1028 replies to this topic

[HBRU]

Manganese puts on senescence cancer cells... so it seems once a week a 25 mg manganese + niacinamide + ribose (fission protocol) + gotu kola + astragalus + pqq can be a good idea for an anti cancer + telomere extension + healthy cell replication protocol... Beeing Mn a bit neurotoxic is good to sleep and be quiet. Not going to mix those with resveratrol, fisetin and copper... As this other combo is good -in another moment- as a light senolytic.

[HBRU]

Here we have this "silly" egoistic cells...

Many downstream factors of the DDR promote cell-cycle arrest in response to damage and appear to protect neurons from apoptotic death. However, neurons surviving with a persistently activated DDR show all the features known from cell senescence; including metabolic dysregulation, mitochondrial dysfunction, and the hyper-production of pro-oxidant, pro-inflammatory and matrix-remodeling factors. These cells, termed senescence-like neurons, can negatively influence the extracellular environment and may promote induction of the same phenotype in surrounding cells, as well as driving aging and age-related diseases. 

 

 The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State? - PubMed (nih.gov)

 

The more I understand about aging the more I am convinced that is a screwed "single cell" pro survival mechanism... 

The matrix-remodeling factors secreted gives exactly the idea of dissolution of the body shape into transformation into something less differentiated... 

 

Edited by HBRU, 09 November 2023 - 01:40 PM.

[HBRU]

Carnosine + Glycine + Lysine + Copper.... with no Vitamin C (as it impairs copper absorption)

 

The paper is in the SOFW Journal

Below is a short version of GHK's anti-cancer actions.
...................

Recently, two compounds out of 1,309 tested, were found to suppress RNA production in 70% of 54 human genes associated with colon cancer metastasis.1 The first compound, GHK (Glycyl-L-Histidyl-L-Lysine), is a human copper-binding, skin-remodeling peptide and Securinine, the second compound is a plant alkaloid. This duo acts to heal wounds, remodel extracellular matrix proteins, and activate macrophages. GHK suppresses cancer metastasis genes at 1x10-6 M and securinine suppresses metastasis at 18x10-6 M.

This tripepeptide has high affinity for copper and is able obtain it from the surrounding biological milieu and also bind with cell receptors and extracellular matrix proteins. These unique properties combined with small size and mobility allows it to regulate copper transport and cell migration. Tripeptide’s copper complex GHK:copper(2+) induces regeneration and repair of aged skin, wounded skin, hair follicles, the stomach and intestinal linings, and bone tissue. The molecule also possesses a broad spectrum of anti-inflammatory activities that suppress inflammatory cytokines while increasing anti-oxidant proteins. 2,3

GHK's regenerative actions begin with its increase of protein P63 which maintains the proliferative capacity of adult stem cells.4 P63 is considered to have anti-senescence properties, foster genomic stability, and increase organismal longevity. The loss of P63 induces cellular senescence, and rapid, premature aging.5-7 Interestingly, research suggests that P63 may suppress cancer.8

Further support for the role of GHK in cancer suppression is based on the small proteoglycan called decorin discovered as a molecule that helps regulate collagen synthesis. GHK-copper(+2) increases the production of decorin.9 Apart of regulating collagen synthesis, decorin also possesses many regenerative and anti-inflammatory actions (regenerating nerves and muscles while suppressing scar formation) that are similar to the actions of GHK.3,4 However, decorin also suppresses tumor growth and metastasis of cancerous tissue (breast, prostate, osteosarcoma) in animal models.10-26

In summary, GHK, at low and non-toxic concentrations, possesses anti-cancer activities and also enhances stem cell proliferation. Thus, normal tissue remodeling and regenerative actions appear to suppress uncontrolled cell growth and may reduce the risk of cancer.

