1033 replies to this topic

[QuestforLife]

So Turbuckle fission part of protocol can also be usueful to make cells replicate without loosing to much telomere lenght..?!? maybe just adding something cheap and simple as Gotu Kola can add the benefit of division without TELOMERE ATTRITION (or with little). I also personally add to this "fission" part Fisetin, Resveratrol and 2 mg of Copper. Copper + Resveratrol to clean out bad DNA around, Fisetin as senolythic. Cell division boost should help the immunitary system to get rid of bad DNA, bad cells. Its a lot oxidizing. But I do this once a week max. The rest of the week I stay into fission (eat chocolate, take glycerol mono stearate, take antioxidants and such) + take pravastatin and small quantity of telmisartan.... COPPER important as it makes cells differentiate. So replication of both cells and mithocondria and differentiation occur during "fission" (also importanto to eat well in this time). Stem cells indifferentiation increase during "fusion"... and here can be done some fasting.

 

Role of Copper on Mitochondrial Function and Metabolism - PMC (nih.gov)

 

Most likely the nicotinamide or niacin that is part of TB's fission protocol would have the effect of reducing telomere loss, based on the papers I have read. It might be that adding a telomerase activator would synergise with that, but that is not something I have tried yet. I do have some very good results with my current protocol, which I will share in due course. Telomerase activators should not be used during the fusion part of TB's protocol - if your aim is reducing epigenetic age - as has been discussed many times before.

to help differentiation and to help eliminating bad mitocondria -perhaps- also vitamin A useful once a week... but this have not done yet. Copper + Vitamin A + Reveratrol + Fisetin ... with lots of nicotinammide :D---- maybe too much

 

Vitamin A supplementation increased mitochondrial superoxide anion radical () production (Table 3) and induced lipid peroxidation, protein carbonylation and nitration, and oxidation of protein thiol groups in mitochondrial membranes isolated from rat cerebral cortex, cerebellum, substantia nigra, striatum, frontal cortex, and hypothalamus [67–69, 76, 78]. 

 

Vitamin A and Retinoids as Mitochondrial Toxicants (hindawi.com)

 

When I was first experimenting with reducing epigenetic age with AKG, I did try adding Vitamin A, but it had no additional benefit, alteast for me.

[QuestforLife]

I read that iron is antagonistic to copper, and when iron gets high, copper can go low; and copper deficiency is known to result in gray or white hair. Copper important for cell differentiation. So IP6 and EDTA to load off iron, and maybe some Copper supplement -some time- seems a good idea.

 

Iron overload can induce mild copper deficiency - PubMed (nih.gov)

 

That is a useful suggestion, and might in part explain the benefits of blood donation (for example). But it assumes, of course, that you need to actually absorb copper. In the case of mixing it with resveratrol to make ROS for the purposes of destroying cell free chromatin/DNA, this could be accomplished in the mouth and stomach, with only the ROS making it through into the blood.

 

But there are also benefits from copper in and of themselves, as you point out. 

 

In my case, I have no grey hair, and a small amount of grey in my beard/stubble. It has been advancing very slowly for the last 3 or 4 years. It would be great to reverse that entirely. 

Edited by QuestforLife, 02 November 2023 - 12:41 PM.

[HBRU]

Most likely the nicotinamide or niacin that is part of TB's fission protocol would have the effect of reducing telomere loss, based on the papers I have read. It might be that adding a telomerase activator would synergise with that, but that is not something I have tried yet. I do have some very good results with my current protocol, which I will share in due course. Telomerase activators should not be used during the fusion part of TB's protocol - if your aim is reducing epigenetic age - as has been discussed many times before.

 

When I was first experimenting with reducing epigenetic age with AKG, I did try adding Vitamin A, but it had no additional benefit, alteast for me.

 

Overdosing Vitamin A looks really dangerous... having good levels of Copper as aid for differentiation (and also reducing Iron as that is the worst Copper competitor) and also keep blood free of DNA errantic pieces seems a better approach. Then dont know what other pro-differentiation supplements/drugs are available ? Can you suggest ?

 

As you and other stated keeping cells well differentiate seems the way to go, and at the same time keep available good stem cell pool (with long telomere)....

 

So I would say that the frame of Turbuckle protocol is good, must just be improved with fisetin, resveratrol + copper + gotu kola in the fission/differentiation part... and a low dose statin + sartan into the fusion/stem cell expansion part (and also again Gotu Kola). I think low dose statin + sartan is safer than c60... dont know if someone combined ROCK inhibitors and C60.

 

Thank you for you precious work QuestForLife...

Edited by HBRU, 02 November 2023 - 01:07 PM.

[HBRU]

In the view of egoist cells....

 

As hair ages, sheds and then repeatedly grows back, increasing numbers of the melanocyte stem cells become sluggish at their job. The stem cells stop roaming around the follicle and become fixed, thereby failing to mature into fully-fledged melanocytes. With no pigment being produced, the hair turns grey, white or silver.

