-65. Is there any chance that it could be made cheaper? Or is anti aging just for the rich after all?

[Logic]

My own research points decaffeinated green coffee bean extract being a telomerase activator:

 

"...telomerase-deficient mice have marked metabolic abnormalities owing to downregulated expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and beta (PGC-1α and PGC-1β)..."

 

"...there seems to be a bidirectional interaction between TERT and Wnt–β-catenin signaling. For example, in mouse embryonic stem cells and Wnt reporter mice, TERT can act as a transcriptional activator of Wnt signaling by complexing with β-catenin (Park et al., 2009). In embryonic stem cells, TERT expression is significantly decreased in the absence of β-catenin, and overexpression of β-catenin increases TERT expression and lengthens telomeres..."
 

"...Western blot analysis indicated that β-catenin levels were significantly elevated by green coffee bean extract supplementation..."

 

"...The decaffeinated green coffee bean extract utilized for this study was provided by Naturex Inc. (Avignon, France) under the trade name Svetol. Svetol was obtained by extracting decaffeinated raw green coffee (Coffea canephora robusta) beans with 30% ethanol at 70°C for 2 h..."

 

Links can be found in my original post here:

http://www.longecity...ndpost&p=667827

[Logic]

1,500 genes that are connected to how we age

http://www.longecity...-to-how-we-age/

 

[Steve H]

@ Logic 

 

"...there seems to be a bidirectional interaction between TERT and Wnt–β-catenin signaling. For example, in mouse embryonic stem cells and Wnt reporter mice, TERT can act as a transcriptional activator of Wnt signaling by complexing with β-catenin (Park et al., 2009). In embryonic stem cells, TERT expression is significantly decreased in the absence of β-catenin, and overexpression of β-catenin increases TERT expression and lengthens telomeres..."

 

Yes and people ignore the WNT pathway when they talk about telomeres despite a number of papers clearly showing the interaction. Telomerase is far more than just lengthening telomeres it has a host of functions including WNT interaction, stem cell mobilization, Mitochondrial function and so on. All this information is available, it is proven by peer review and yet people only focus on telomeres which whilst important in maintaining a stable genome are not the full telomerase story.

[HighDesertWizard]

 

Telomerase obviously plays a key role in rate of many aspects of ageing the evidence is everywhere. NF-KB and telomerase is related strongly and another possibly important mechanism I have noticed below:

I recently read this new paper that shows how ALA induced up-regulation of PCG-1a modulates telomerase:

 

http://www.cell.com/...(15)00825-6.pdf

 

This carried a host of benefits and was tested on a range of phenotypes which is good and builds on previous papers by the same group. In short:

1: PGC-1a disruption promotes vascular aging and
atherosclerosis
2: PGC-1a modulates telomere function and length as well as
DNA damage
3: High-fat diet reduces PGC-1a-TERT signaling to drive
vascular aging and arteriopathy
4: Enabling PGC-1a-modulated TERT and ARE/ERE signaling
obviates age-related pathology

 

<< SNIP >>

 

About NF-kB Inhibition and Telomerase Expression...

 

We've discussed this point before upthread... To my knowledge...

• there is no Telomerase Expression activator that isn't also an NF-kB Activation  Inhibitor...
• Meanwhile, there are many NF-kB Inhibitors that have also been shown to be Telomerase Expression Inhibitors...

Referencing Epel/Blackburn, Fredrickson/Cole, and Kevin Tracey up thread, I've made the argument that aging is a lot about a "Leak of Vagal Tone," especially because of Uremic Toxins, resulting in increased NF-kB Activation, Reduced Telomere length... (I highlight Tracey's name above because the best way to understand the link between Vagal Tone and HRV and the link to NF-kB Activation and Telomerase Expression Activation is to understand the 3 links I've provided up thread to Tracey...

 

Referencing Steve H's embedded quote above and the Vagal Tone concept... here's some relevant evidence...

 

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

The p65 subunit of NF-kappaB binds to PGC-1alpha, linking inflammation and metabolic disturbances in cardiac cells

 

From the study abstract... "Our data show that the increased physical interaction between p65 and PGC-1alpha after NF-kappaB activation is responsible for the reduction in PGC-1alpha expression and subsequent dysregulation of glucose oxidation."

 

ALA is a kind of Omega 3 fatty acid... Lots of links available about that...