References

1. Hong Y, Downey T, Eu KW, et al. A 'metastasis-prone' signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis. 2010;27:83-90.
2. Pickart L. The human tri-peptide GHK and tissue remodeling. J Biomater Sci Polym Ed. 2008;19:969-88.
3. Pickart L. The Human Tripeptide GHK (Glycyl-L-Histidyl-L-Lysine), The Copper Switch, and The Treatment of the Degenerative Diseases of Aging. In: Anti-Aging Therapeutics, Volume XI, 301-312, Chicago, IL, USA: American Academy of Anti-Aging Medicine, 2009.
4. Kang YA, Choi HR, Na JI, et al. Copper-GHK increases integrin expression and p63 positivity by keratinocytes. Arch Dermatol Res. 2009;301:301-6.
5. Su X, Flores ER. TAp63: The fountain of youth. Aging (Albany NY). 2009;1:866-9.
6. Keyes WM, Mills AA. p63: a new link between senescence and aging. Cell Cycle. 2006;5:260-5.
7. Beaudry VG, Attardi LD. SKP-ing TAp63: stem cell depletion, senescence, and premature aging. Cell Stem Cell. 2009;5:1-2.
8. Collavin L, Lunardi A, Del Sal G. p53-family proteins and their regulators: hubs and spokes in tumor suppression. Cell Death Differ. 2010 Apr 9. [Epub ahead of print] .
9. Siméon A, Wegrowski Y, Bontemps Y, Maquart FX. Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J Invest Dermatol. 2000;115:962-8.
10. Border WA, Noble NA, Yamamoto T, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature. 1992;360:361-4.
11. Logan A, Baird A, Berry M. Decorin attenuates gliotic scar formation in the rat cerebral hemisphere. Exp Neurol. 1999;159:504-10.
12. Fukui N, Fukuda A, Kojima K, et al. Suppression of fibrous adhesion by proteoglycan decorin. J Orthop Res. 2001;19:456-62.
13. Fukushima K, Badlani N, Usas A, et al. The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med. 2001;29:394-402.
14. Grisanti S, Szurman P, Warga M, et al. Decorin modulates wound healing in experimental glaucoma filtration surgery: a pilot study. Invest Ophthalmol Vis Sci. 2005;46:191-6.
15. Weis SM, Zimmerman SD, Shah M, et al. A role for decorin in the remodeling of myocardial infarction. Matrix Biol. 2005;24:313-24.
16. Zhang Z, Garron TM, Li XJ, et al. Recombinant human decorin inhibits TGF-beta1-induced contraction of collagen lattice by hypertrophic scar fibroblasts. Burns. 2009;35:527-37.
17. Davies JE, Tang X, Denning JW, et al. Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. Eur J Neurosci. 2004;19:1226-42.
18. Minor K, Tang X, Kahrilas G, et al. Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. Neurobiol Dis. 2008;32:88-95.
19. Davies JE, Tang X, Bournat JC, Davies SJ. Decorin promotes plasminogen/plasmin expression within acute spinal cord injuries and by adult microglia in vitro. J Neurotrauma. 2006;23:397-408.
20. Li Y, Li J, Zhu J, Sun B, et al. Decorin gene transfer promotes muscle cell differentiation and muscle regeneration. Mol Ther. 2007;15:1616-22.
21. Reed CC, Waterhouse A, Kirby S, et al. Decorin prevents metastatic spreading of breast cancer. Oncogene. 2005;24:1104-10.
22. Shintani K, Matsumine A, Kusuzaki K, et al. Decorin suppresses lung metastases of murine osteosarcoma. Oncol Rep. 2008;19:1533-9.
23. Goldoni S, Seidler DG, Heath J, et al.An antimetastatic role for decorin in breast cancer. Am J Pathol. 2008;173:844-55.
24. Goldoni S, Iozzo RV. Tumor microenvironment: Modulation by decorin and related molecules harboring leucine-rich tandem motifs. Int J Cancer. 2008;123:2473-9.
25. Araki K, Wakabayashi H, Shintani K, et al. Decorin suppresses bone metastasis in a breast cancer cell line. Oncology. 2009;77:92-9.
26. Hu Y, Sun H, Owens RT, et al. Decorin suppresses prostate tumor growth through inhibition of epidermal growth factor and androgen receptor pathways. Neoplasia. 2009;11:1042-53.

[HBRU]

Poor anti aging results of people here fearing COPPER... as it's really important.