 

Cause of grey hair may be 'stuck' cells, say scientists - BBC News

 

So problem is not just depleting stem cells as Turbuckle view, but depleting good stem cells that are those not sluggish at their job. The older stem cells stop roaming around the follicle and become fixed, thereby failing to mature into fully-fledged melanocyte....

 

What makes older stem cells sluggish ?!?? Shorter telomere ? Programming... ?!? High Iron and low Copper ?!????

 

Rock inhibitors have this potential of cells structure resetting that makes them interesting.

Edited by HBRU, 02 November 2023 - 01:30 PM.

[HBRU]

Acitretin a powerful synthetic vitamin A analougue caused hair repigmentation....

 

Repigmentation and curling of hair after acitretin therapy - PubMed (nih.gov)

 

 

Edited by HBRU, 02 November 2023 - 01:22 PM.

[HBRU]

Vitamin C

Although vitamin C supplements have produced copper deficiency in guinea pigs (7), animals requiring dietary vitamin C, the effect of vitamin C supplements on copper nutritional status in humans is less clear. Two small studies in healthy young adult men indicate that the oxidase activity of ceruloplasmin may be impaired by relatively high doses of supplemental vitamin C. In one study, vitamin C supplementation of 1,500 mg/day for two months resulted in a significant decline in ceruloplasmin oxidase activity (8). In the other study, supplements of 605 mg of vitamin C/day for three weeks resulted in decreased ceruloplasmin oxidase activity, although copper absorption did not decline (9). Neither of these studies found vitamin C supplementation to adversely affect copper nutritional status.

 

http://lpi.oregonsta...pper/index.html

 

Copper and vitamin C. Copper and vitamin C are direct antagonists. This means that they oppose each other in the body. This is one reason many people feel better taking a lot of vitamin C. Copper tends to oxidize and destroy vitamin C in the body. Meanwhile, vitamin C chelates or removes copper from the body. This requires a dose of vitamin C of at least about 500 mg daily, far higher than the minimum daily requirement of about 60 mg. Many readers know that vitamin C is critical for connective tissues. One of the prominent symptoms of scurvy, or vitamin C deficiency, is bleeding, such as bleeding gums. This is due to connective tissue weakness.

Thus, a copper excess can easily lead to a deficiency of vitamin C in the body and with it many symptoms of vitamin C deficiency. Oddly, however, a copper deficiency also causes connective tissue problems, especially in the heart and cardiovascular system where it is associated with a tendency for aneurisms and atherosclerosis.

 

http://www.drlwilson...ty_syndrome.htm

[HBRU]

seems I have understated the importance of copper, that is something that "keeps clean"

 

 

 

Copper inhibits beta-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion.
Borchardt T, Camakaris J, Cappai R, Masters CL, Beyreuther K, Multhaup G.

ZMBH-Center for Molecular Biology Heidelberg, University of Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany.


Abstract
Previous studies have demonstrated that amyloid precursor protein (APP) can bind and reduce Cu(II) to Cu(I), leading to oxidative modification of APP. In the present study we show that adding copper to Chinese-hamster ovary (CHO) cells greatly reduced the levels of amyloid Abeta peptide (Abeta) both in parental CHO-K1 and in copper-resistant CHO-CUR3 cells, which have lower intracellular copper levels. Copper also caused an increase in the secretion of the APP ectodomain, indicating that the large decrease in Abeta release was not due to a general inhibition in protein secretion. There was an increase in intracellular full-length APP levels which paralleled the decrease in Abeta generation, suggesting the existence of two distinct regulating mechanisms, one acting on Abeta production and the other on APP synthesis. Maximal inhibition of Abeta production and stimulation of APP secretion was achieved in CHO-K1 cells at about 10 microM copper and in CHO-CUR3 cells at about 50 microM copper. This dose 'window of opportunity' at which copper promoted the non-amyloidogenic pathway of APP was confirmed by an increase in the non-amyloidogenic p3 fragment produced by alpha-secretase cleavage. Our findings suggest that copper or copper agonists might be useful tools to discover novel targets for anti-Alzheimer drugs and may prove beneficial for the prevention of Alzheimer's disease.

PMID: 10567229 [PubMed - indexed for MEDLINE]

 

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

 

J Alzheimers Dis. 2005 Nov;8(2):201-6; discussion 209-15.

Involvement of amyloid beta precursor protein (AbetaPP) modulated copper homeostasis in Alzheimer's disease.
Bayer TA, Multhaup G.