 

Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective

 

Abstract

INTRODUCTION:

Fish oil-based nutrition is protective in severe critical care conditions. Regulation of the activity of transcription factor NF-kappaB is an important therapeutic effect of the major omega-3 fatty acids in fish oil, eicosapentaenoic and docosahexaenoic acid (EPA and DHA).

METHODS AND RESULTS:

Using the articles obtained by a Pubmed research, this article reviews three aspects of NF-kappaB/inflammatory inhibition by fish oil. (1) Inhibition of the NF-kappaB pathway at several subsequent steps: extracellular, free omega-3 inhibits the activation of the Toll-like receptor 4 by endotoxin and free saturated fatty acids. In addition, EPA/DHA blocks the signaling cascade between Toll-like/cytokine receptors and the activator of NF-kappaB, IKK. Oxidized omega-3 also interferes with the initiation of transcription by NF-kappaB. (2) The altered profile of lipid mediators generated during inflammation, with production of the newly identified, DHA-derived inflammation-resolving mediator classes (in addition to the formation of less pro-inflammatory eicosanoids from EPA). Resolvin D1 and Protectin D1 are potent, endogenous, DHA-derived lipid mediators that attenuate neutrophil migration and tissue injury in peritonitis and ischemia-reperfusion injury. Their production is increased in the later stages of an inflammatory response, at which time they enhance the removal of neutrophils. (3) Modulation of vagal tone with potential anti-inflammatory effects: vagal fibers innervating the viscera down-regulate inflammation by activating nicotinic receptors upon infiltrating and resident macrophages. Stimulation of the efferent vagus is therapeutic in experimental septic shock. Fish oil supplementation increases vagal tone following myocardial infarction and in experimental human endotoxinemia.

CONCLUSION:

It remains to be shown whether these pleiotropic actions of EPA/DHA contribute to fish oil's therapeutic effect in sepsis.

 

:-)

Edited by HighDesertWizard, 25 October 2015 - 09:16 PM.

[Logic]

"...the long telomere ends of the DNA strand curl round and affect genes closer to the centre of the strand in a epigenetic way.
So its not simply a case of trying to keep the critically short telomeres from causing 'glitches in the program'..."

http://www.longecity...ndpost&p=721913

 

"...Under increased oxidative stress telomerase is excluded from the nucleus and can be found within the mitochondria..."
 

"...While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. This is because TERT is reversibly excluded from the nucleus under stress in a dose- and time-dependent manner..."
...Extranuclear telomerase colocalises with mitochondria. In TERT-overexpressing cells, [mitochondrial DNA] is protected, mitochondrial membrane potential is increased and mitochondrial superoxide production and cell peroxide levels are decreased, all indicating improved mitochondrial function and diminished retrograde response. We propose protection of mitochondria under mild stress as a novel function of TERT.
..."
 

The Emerging Role of Telomerase Reverse Transcriptase in Mitochondrial DNA Metabolism
 

A new study provides insight into aging and age-related diseases by linking telomere dysfunction to a decline in mitochondrial number and function.

 

http://www.longecity...s-home/page-104

[Santi]

HighDesertWizard, 

 

Great information. As there are a multitude of things that lower NF-κB, there seems to be many with side effects such as increased blood pressure or that are not very selective and affect other pathways as well. As you are extremely knowledgeable about NF-κB I would like to know what supplement or medicine do you believe is the best to take to lower their NF-κB? 

[Rocket]

HighDesertWizard, 

 

Great information. As there are a multitude of things that lower NF-κB, there seems to be many with side effects such as increased blood pressure or that are not very selective and affect other pathways as well. As you are extremely knowledgeable about NF-κB I would like to know what supplement or medicine do you believe is the best to take to lower their NF-κB? 

 

Apparently triptorelin is a potent GNRH that is available.  In the study, some mice were injected into the hypothalamus and it caused neurogenesis to occur.  Other mice were injected (I'm assuming subq) and it reversed the "signs" of aging. 

 

The problem is (and some people won't mind!) is that doses of around 1mg triptorelin causes the testicles to stop producing testosterone. 

[ceridwen]

Yes it won't bother women at all

[Logic]

TGF-β1 is increased by Advanced Glycation End Products. (AGEs)

 

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

 

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

 

Also note that most all AGE blockers and breakers are chelators..!

[Logic]

 

<< 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.