 

The cellular mechanisms that regulate the maintenance of adult tissue stem cells are still largely unknown. We show here that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely. Specifically, we have developed a TAp63 conditional knockout mouse and used it to ablate TAp63 in the germline (TAp63−/−) or in K14-expressing cells in the basal layer of the epidermis (TAp63fl/fl;K14cre+). TAp63−/− mice age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis. These phenotypes are likely due to loss of TAp63 in dermal and epidermal precursors since both cell types show defective proliferation, early senescence, and genomic instability. These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging.

 

TAp63 prevents premature aging by promoting adult stem cell maintenance - PMC (nih.gov)

[QuestforLife]

Carnosine + Glycine + Lysine + Copper.... with no Vitamin C (as it impairs copper absorption)

 

The paper is in the SOFW Journal

Below is a short version of GHK's anti-cancer actions.
...................

 

You can also get GHK complexed with other things - its been ages since I've looked at this so I can't remember - but it would be interesting to see what part of the benefits of GHK-Cu are just down to increases Cu concentration and what part due to the peptide itself.

 

We are off on somewhat of a tangent here however, as I would focus on the anti-cancer action of the ROS produced by res-Cu. That way you are intercepting any illegitimate DNA that might otherwise be taken up by healthy cells - surely a big issue with cancer, which has a high turnover of cells that must be constantly spewing their contents into the bloodstream. This is probably a mechanism for metastasis, i.e. not cancer cells moving around the body, but normal cells remote from the cancer becoming contaminated and in some cases becoming cancerous themselves. This might be why chemotherapy is such a two edged sword: it kills cancer cells, but it also spreads them. 

[HBRU]

Ok, you right. Anti cancer routine + GHK-Cu benefits.

 

day 1 to 5 morning: Carnosine + Glycine + Lysine + TMG + Copper (daily 6 mg) for GHK-Cu.....Lysine + TMG good for building up muscles.

day 6 morning: Carnosine + Copper (daily 6 mg) plus Resveratrol 500mg + FISETIN 400 mg + AKG.... (dont like quercitin as senolytic)

day 7 morning: Nicotinnammide + Ribose + PQQ day (fission)... toghether with Gotu Kola and Astragalus... that is cell expansion, mito fission, telomere elongating day..... + vigorous gymnastic

 

Evening 1-5 and 7 I take all the other supps including AKG and mito FUSION supps,

Evening of day 6 where I take Nicotinnammide + Ribose + Gotu Kola and Astragalus + PQQ + Manganese 25 mg (p53) + AKG + Black Seed Oil (p53) one teaspoon (both Manganese and Black Seed Oil puts cancer cells to sleep) + ZINC.... maybe good also theanine just to relax as much as possible and avoid Manganese toxicity to nervous system.

 

Zinc is relaxing so helps against Manganese neuro toxicity, and also Zinc protects p53 gene against cancer causing mutations

Day 6 is anti cancer, anti senesence day....

Day 7 is cell expansion day, mito fission, telomere elongating day.... and manganese can put to senesence alredy weak cancer cells

Edited by HBRU, 10 November 2023 - 02:07 PM.

[HBRU]

Forget; evening of day 5, no pro fusion food or supplements. As system needs to clean out before taking fission substances...

Maybe a couple of days in the week (evening 1 and 2) ROCK inhibitors toghether with AKG, as both interventions has the purpose to take away something (metilation and cell cytoskeleton reset)...

 

Taking Zink toghether with Manganese seems a good idea for nervous system protection....

 

In physiological concentrations zinc exhibits neuroprotective activity, although high concentrations of zinc are neurotoxic (Choi et al., 1988; Perry et al., 1997; Cote et al., 2005; Plum et al., 2010). Therefore, an imbalance of zinc homeostasis will have complex implications in a number of brain processes then leading to the onset of chronic pathologies such as depression, schizophrenia, Alzheimer's disease (AD), Parkinson's disease, aging, or amyotrophic lateral sclerosis (ALS). Given the complex nature of zinc homeostasis in the brain, it is not surprising that several different groups of proteins are involved in managing its cellular levels. The first group consists of are membranous transporters (ZnTs) mediating the zinc efflux from cells or influx into cellular compartments or organelles (Huang and Tepaamorndech, 2013). The second group is members of the Zip family (zinc-regulated and iron-regulated transporter proteins) that promote zinc transport from the extracellular space or from intracellular vesicles to the cytoplasm (Cousins et al., 2006).