Universität des Saarlandes, Klinik für Psychiatrie, Abteilung für Neurobiologie, D-66421 Homburg, Germany. thomas.bayer@uniklinik-saarland.de


Abstract
AbetaPP is involved in Cu homeostasis in mouse and man. In vitro observations and in vivo data obtained from AbetaPP mouse models at least provide strong evidence that AbetaPP and Abeta overproduction enables intracellular Cu to be transported out of the cell. The increased Cu efflux seems to lead to a Cu deficiency and a subsequently reduced SOD-1 activity. Studies have shown that a disturbed metal-ion homeostasis with elevated serum Cu levels occurs in Alzheimer and Down's patients and lowered levels in post-mortem AD brain. We conclude that bioavailable Cu has beneficial and specific effects in Alzheimer's disease transgenic mice, and suggest that our observation can be regarded as a proof-of-concept for a prophylactic approach to overcome the observed CNS Cu deficiency in the brain of Alzheimer's disease patients.

PMID: 16308488 [PubMed - indexed for MEDLINE]

[QuestforLife]

 

Rock inhibitors have this potential of cells structure resetting that makes them interesting.

 

Rock inhibitors do seem to reduce epigenetic age; I used the statin+sartan combination for this in the past, see: https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-3#entry873678

 

It is complicated as to how they do this. They seem to de-differentiate cells by reducing the cytoskeleton scaffolding within cells. So, if you have a lot of 'stuck' cells, ROCK inhibitors can restore the normal process of alternate differentiation and proliferation. It is important to note that it is not just a case of increasing the symmetric division of stem cells, as it has been shown in the past that the selection for 'selfish' stem cells that are more likely to divide symmetrically, eventually leads to the thinning of skin, due to lack of differentiation and a ROCK inhibitor can fix this, see: https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-4#entry879560

[QuestforLife]

Acitretin a powerful synthetic vitamin A analougue caused hair repigmentation....

 

Repigmentation and curling of hair after acitretin therapy - PubMed (nih.gov)

 

mechanism of action seems to be normalisation of differentiation, for which it is used as for psoriasis, which fits with what we've been saying. It sounds similar to retinoids and therefore linked to Vit A. 

[HBRU]

But important to increase copper just once in a while (I say once in a week, toghether with 500 mg Reveratrol another nasty but usefull supplement)....

 

Copper/zinc ratio and systemic oxidant load: effect of aging and aging-related degenerative diseases

A Mezzetti 1, S D Pierdomenico, F Costantini, F Romano, D De Cesare, F Cuccurullo, T Imbastaro, G Riario-Sforza, F Di Giacomo, G Zuliani, R Fellin

Affiliations expand

• PMID: 9801067
•  
• DOI: 10.1016/s0891-5849(98)00109-9

Abstract

There is evidence that copper and zinc have pro-oxidant and antioxidant properties, respectively, so that their imbalance may be expected to condition oxidative stress status. Oxidative stress is relevant in aging and in age-related degenerative diseases. In this study, blood content of copper, zinc, and ceruloplasmin as well as of lipid peroxides were investigated in 81 healthy and 62 disabled octo-nonagenarians affected by chronic degenerative diseases, and in 81 healthy adults. Serum copper/zinc ratio and ceruloplasmin were significantly higher in the elderly than in the healthy adults. Moreover, all these parameters were significantly higher in the disabled than in the healthy elderly. Notably, the increased copper/zinc ratio found in healthy elderly was due to high copper values, whereas in the disabled, both high copper and low serum zinc concentrations were present. The copper/zinc ratio was significantly and positively related to systemic oxidative stress status in all groups. The higher the serum copper/zinc ratio the higher the lipid peroxides plasma content. We conclude that there is a strict relationship between copper/zinc ratio and systemic oxidant burden. Moreover, advanced age and, particularly, advanced age-related chronic degenerative diseases are associated with a significant increase in the copper/zinc ratio and systemic oxidative stress.

 

[HBRU]

Rock inhibitors do seem to reduce epigenetic age; I used the statin+sartan combination for this in the past, see: https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-3#entry873678

 

It is complicated as to how they do this. They seem to de-differentiate cells by reducing the cytoskeleton scaffolding within cells. So, if you have a lot of 'stuck' cells, ROCK inhibitors can restore the normal process of alternate differentiation and proliferation. It is important to note that it is not just a case of increasing the symmetric division of stem cells, as it has been shown in the past that the selection for 'selfish' stem cells that are more likely to divide symmetrically, eventually leads to the thinning of skin, due to lack of differentiation and a ROCK inhibitor can fix this, see: https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-4#entry879560

 

 yeah, increasing selfish cells number (stem or differentiated) is something we really dont want

[HBRU]

ROCK inhibitor may be good for this inflammatory vascular disease.... as resetting the epigenetic expression of cytoskeleton-related genes... 

 

A recent genome-wide DNA methylation study uncovered an important role for epigenetic remodeling of cytoskeleton-related genes in the pathogenesis of Behçet's disease and suggested that reversal of some of these DNA methylation changes associates with disease remission.

 

Epigenetics and Vasculitis: a Comprehensive Review - PubMed (nih.gov)

 

Dysregulation in the Rho/ROCK pathway may represent a common pathogenic mechanism in multiple autoimmune disorders. Current evidence indicate that Rho/ROCK genes might be risk factors, and can contribute to susceptibility and development of systemic sclerosis and Behçet's disease. These studies may also provide important insights into the future development or use of potential novel therapeutic approaches, such as selective Rho-kinase inhibitors, for the treatment of patients with systemic sclerosis and Behçet's disease.