 

 

Feeding Rats Activated Charcoal Gives 43% Greater Longevity

http://www.longecity...ater-longevity/

[Steve H]

And as I have discussed with people before, TGF-b inhibits telomerase via TERT and c-MYC pathways so once TGF-b builds up it becomes a pro-aging factor instead of a pro-youthful factor. The more TGF-b that builds up the more and more dysfunctional the stem cells become and the more tissue repair and regeneration fails. 

 

http://www.ncbi.nlm....pubmed/16785237

 

So Advanced Glycation End Products.increase TGF-b - Rising TGF-b reduces telomerase production in stem cells leading to increase quiescence and reduction of repair and maintainance - lack of maintainance leads to dysfunctional telomeres and increased P53 which links directly and indirectly to mitochondrial function and ultimately its failure. Dephino shows this P53 "aging axis" in a number of papers demonstrating that stem cells, telomeres and mitochondria are closely linked. 

[Steve H]

This new review from the Conboys is very interesting, the concluding remarks are of the most interest to me, it suggests a "trinity" using TGF-b blockading, Senesecent cell removal and mTOR inhibiting should provide robust rejuvenation. 

http://www.impactagi...ull/100819.html

I would like to put this trinity to the test as it also shows what SENS gets for free when they can remove AGE. If AGE increases TGF-b removing AGE is most certainly a very viable SENS strategy and probably why they fund the Conboys so they can see the effects of AGE removal whilst they develop something to actually remove it.

Edited by Steve H, 08 November 2015 - 12:25 PM.

[HighDesertWizard]

 

 

<< SNIP >>
 
Also of interest is TGF-beta 1...

<< SNIP >>

 
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.

 

 
Feeding Rats Activated Charcoal Gives 43% Greater Longevity
http://www.longecity...ater-longevity/

 

 
We, Longevity Science Enthusiasts, have imagined that increased Oxidative Stress during aging is due to a set of more or less amorphous factors that we can take anti-oxidants for, but can't specifically target. And it turns out, that's not entirely true...
 
The science is clear--reference links provided up thread--that, to some significant degree, the Uremic Toxins, including Indoxyl Sulfate and p-Cresyl Sulfate, are implicated in what I still like to call a Leak of Vagal Tone. I like that phrase for several reasons.
 
Soon after I learned and posted up thread about Uremic Toxins, I began to take Activated Charcoal. It's cheap. But I have no idea about optimal dose timing and size. I don't have the time to create it myself, but I'd take an active interest in a forum thread devoted to discussing its practical use.
 
Another piece of evidence supporting the use of Activated Charcoal is in a Patent Application entitled The use of charcoal for treating inflammatory conditions. I found it in google searches of the phrase "indoxyl sulfate activated charcoal." There are several survival curves shown in the patent, including one for Sepsis survival. There are also references to levels of TNF and HMGB1. Take a look at the survival curves of Figure 16 shown below. Don't they look remarkably like the Survival Curves for Wild-Type Humans shown in this thread's opening post? Only after noticing the references to Sepsis, TNF, HMGB1, and seeing the Survival Curves did I bother to check out the list of people on the Patent... 
 
Yes. Sure enough... Kevin J. Tracey, Tip of the Spear Scientist of our Innate Mechanism for Inhibiting NF-kB via the Cholinergic Anti-Inflammatory Pathway via Vagus Nerve Stimulation, including our Innate Autonomic Nervous System Dashboard, HRV... Yep... Kevin Tracey is on the patent application that shows Activated Charcoal to reduce HMGB1 and TNF and increase survival in 
 
So here are the Survival Curves that got my attention and triggered my decision to start taking Activated Charcoal...
 
1 - Figure 16 of the charcoal patent application referenced above. Notice Survival Curves in (b) and ©.

2 - Comparable Survival Curves from one of Tracey's key study summaries that I've posted before where the independent variable is Cholinergic Anti-Inflammatory Pathway activation @ The Spleen via the Vagus Nerve... (And remember, the CAIP has a general measure, HRV)...

 

And what, specifically, does the CAIP do? Multiple studies have conclusively shown that it Inhibits NF-kB Activation, in the literature, aka, "Translocation to the Nucleus"...

 

3 - This thread's opening graphic figure, showing Survival Curves in Wild-Type Humans, is worth showing again to highlight why Activated Charcoal seems like a good idea to me -->> it appears to have a comparable effect that Vagus Nerve Stimulation and Higher HRV has NF-kB Inhibition and increased survival odds...

 

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 November 2015 - 09:43 PM.