 

Frontiers | Zinc homeostasis and neurodegenerative disorders (frontiersin.org)

 

As I know Manganese and Iron proteine transporters are the same...

Edited by HBRU, 10 November 2023 - 03:04 PM.

[HBRU]

No sense of fearing COPPER....

 

Despite unquestionable essentiality of copper, unregulated copper ions may increase oxidative damage. It is known that amyloid precursor protein (APP) implicated in development of Alzheimer's disease (AD) can convert Cu (II) into Cu (I) potentially increasing oxidative damage [19]. However, it remains unclear whether copper accumulation in senile plaques of AD patients is a cause or a consequence of pathological processes observed in AD. According to Exley followed by Bolognin et al., only aluminum, but not copper or iron, is capable of triggering amyloid precipitation and APP and tau181 protein overproduction [20, 21]. The study by Kawahara et al. showed that copper and carnosine attenuate neurotoxicity of another compound involved in neurodegeneration—prion protein [22]. Bishop and Robinson observed that amyloid beta protein may be neuroprotective when combined with copper. According to these authors, amyloid beta injected simultaneously with copper was not toxic, while iron and zinc complexed with amyloid beta were more toxic than amyloid beta alone [23].

 

Since copper accumulates in senile plaques of AD patients, some authors proposed dietary restriction of copper or intake of copper chelators as a preventive therapy for the elderly. However, several studies demonstrated that AD patients have reduced, not elevated, brain and cerebrospinal fluid copper level [24, 25]. Currently, many authors suggest mild copper deficiency as a causative factor in AD and possibly other neurodegenerative disorders [26, 27]. In a placebo-controlled, double-blinded, randomized clinical trial, oral copper supplementation (8 mg/day) in 68 AD patients had a beneficial effect on relevant AD biochemical markers. The authors concluded that long-term intake of copper can be excluded as a causative factor in AD and may in fact be protective [28]. In addition, several studies revealed molecular mechanisms underlying beneficial effects of copper in AD, such as an inhibition of beta-amyloid peptide production [29].

 

The Human Tripeptide GHK-Cu in Prevention of Oxidative Stress and Degenerative Conditions of Aging: Implications for Cognitive Health - PMC (nih.gov)

[rarefried]

HBRU, if you don't mind sharing the information, what brand and formulation of copper supplement are you taking?   

 

Carnosine + Glycine + Lysine + Copper.... with no Vitamin C (as it impairs copper absorption)

 

The paper is in the SOFW Journal

Below is a short version of GHK's anti-cancer actions.

 

[HBRU]

Piping Rock brand...

[marcobjj]

What kind of telomerase activator are they using in corporate cultured meat labs? The article mentions “immortalized cells” . Has someone figured out a breakthrough activator or are they culturing cancer cells ?

https://nypost.com/2...grown-meat/amp/

[QuestforLife]

What kind of telomerase activator are they using in corporate cultured meat labs? The article mentions “immortalized cells” . Has someone figured out a breakthrough activator or are they culturing cancer cells ?

https://nypost.com/2...grown-meat/amp/

None. They are immortalised permanently through transfecting them with viral genes.

I'd call them cancer cells if they don't have the correct number of chromosomes. I'd hope these cultured cells aren't that, but god knows.

Edited by QuestforLife, 21 November 2023 - 06:26 PM.

[HBRU]

Does this increase risk of cancer ? Specially in the bowels ?

[QuestforLife]

Does this increase risk of cancer ? Specially in the bowels ?

That's a good question and I don't know the answer.

I more general related question is: when you eat any kind of meat,does the DNA make it into the blood stream?

[HBRU]

I suppose risk is greater in case of 1) using acid suppressant drugs like pantoprazole 2) leaky gut... Anyway pieces of random DNA around the blood is a wider problem than "artificial meat"

[QuestforLife]

True it is a wider problem. But as a meat eater I'd like to understand what any additional burden there might be.

[HBRU]

Yeah, this viral DNA code that let indefinite replication is really worrying me. Are you sure this is the way they obtain this type of meat cellular lines ?