 

Contribution of the Rho-kinase to Systemic Sclerosis and Behçet's Disease - PubMed (nih.gov)

 

Edited by HBRU, 02 November 2023 - 03:50 PM.

[HBRU]

Resetting skin cytoskeleton seems reducing it's antigen stimulating effect on immunitary system ?

 

This meta-analysis showed that oral statins may decrease the severity of psoriatic lesions after just eight weeks. Both of the studies with simvastatin reported a reduction in the severity of psoriasis [11, 27], but two studies that compared atorvastatin with placebo did not show any effect [14, 26]. In one study, the addition of atorvastatin to standard therapy improved the severity of psoriasis [12]. In subgroup analyses, a significant decrease in PASI values was observed for simvastatin only.

 

The effect of statins on psoriasis severity: a meta-analysis of randomized clinical trials - PMC (nih.gov)

[HBRU]

Importantly, Murasawa et al25 have observed recently that overexpression of human telomerase reverse transcriptase in early EPCs increased their migratory activity and postnatal neovascularization capacity, suggesting that senescence and telomerase activity are important factors regulating EPC function. In the present study, we have characterized EPC senescence in prehypertensive and hypertensive patients and its relation to EPC endothelial repair capacity. Notably, both measurements of telomere length and SA-β-Gal staining indicated an increased senescence of early EPCs from prehypertensive and hypertensive subjects that was related to an impaired in vivo endothelial repair capacity of early EPCs.

 

so more telomerase, more mobility and less stiffness of THE SAME EPCs cells (Endothelial progenitor stem cell)...

 

Impaired Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Prehypertension | Hypertension (ahajournals.org)

[HBRU]

Cu required as differentiation and growth factor.... as said above Iron overload & Vitamin C antagonize Cu

Cu important for growing up massive livestock

 

Rabbits require Cu to prevent anemia and dermatosis and to maintain the integrity of bone and the cardiovascular system (Omole 1980). To meet rabbits’ needs, a dietary Cu level of 5 ppm in the dry feed is recommended by NRC (1977). Thus, Cu deficiency is rare in rabbits fed balanced diets but could happen under certain conditions. For example, Omole (1980) reviewed the interrelationships between copper deficiency and other feed constituents such as ascorbic acid, fiber, and minerals.

Copper also as an alternative to antibiotic growth promoter

Cu has potential antimicrobial and growth-promoting properties that make it a promising alternative to antibiotic growth promoter (AGP). For example, Arias and Koutsos (2006) reported that chicks given supplemental dietary Cu of 188 mg/kg from TBCC or CuSO4 had a similar or more consistent growth and performance as chicks given antibiotic growth promoters. Also, Pesti and Bakalli (1996), Banks et al. (2004a), and Banks et al. (2004b) reported that different Cu sources could be used as growth promoters, but with different efficacy, e.g., cupric citrate is more efficient for growth promotion at lower Cu levels than cupric sulfate pentahydrate, resulting in reduced litter copper (Pesti and Bakalli 1996). As with chickens, Wu et al. (2013) reported that ducks given supplemental dietary 150 Cu mg/kg feed from TBCC or CuSO4, as an alternative to antibiotics, had a similar body weight, body weight gain, feed intake, and mortality rate as ducks given AGP.

 

 

Copper: benefits and risks for poultry, livestock, and fish production | Tropical Animal Health and Production (springer.com)

 

Iron -on the contrary- can increase bacterial replication

Iron overload favours certain infections, including tuberculosis in humans as well as in animal models. Iron overload supports the growth of mycobacteria and accelerates the development of tuberculosis in humans and mice. Iron is also a modulator of both innate as well as acquired immunity.

:text=Iron%20overload%20favours%20certain%20infections%2C%20including%20tuberculosis%20in,of%20both%20innate%20as%20well%20as%20acquired%20immunity.' class='bbc_url' title='External link' rel='nofollow external'>Iron and microbial infection | Nature Reviews Microbiology

So important reduce IRON/COPPER ratio

 

Cu required as differentiation and growth factor.... as said above Iron overload & Vitamin C antagonize Cu

Cu important for growing up massive livestock

 

Rabbits require Cu to prevent anemia and dermatosis and to maintain the integrity of bone and the cardiovascular system (Omole 1980). To meet rabbits’ needs, a dietary Cu level of 5 ppm in the dry feed is recommended by NRC (1977). Thus, Cu deficiency is rare in rabbits fed balanced diets but could happen under certain conditions. For example, Omole (1980) reviewed the interrelationships between copper deficiency and other feed constituents such as ascorbic acid, fiber, and minerals.