[QuestforLife]

It wasn't long ago someone else raised this artificial meat thing on this thread (implying it was a breakthru) and I pointed out immortalised cell lines is old technology (1990s) I also said something along the lines of 'why don't they do conditional reprogramming' (as those cells de-immortalise when you remove the special culture)?

But yeah, pretty sure inserted viral genes is exactly what they do to keep the muscle cells dividing indefinitely. They might have used a more advanced technique that require a drug activator to turn on the inserted genes. That is possible. I'll look into it.

[QuestforLife]

This is a decent paper on the subject.

doi: 10.3390/ijms222111660

Immortalizing Cells for Human Consumption

The techniques used, as reported by the paper, are not particularly advanced.

Quoting from the text:

1. One example of spontaneously immortalized cell lines in cultured meat is the chicken fibroblast line used by the company Future Meat...however, spontaneously immortalized cells may be held with concern as equivalent to cancerous cells. As noted in the HeLa cell line, the process of spontaneous immortalization often results in a number of additional mutations that are not required for immortalization, and which may alter other aspects of the cells in unpredictable ways.

This sounds like a crude and unsafe way to immortalise cells.

2. human fibroblast and keratinocyte cell line have been immortalized by infection with retroviruses expressing human TERT [23,24]. Human endothelial cells have also been immortalized by the ectopic expression of hTERT via plasmid transfection [25]. The authors have not found any published work that applies this method to agriculturally relevant cell lines for cellular agriculture.

This second way is familiar to me. It would IMO be safer than method 1 (though I still wouldn't rely on it being safe),but isn't used in artificial meat, as far as the authors could tell.

3. Inhibition or mutation of p16 and Rb, ther ore, can allow cells to continue DNA replication, leading to cell division without regulation.

It should go without saying that bypassing the stress response is a bad idea if you want to continue to culture non cancerous cells.

4. A combined approach, I.e. In many cases, TERT expression or inactivation of p15/p16/Rb alone are not sufficient to immortalize a cell line, suggesting that both telomere shortening and the p53/p16/Rb stress response must be bypassed. Myoblasts have previously been shown to require the bypass of both senescence triggers to become immortal [38]. In 2016, the cultured meat company Upside Foods submitted a patent to immortalize cell lines by overexpressing TERT and using CRISPR to knock out expressions of p15 and p16 in skeletal chicken muscle cells.

None of these methods is very subtle or conditional in any way. I wouldn't eat food made using any of these methods and I'd be suprised if they were approved by regulators.

Edited by QuestforLife, 21 November 2023 - 10:23 PM.

[marcobjj]

They mention "spontaneous" as an actual method? or is it just another way of saying non-lab induced immortalization, which is basically cancer in humans, except for a few specific cell lines. Sorry to ask this, I don't have access to the paper atm.

[HBRU]

I think after mRNA vaccines this is the next topic of bloody discussions around. From one side this tipe of meat can be more healthy as without hormones, bacteria, viruses... BUT the telomerase activity is MAYBE something worrying. Italian government is prudent and say no to this... We let others try this and watch if something bad arises.

[HBRU]

Also Muslims and most probably Hebrew will not eat this, as meat should be "Halal". A special prayer is needed while killing the animal, and only certain animals can be eaten.

[QuestforLife]

They mention "spontaneous" as an actual method? or is it just another way of saying non-lab induced immortalization, which is basically cancer in humans, except for a few specific cell lines. Sorry to ask this, I don't have access to the paper atm.

Spontaneous is just when a mouse cell (say) in culture has a mutation or series of mutations that allows it to proliferate indefinitely. They then select for this kind of cells. So yes, they are basically cultivating cancer.

[QuestforLife]

How is #983 a dangerous/irresponsible post? Mouse cells are known to spontaneously immortalise in culture. Many of these cells have abnormal karyotype. Selecting intentionally for these cells is literally cultivating cancer.  

Edited by QuestforLife, 23 November 2023 - 10:45 AM.

[HBRU]

Not your post is dangerous/irresponsible... The tech is dangerous/irresponsible

[HBRU]

This is interesting

https://futurism.com...le-ant-lifespan

[QuestforLife]

Where does the telomere theory of aging stand at present?

 

It is my intention in this short note to discuss the main problems with the theory and its application as a practical treatment against aging.  

 

But first, why do we want to measure telomere length and is it useful? It is a complex question but it gets to the root of why the telomere theory of aging has not been widely accepted. Ultimately, the reason is that both in the cell and the organism, deterioration in function can be detected before telomere shortening. The best example is this paper (REF #1), where they look at a whole bank of aging tests, on cells from aging humans and those aged in a petri dish. What is remarkable is that the so-called causes of aging, i.e. telomere shortening, DNA damage, cellular senescence and dysregulated methylation, etc. do not precede their supposed consequences, but actually follow them. Of all the methods for detecting aging, inflammation was the earliest indicator. Does this mean we should throw our theories away? Not so fast. Though my views on aging are constantly evolving, and I am not attached to telomere shortening being the single all powerful cause, it would be somewhat premature to throw it all out now. 

 

Previously I reviewed this Calico study (ref #2), which I loudly trumpeted ‘proved the telomere theory of aging.’ Although all the paper did was repeat Hayflick’s work from many decades before with modern methods, it highlighted some extremely useful things, which have been suggested by the likes of Michael Fossel, Shay & Wright and Bill Andrews to be the case: namely, that cellular senescence is only the final stage of telomere shortening, and that deterioration of the cell is gradual and occurs long before telomeres reach a critically short length. This was proven by the Calico paper, and what is more they highlighted some important mechanisms by which it occurs. They showed that chromatin accessibility was increased by demethylation and acetylation and that the areas most affected were those genes involved in inflammation.  How did this occur? The highlighted mechanism was by depletion of NAD and SAM through adjustments in metabolism of cells via upregulation of a protein called Nicotinamide N-methyltransferase (NNMT).

 

So what does that mean for us? Even if we could measure telomeres accurately and cheaply, which we can’t at present, we will be measuring what is likely a lagging indicator. We would for the time being be better off measuring either inflammation as I have suggested here (ref #3) or use metabolic tests looking at NAD+ (although I should say I have no information on how good or accurate these tests are and I have not used them myself). 

 

What other issues are there with using telomeres as our point of intervention in aging? I have discussed previously other things that could cause telomere shortening, i.e., is it simply normal and unavoidable cell replication, or is it excessive cell replication caused by another issue (for example this: ref #4, or this: ref #5) and therefore would addressing these be a better point of intervention and not telomeres? Finally, if we do want to treat telomeres directly, telomerase activators as available at present are not very effective and only reduce the rate of telomere shortening (contrary to widely reported claims that only show results in downstream cells), and in fact we can reduce telomere shortening more by using products that aren’t even telomerase activators (ref #7).

 

Conclusions

 

So here we have the tangled web of the telomere theory of aging as it stands at present. Absolutely nothing has been discovered to discredit it, it remains the most likely cause of aging in humans,  but we are no closer to implementing it as a treatment for aging. Why is this? In summary: 

1. Measuring telomeres is not that useful as it is a lagging indicator of deterioration even if it is the cause of the deterioration

2. Even if telomere shortening is the nexus of aging (as seems likely), it is possibly driven by other factors, which might be as/or more effective points of intervention. Note this is a somewhat dangerous assumption.

3. Telomere activators are so weak, we can’t yet prove telomeres are the best point of intervention and we can’t completely prove the telomere theory of aging.

What is the best way forward? 

1. Better, more accurate and cheaper telomere tests. This will enable us to test the contribution of different factors to telomere shortening, and perhaps show causation between telomere shortening, metabolic changes, and inflammation, as measured by those other tests.  

2. More powerful telomerase activators. Goes without saying really, but to test a theory, you need an effective treatment that directly addresses the proposed cause of aging. 

 

References

 

1] Hartmann C, Herling L, Hartmann A, Köckritz V, Fuellen G, Walter M, Hermann A. Systematic estimation of biological age of in vitro cell culture systems by an age-associated marker panel. Front Aging. 2023 Feb 15;4:1129107. doi: 10.3389/fragi.2023.1129107. PMID: 36873743; PMCID: PMC9975507.