Copper also as an alternative to antibiotic growth promoter

Cu has potential antimicrobial and growth-promoting properties that make it a promising alternative to antibiotic growth promoter (AGP). For example, Arias and Koutsos (2006) reported that chicks given supplemental dietary Cu of 188 mg/kg from TBCC or CuSO4 had a similar or more consistent growth and performance as chicks given antibiotic growth promoters. Also, Pesti and Bakalli (1996), Banks et al. (2004a), and Banks et al. (2004b) reported that different Cu sources could be used as growth promoters, but with different efficacy, e.g., cupric citrate is more efficient for growth promotion at lower Cu levels than cupric sulfate pentahydrate, resulting in reduced litter copper (Pesti and Bakalli 1996). As with chickens, Wu et al. (2013) reported that ducks given supplemental dietary 150 Cu mg/kg feed from TBCC or CuSO4, as an alternative to antibiotics, had a similar body weight, body weight gain, feed intake, and mortality rate as ducks given AGP.

 

 

Copper: benefits and risks for poultry, livestock, and fish production | Tropical Animal Health and Production (springer.com)

 

Iron -on the contrary- can increase bacterial replication

Iron overload favours certain infections, including tuberculosis in humans as well as in animal models. Iron overload supports the growth of mycobacteria and accelerates the development of tuberculosis in humans and mice. Iron is also a modulator of both innate as well as acquired immunity.

:text=Iron%20overload%20favours%20certain%20infections%2C%20including%20tuberculosis%20in,of%20both%20innate%20as%20well%20as%20acquired%20immunity.' class='bbc_url' title='External link' rel='nofollow external'>Iron and microbial infection | Nature Reviews Microbiology

So important reduce IRON/COPPER ratio

 

[HBRU]

High manganese levels bad for reverse transcriptase and so bad for telomerase....

So I think a mild chelating with IP6 and maybe EDTA for Iron and Manganese and supplementation with Copper -just in some "fission" days- is a good idea.

 

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

 

Inhibition of reverse transcription in vivo by elevated manganese ion concentration.Bolton EC, Mildvan AS, Boeke JD.

Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

Mutations in PMR1, a yeast gene encoding a calcium/manganese exporter, dramatically decrease Ty1 retrotransposition. Ty1 cDNA is reduced in pmr1 mutant cells, despite normal levels of Ty1 RNA and proteins. The transposition defect results from Mn(2+) accumulation that inhibits reverse transcription. Cytoplasmic accumulation of Mn(2+) in pmr1 cells may directly affect reverse transcriptase (RT) activity. Trace amounts of Mn(2+) potently inhibit Ty1 RT and HIV-1 RT in vitro when the preferred cation, Mg(2+), is present. Both Mn(2+) and Mg(2+) alone activate Ty1 RT cooperatively with Hill coefficients of 2, providing kinetic evidence for a dual divalent cation requirement at the RT active site. We propose that occupancy of the B site is the major determinant of catalytic activity and that Mn(2+) at this site greatly reduces catalytic activity.

[QuestforLife]

High manganese levels bad for reverse transcriptase and so bad for telomerase....
So I think a mild chelating with IP6 and maybe EDTA for Iron and Manganese and supplementation with Copper -just in some "fission" days- is a good idea.

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

I wouldn't use IP6. it has been shown to shorten telomeres, atleast in yeast, which might be why it is good to take if you have cancer.

https://pubmed.ncbi....h.gov/15665079/

[QuestforLife]

so more telomerase, more mobility and less stiffness of THE SAME EPCs cells (Endothelial progenitor stem cell)...

Impaired Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Prehypertension | Hypertension (ahajournals.org)

Makes sense. Covered something similar before, showing how cardiovascular disease is likely mediated by shortening telomeres in endothelial cells.

Ability of endothelial cells to make new lining is telomere length dependent:

https://www.longecit...-17#entry906088

Edited by QuestforLife, 03 November 2023 - 08:42 AM.

[HBRU]

High manganese levels bad for reverse transcriptase and so bad for telomerase....

So I think a mild chelating with IP6 and maybe EDTA for Iron and Manganese and supplementation with Copper -just in some "fission" days- is a good idea.

 

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

 

Inhibition of reverse transcription in vivo by elevated manganese ion concentration.Bolton EC, Mildvan AS, Boeke JD.

Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

Mutations in PMR1, a yeast gene encoding a calcium/manganese exporter, dramatically decrease Ty1 retrotransposition. Ty1 cDNA is reduced in pmr1 mutant cells, despite normal levels of Ty1 RNA and proteins. The transposition defect results from Mn(2+) accumulation that inhibits reverse transcription. Cytoplasmic accumulation of Mn(2+) in pmr1 cells may directly affect reverse transcriptase (RT) activity. Trace amounts of Mn(2+) potently inhibit Ty1 RT and HIV-1 RT in vitro when the preferred cation, Mg(2+), is present. Both Mn(2+) and Mg(2+) alone activate Ty1 RT cooperatively with Hill coefficients of 2, providing kinetic evidence for a dual divalent cation requirement at the RT active site. We propose that occupancy of the B site is the major determinant of catalytic activity and that Mn(2+) at this site greatly reduces catalytic activity.