 

2] Has the Telomere Theory of Aging been proven? https://www.longecit...-26#entry915078

 

3]NLR and CRP https://www.longecit...-19#entry906563

 

4] Are we being poisoned? https://www.longecit...-30#entry920902

 

5] oxidative stress in rat hearts https://www.longecit...-31#entry926109

 

6] What is the optimal strategy for slowing telomere loss? It is not telomerase activators https://www.longecit...-30#entry923584

 

[QuestforLife]

Is the epigenetic age acceleration caused by telomerase activators caused by nucleotide depletion?

 

I've put forward theories on why using telomerase activators (TAs) with Turnbuckle’s stem cell protocol results in epigenetic age acceleration. For example, here [1] I guessed that symmetric division would give somatic cells an advantage, if they are granted more divisions by TAs. I've discussed how this effect is temporary, here [2]. I’ve also discussed how telomerase activators depleted my glutamine, even whilst taking AKG [3]. I said at the time that perhaps this could be a mechanism by which epigenetic aging acceleration occurs; if TAs reduce AKG that could increase epigenetic age. I'd like to expand on that today with a new hypothesis I will test. 

 

Telomeres are made out of nucleotides, primarily guanine (half of TTAGGG), and I've suggested before that we could eat anchovies or Herring to boost the supply of guanine for telomeres [4]. But given we know telomerase activators can drain glutamine supply, perhaps they could also drain nucleotides like guanine. And could this interfere with mitochondrial fusion?

 

A relevant paper, discussed previously [5], shows how three amino acids - glutamine, leucine and arginine - can trigger mitochondrial fusion after a fast. So, what might be happening is this: taking telomerase activators can deplete guanine which may stop fusion from working properly. The way that this occurs is somewhat complicated, but in the paper they showed that the three amino acids stimulated prenylation (granting a fatty head) to GTP (Guanosine-5'-triphosphate) associated proteins , and this allowed the fusion protein Mfn1 to do its job. Clearly, GTP is required for this process [footnote]. If guanine is depleted by being used by being added to the telomere, fusion may not occur. If you then stimulate cells to divide with c60 whilst guanine is depleted, you are not specifically stimulating symmetric division, because fusion is not occurring at an elevated level. Taking extra nucleotides should in theory ensure fusion occurs and symmetric division happens instead. 

 

Thanks for sticking with me! This hypothesis should be testable by adding telomerase activators to the stem cell protocol, but with nucleotides, and this should prevent epigenetic aging acceleration. I intend to test this and will report back.

 

Footnote: actually GTP to GDP conversion is required in both fusion and fission, as published here [6]

 

 

References

 

[1] https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-29#entry919095

 

[2] https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-30#entry922401

 

[3] https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-24#entry911858

 

[4] https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-15#entry904277

 

[5] https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-27#entry918095

 

[6] Martínez RAS, Pinky PD, Harlan BA, Brewer GJ. GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer's disease. Geroscience. 2023 Apr;45(2):757-780. doi: 10.1007/s11357-022-00717-x. Epub 2023 Jan 9. PMID: 36622562; PMCID: PMC9886713.

Edited by QuestforLife, 14 February 2024 - 09:00 AM.

[QuestforLife]

More proof that manganese is good for telomeres

 

Previously, we discussed (thanks to HBRU) the benefits of higher maternal plasma manganese levels on the telomere length of newborns [1]. The benefits seemed to be quite substantial; 10% more length. 

 

The mechanism for how this happens is unknown, but I proposed an exciting mechanism [2] by which the manganese ion enables the terminal transferase ability of telomerase. This means that telomerase protein (TERT) is no longer ‘quality controlled’ by the RNA template (TERC) and can add any nucleotide available to the telomere in any order or number (depending on the combination of nucleotides present and the amount of TERC). This is speculative on my part, it might be that manganese simply increases antioxidant levels (i.e. MnSOD), which is the ‘go-to’ explanatory mechanism for any beneficial effect for any supplement ever.  