 

Well Manganese seems something critical, as it also inactivate RhoA activity.

 

RhoA inactivation is crucial to manganese-induced astrocyte stellation - ScienceDirect

 

Manganese as replacement of statins...

 

Common dietary nutrient blasts blood vessel plaques in study (newatlas.com)

 

Finally Statins & Manganese both increase risk of Parkinson. That's why IMHO is better using Pravastatin as beeing idrofillic substance should not pass the blood brain barrier.

Edited by HBRU, 03 November 2023 - 09:16 AM.

[HBRU]

I wouldn't use IP6. it has been shown to shorten telomeres, atleast in yeast, which might be why it is good to take if you have cancer.

https://pubmed.ncbi....h.gov/15665079/

 

thank you, interesting...

Edited by HBRU, 03 November 2023 - 09:31 AM.

[HBRU]

this also really interesting....

 

Stimulatory effect of boron and manganese salts on keratinocyte migration.
Chebassier N, Ouijja el H, Viegas I, Dreno B.

Laboratoire d'Immuno-dermatologie, CHU Hotel-Dieu, Nantes, France.

Abstract
Keratinocyte proliferation and migration are essential for the reconstruction of the cutaneous barrier after skin injury. Interestingly, thermal waters which are rich in trace elements (e.g. boron and manganese), are known to be able to improve wound healing. In order to understand the mechanism of action of this effect, our study investigated the in vitro modulation of keratinocyte migration and proliferation by boron and manganese salts, which are present in high concentrations in a thermal water (Saint Gervais). Our in vitro study demonstrated that incubating keratinocytes for 24 h with boron salts at concentrations between 0.5 and 10 microg/ml or manganese salts at concentrations between 0.1 and 1.5 microg/ml accelerated wound closure compared with control medium (+20%). As this acceleration was not related to an increase in keratinocyte proliferation we suggest that boron and manganese act on wound healing mainly by increasing the migration of keratinocytes.

[HBRU]

Extreme importance of Manganese

 

the vast majority of kinases are either Mn²⁺- or Mg²⁺-dependent, Mn²⁺ can act as a potent cell signaling modifier. Mn²⁺ can activate ERK, AKT, mTOR, ATM, and JNK in vitro and in vivo [2, 4,5,6,7,8,9,10,11,12,13]. As these kinases regulate transcription factors (CREB, p53, NF-kB, FOXO), Mn²⁺ can also modulate cell function at the transcriptional level [7, 14,15,16]. Consequently, the roles of Mn²⁺ homeostasis and associated signaling in both the essentiality and toxicity of Mn²⁺ are an important area of investigation...............

 

.............................. Evidence supporting a role for insulin/IGF-1 synergistic cross-talk with Mn²⁺ has been slowly amassing, but is incompletely understood. Mn²⁺ deficiency in rodent models reduces insulin production and causes glucose intolerance, while Mn²⁺ supplementation can protect against diet-induced diabetes, rescue glucose intolerance, and increase insulin and IGF-1 ligand levels in rodents [49,50,51,52,53,54,55,56,57,58]. Furthermore, Mn²⁺ administration stimulates insulin-linked glucose transport and related phosphodiesterase activity in adipocytes, though insulin/IGF receptor activity was not investigated [59]. Two prior studies have examined how supra-physiological Mn²⁺ (1–10 mM) activates insulin receptor activity using non-living, permeabilized rat adipocytes or purified biochemical systems and have shown that Mn²⁺ directly increases net autophosphorylation of IR/IGFR by both enhancing kinase activity and inhibiting receptor dephosphorylation [60, 61]......................

 

Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington’s Disease Cells | Molecular Neurobiology (springer.com)

[HBRU]

I read that iron is antagonistic to copper, and when iron gets high, copper can go low; and copper deficiency is known to result in gray or white hair. Copper important for cell differentiation. So IP6 and EDTA to load off iron, and maybe some Copper supplement -some time- seems a good idea.

 

Iron overload can induce mild copper deficiency - PubMed (nih.gov)

 

Copper is antagonist to Hg, Cd, Pb, Selenium, Boron, Silver, Calcium, Molbydenium and finally Fe... as well as vitamin C, B3, curcumin... and many many many others. Incredible. A lot of bad guys among some good ones.

 

Chapter 24: 45 Copper Antagonists (Some are also synergists!) - RevealingFraud.com

 

What helps Copper absorbtion ? Carnosine.

As Copper is essential for DIFFERENTIANTION and aging is essentially A SLOW LOSS OF DIFFERENTIATION it's not difficult to understant that COPPER deficiency play a central role in aging.

 

Also Copper strong bacteriostatic (I think similar to Silver) so having Copper can avoid bacterial infections. 

Edited by HBRU, 03 November 2023 - 11:39 AM.