 

In the current study [3] , Chinese statisticians looked at the levels of 22 metals in the blood of workers in a coke plant, and their correlations with leukocyte telomere length. After various corrections (statisticians feel free to read and elucidate exactly how they separated out the metal contributions,) the only metal that stood out as an independent predictor of telomere length was manganese. The size of the effect was not huge, a 0.15% increase in telomere length for each 1% increase in blood manganese level. It is interesting however that the manganese levels were not high compared to other studies in China, suggesting that working in the coke plant was not the primary source of the manganese levels in their blood. We don’t know where the benefits would top out (but [1] suggests at least 10% increase in LTL is possible). Some other observations: age wasn’t a big factor in LTL over the approx. 16 years in range in the study; the manganese effect was the main factor along with some genetic mutations. Those study participants with mutations in TERT and another (telomere length) relevant gene CLTPM1L  known to lead to longer telomeres, had longer telomeres independent from the manganese effects, i.e., manganese gave you longer telomeres whether or not you already had longer telomeres due to various mutations. 

 

What this paper does not give us is any confirmation or denial of the proposed mechanism for telomere elongation via manganese, they trot out the standard antioxidant mechanism that may or may not be true. Regardless, the case for taking manganese for increasing telomere length is looking stronger and stronger. 

 

[1] https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-32#entry927203

 

[2] https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-32#entry927276

 

[3] Bai Y, Fu W, Guan X, Wu X, Li G, Wei W, Feng Y, Meng H, Li H, Li M, Fu M, Jie J, Wang C, Zhang X, He M, Guo H. Co-exposure to multiple metals, TERT-CLPTM1L variants, and their joint influence on leukocyte telomere length. Environ Int. 2020 Jul;140:105762. doi: 10.1016/j.envint.2020.105762. Epub 2020 May 4. PMID: 32380304.

 

Edited by QuestforLife, 26 February 2024 - 01:18 PM.

[QuestforLife]

A four year intervention study with six years follow up shows selenium and CoEnzyme Q10 prevents telomere shortening in leukocytes and reduces mortality [1]

 

Elderly Swedish people (mean age at outset 77, total number treated=67, controls=51) who had low levels of selenium in their blood (common in many areas) were treated with selenium and coEnzyme Q10 for 4 years.

 

Compared to controls telomere shortening was prevented over the 4 years* by the treatment (+1.9% in treated vs. -12.9% in controls, p value=0.02).

 

People who died of cardiovascular disease during the 6 years after the end of treatment had shorter telomeres at the end of the 4 years* than those who survived (79.1% at year 4 compared to the start vs. 94.1% for survivors, p-value=0.01).

 

The study also provided a survival curve covering the 10 years of the total study time. I assume this is total mortality (not just CV mortality, the study doesn't specify), showing significantly longer survival for the study participants in the quartile with the least telomere shortening (I assume in the 4 years* of the first part of the study). I don't know why the x-axis starts on day 1000.

 

*note measurement was actually taken at 3 1/2 years, 6 months before the end of treatment but...hey ho!

 

My Notes

 

It is annoying we don't know if the benefits were down to selenium, CoEnzyme Q10 or both. It appears that the benefits are mediated by telomere length (as TL in leukocytes is correlated with TL in the aortic wall [2]), although we cannot eliminate some intervening factor like inflammation. 

 

The study was in part sponsored by pharma Nord who provided the supplements, but they don't appear to have had anything to do with running the study.  

 

Bottom Line

 

Is selenium and coEnzyme Q10 worth taking for telomeres based on this study? Yes, especially if you are in your 70s. But it might be worth getting your blood selenium levels tested first. 

 

References

 

[1] Opstad TB, Alexander J, Aaseth JO, Larsson A, Seljeflot I, Alehagen U. Selenium and Coenzyme Q10 Intervention Prevents Telomere Attrition, with Association to Reduced Cardiovascular Mortality-Sub-Study of a Randomized Clinical Trial. Nutrients. 2022 Aug 15;14(16):3346. doi: 10.3390/nu14163346. PMID: 36014852; PMCID: PMC9412367.

 

[2] Wilson WR, Herbert KE, Mistry Y, Stevens SE, Patel HR, Hastings RA, Thompson MM, Williams B. Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease. Eur Heart J. 2008 Nov;29(21):2689-94. doi: 10.1093/eurheartj/ehn386. Epub 2008 Sep 1. PMID: 18762552.

Edited by QuestforLife, 01 March 2024 - 03:35 PM.