[HBRU]

Newborn telomere length increased with maternal manganese concentrations. The second trimester was the critical window of maternal manganese concentrations. Telomere length (TL) is a biomarker for biological aging, and the initial setting of TL at birth is a determinant factor of TL in later life.

 

:text=Newborn%20telomere%20length%20increased%20with%20maternal%20manganese%20concentrations.,a%20determinant%20factor%20of%20TL%20in%20later%20life.' class='bbc_url' title='External link' rel='nofollow external'>Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study - ScienceDirect

 

 

Edited by HBRU, 03 November 2023 - 02:12 PM.

[HBRU]

low copper ??? high istamine and so hayfewer. It seems copper is the most underrated supp....

 

7+ copper enzymes that act as antihistamines - RevealingFraud.com

Edited by HBRU, 05 November 2023 - 09:13 PM.

[QuestforLife]

Newborn telomere length increased with maternal manganese concentrations. The second trimester was the critical window of maternal manganese concentrations. Telomere length (TL) is a biomarker for biological aging, and the initial setting of TL at birth is a determinant factor of TL in later life.

 

Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study - ScienceDirect

 

This is very interesting, and not something I'd picked up on before. From what I can tell however, they didn't actually show increase TL in newborns, just a temporary increase in the TL of cord blood during pregnancy. That is not to say there will be no benefit, as I'd expect some downstream benefit in the child down the line. I suspect the TL increase it is purely down to Rho Kinase inhibition in proliferating progenitor cells, as I've seen this before in other contexts. Generally it is a beneficial effect, but not transformative as the effect size is not huge (in terms of HTERT activation). 

Edited by QuestforLife, 06 November 2023 - 03:34 PM.

[HBRU]

just a temporary increase in the TL of cord blood during pregnancy.

 

They just check the TL in the cord blood (at time of birth) and correlate with maternal Manganese blood concentration during pregnancy.

For males babies it is almost 10% longer... 

 

An experimental animals study revealed that the superoxide dismutase activity was higher in mice with longer telomeres (Stauffer et al., 2018). One recent study found that the nanoparticles of multi-enzyme mimic Mn compounds can inhibit oxidative stress and further protect DNA from damage (Singh et al., 2019). All of the above studies meaning that the positive effect of maternal Mn exposure on newborn TL may explain, at least partly by its antioxidant defense. In addition, Bai et al. (2020) also found that Mn exposure was positively correlated with TL in general population which was consistent with our finding.

 

TL was more evident in male infants. TL was vulnerable to oxidative stress. Previous study has suggested that there is a marked gender disparity in antioxidant defense (Stauffer et al., 2018). Compared with males, females have lower levels of oxidative stress markers, more effective glutathione metabolism (defense of glutathione is specifically used to detoxify peroxides) (Lavoie and Tremblay, 2018), and significant higher level of estrogen which can up-regulate the expression of antioxidant genes (Viña et al., 2005, Tarry-Adkins et al., 2006) and promote the activation of telomerase (Kyo et al., 1999, Misiti et al., 2000). These complex anti-oxidative mechanisms in females may mask the effects of the Mn on anti-oxidative.

Edited by HBRU, 07 November 2023 - 02:08 PM.

[QuestforLife]

They just check the TL in the cord blood (at time of birth) and correlate with maternal Manganese blood concentration during pregnancy.

For males babies it is almost 10% longer... 

 

An experimental animals study revealed that the superoxide dismutase activity was higher in mice with longer telomeres (Stauffer et al., 2018). One recent study found that the nanoparticles of multi-enzyme mimic Mn compounds can inhibit oxidative stress and further protect DNA from damage (Singh et al., 2019). All of the above studies meaning that the positive effect of maternal Mn exposure on newborn TL may explain, at least partly by its antioxidant defense. In addition, Bai et al. (2020) also found that Mn exposure was positively correlated with TL in general population which was consistent with our finding.

 

TL was more evident in male infants. TL was vulnerable to oxidative stress. Previous study has suggested that there is a marked gender disparity in antioxidant defense (Stauffer et al., 2018). Compared with males, females have lower levels of oxidative stress markers, more effective glutathione metabolism (defense of glutathione is specifically used to detoxify peroxides) (Lavoie and Tremblay, 2018), and significant higher level of estrogen which can up-regulate the expression of antioxidant genes (Viña et al., 2005, Tarry-Adkins et al., 2006) and promote the activation of telomerase (Kyo et al., 1999, Misiti et al., 2000). These complex anti-oxidative mechanisms in females may mask the effects of the Mn on anti-oxidative.

 

Thanks for clarifying that. the wording of the paper is very unclear. In the methods I see you are right, the TL is measured only on delivery, but Mn conc is taken via urine once in each trimester. But in the results section they state: 'Compared with the lowest tertile, women with the highest tertile of maternal urinary Mn had 9.67% (95% CI: 2.13%, 17.78%) longer cord blood TL during the second trimester,...', which suggests multiple samplings of TL during pregnancy.

 

I will have a deeper read on manganese as soon as I get the chance...

[QuestforLife]

TERT without the TERC?

 

In digging for a mechanism by which Manganese increases telomere length I have uncovered a possible explanation (different to ROCK inhibition as already discussed). 

 

This study [1] discusses the reverse transcriptase action of telomerase, and how in telomerase the active protein consists of two main components, TERT: the catalytic part that adds TTAGGG units to the telomere, and TERC: the template part that attaches to the telomeres and allows TERT to do its work by adding the correct nucleotides.  

 

I have discussed before how both TERT and TERC are needed, albeit with TERT being the limiting factor in human cells, and we have also engaged in (educated) speculation over the benefits of increasing the efficiency of the association of TERT and TERC.

For more information see this post: https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-26#entry915527

 

In the current study (from 2005), they reveal that in some circumstances telomerase can forgo the requirement for the RNA template (TERC) and act directly to extend the telomere. This is termed terminal transferase activity.

Key to this is the effect of metal ions on polymerases (this will require a post in itself), and you guessed it, in the presence of sufficient manganese TERT does not need TERC to add to the telomere. 

 

Getting into the nitty gritty of the paper, they did a series of experiments adding dGTP and dTTP to provide Gs and Ts for the telomere, using different primers and checked how many nucleotides were added in the presence or absence of Manganese (Mn 2+). Manganese decreased the efficiency of telomerase in adding repeats in the presence of both dGTP and dTTP but increased the number of base pairs added when only dGTP or dTTP was present. They explain this by the competition of two different mechanisms, i.e., Mn ions relaxing the requirement to add the correct nucleotide normally ensured by the RNA template. To test this they treated telomerase with an RNAase (to remove the RNA TERC template component of the protein) and then repeated their tests, finding that telomerase activity (i.e. nucleotide adding ability) was abolished in the absence of Mn2+ but only reduced 2-fold when Mn2+ was present. Remarkably, they also found that they could add other nucleotides (i.e. A and C) that are either not supposed to be in the telomere (the C) or shouldn't be in that position (the A), in the absence of the RNA template but when Mn2+ was present. The activity of adding these ‘improper’ nucleotides was actually enhanced in the absence of the RNA template, suggesting that TERC s acting as a quality control mechanism, as hypothesized. 

 

As a side note, I’ve covered in the past that the speed of telomerase adding nucleotides is limited by the addition step of one of the Gs and that this can be overcome with more GTP: https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-15#entry904277

 

It is interesting to speculate whether the presence of Mn2+ could lead to a faster rate of telomere nucleotide addition, because of the relaxation of the requirements to use the proper nucleotides. This could lead to longer telomeres even with the same concentration of telomerase, given that telomerase only has a limited time to do its work during S-phase. Further to this it is interesting to think about whether it would matter if your telomeres did not have the proper nucleotide sequence. A few extra As and Cs to my mind would not matter, as the telomere would still be doing its job of preventing the end of the strand being recognised as broken DNA. But TERT does seem to have a preference for DNA with many Gs, so you wouldn’t want to alter the telomere composition too much. 

 

Does this paper have any practical in vivo consequences? Given the concentrations of Mn2+ used in this study, far above normal physiological levels, I am inclined to say no. But then we’ve just been discussing a paper where mothers with the highest tertile of Mn2+ concentration in their urine  in the second trimester gave birth to babies with 10% longer telomeres [2]! The mechanism we have discussed in this post seems like a plausible explanation for this remarkable effect. Then again, it may be completely irrelevant. One way to find the answer might be to do full nucleotide sequencing on the blood samples they obtained in the pregnancy study and determine if the babies with longer telomeres had more variety in the nucleotide sequence of their telomeres. If they had more divergence from TTAGGG than the shorter telomere’d cohort,  then this would be a slam dunk for this theory. 

 

If and when telomere tests become more widely (and cheaply) available, it might also be worth biohackers like us seeing if the addition of a manganese supplement has any effect on the length of our leukocyte telomeres. 

 

References

 

[1] Lue NF, Bosoy D, Moriarty TJ, Autexier C, Altman B, Leng S. Telomerase can act as a template- and RNA-independent terminal transferase. Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9778-83. doi: 10.1073/pnas.0502252102. Epub 2005 Jun 30. PMID: 15994230; PMCID: PMC1174988.

 

[2] Bi J, Wu M, Liu Y, Song L, Wang L, Liu Q, Chen K, Xiong C, Li Y, Xia W, Xu S, Zhou A, Wang Y. Association between maternal urinary manganese concentrations and newborn telomere length: Results from a birth cohort study. Ecotoxicol Environ Saf. 2021 Apr 15;213:112037. doi: 10.1016/j.ecoenv.2021.112037. Epub 2021 Feb 18. PMID: 33609998.

 

Edited by QuestforLife, 08 November 2023 - 11:37 AM.

[HBRU]

EU new safe levels of copper in food is 0,07 mg/Kg... So for a 70 kg man is around 5mg a day

https://www.efsa.eur...-new-safe-level