Posted 02 July 2024 - 09:38 AM
Check out this piece of news
it says a new molecule extends telomeres
https://www.lifespan..._cid=c0019c2d4d
the strange part is that they do not name the compound in the article and refer to it as TAC, but in the link above the very structure is given
Any idea if this is something potentially available and may be possible to use somewhat safely?
Posted 04 July 2024 - 01:43 PM
Frustratingly, not free access
This is the paper:
https://pubmed.ncbi....h.gov/38908367/
Shim HS, Iaconelli J, Shang X, Li J, Lan ZD, Jiang S, Nutsch K, Beyer BA, Lairson LL, Boutin AT, Bollong MJ, Schultz PG, DePinho RA. TERT activation targets DNA methylation and multiple aging hallmarks. Cell. 2024 Jun 21:S0092-8674(24)00592-0. doi: 10.1016/j.cell.2024.05.048. Epub ahead of print. PMID: 38908367.
I do believe they injected from the details I've been able to get at.
If anyone can get hold of this paper, let us know!
I've been wondering what Ron DePinho was doing all these years since he did the breakthrough work on ageing of telomerase negative mice.
Posted 05 July 2024 - 12:41 AM
I have the paper and it shows the molecule. The molecule is https://pubchem.ncbi...rmation-Sources
The results in the paper are very promising. I'm planning on getting some made.
If anyone wants to get some let me know how much you would be interested in.
The human equivalent dose is about 1mg a kilo. They did testing from 1 week to 6 months.
DM me for paper.
Posted 05 July 2024 - 08:01 AM
Quite interesting comparing this molecule to those investigated by Sierra Sciences some time ago.
https://patents.goog...ndrews&sort=new
https://patents.goog...ndrews&sort=new
Bill Andrews says that they have kept the molecular structure of TAM818 a trade secret and it is not in any of these documents. I wonder though if we'll find out this new molecule is closely related.
Posted 05 July 2024 - 08:21 AM
I have the paper and it shows the molecule. The molecule is https://pubchem.ncbi...rmation-Sources
The results in the paper are very promising. I'm planning on getting some made.
If anyone wants to get some let me know how much you would be interested in.
The human equivalent dose is about 1mg a kilo. They did testing from 1 week to 6 months.
DM me for paper.
Before we pull the trigger on this one, can you elaborate a bit on the paper? Or maybe the resident expert QuestForLife can DM you and then tell us what he thinks
Cannot tell you guys how valuable all of your contributions are
(EDIT: wrote the above sentence before I realized QFLife had already commented)
Edited by sub7, 05 July 2024 - 08:22 AM.
Posted 05 July 2024 - 01:30 PM
Quite interesting comparing this molecule to those investigated by Sierra Sciences some time ago.
https://patents.goog...ndrews&sort=new
https://patents.goog...ndrews&sort=new
Bill Andrews says that they have kept the molecular structure of TAM818 a trade secret and it is not in any of these documents. I wonder though if we'll find out this new molecule is closely related.
Patent application says "8-Hydroxy quinoline derived compounds"
Is 8-Hydroxy quinoline obtainable somewhat easily? Can we go ahead and use that, hoping that it will have similar effects?
BTW QuestForLife,
You have previously mentioned that a multi-pronged approach may be needed to elongate Telomeres, such as combining Epitalon with something else. Do you think that a combination approach will be required no matter what new compound we utilize (because biochemically a single molecule is very unlikely to activate all the required pathways for Telomere elongation)? Or does it sound conceivable to you that researchers can come up with a single compound to get the job done; hence not requiring a multi-compound approach henceforth?
Posted 05 July 2024 - 02:39 PM
Patent application says "8-Hydroxy quinoline derived compounds"
Is 8-Hydroxy quinoline obtainable somewhat easily? Can we go ahead and use that, hoping that it will have similar effects?
BTW QuestForLife,
You have previously mentioned that a multi-pronged approach may be needed to elongate Telomeres, such as combining Epitalon with something else. Do you think that a combination approach will be required no matter what new compound we utilize (because biochemically a single molecule is very unlikely to activate all the required pathways for Telomere elongation)? Or does it sound conceivable to you that researchers can come up with a single compound to get the job done; hence not requiring a multi-compound approach henceforth?
I will wait till I read the paper before I decide how 'potent' this TAM molecule is. Based on what I've seen before, I would be suprised if it is very potent, academic papers like to exaggerate what they have found: remember most benefits of TAM will be from mitochondrial effects rather than telomere elongation, which is not needed in most lab mice species. I will be looking for RNA HTERT levels, preferably in comparison with embryonic stem cells or cancer cells (like HELA), telomerase activity levels (ability to add telomerase repeats to a telomere like strand - again compared to HELA or ESC levels), and ability to extend the replicative lifespan of differentiated human cells like fibroblasts, ideally to several hundred population doublings.
The requirement for a synergy of a TAM with other compounds is necessary to maximise each step (RNA production, telomerase assembly, telomerase activity, etc) because nothing found so far has been remotely potent enough to do the job on its own.
I wouldn't expect the various quinoline molecules listed in the Sierra Sciences patent to be as strong as TAM818, which is a trade secret; nor is TAM818 strong enough.
Edited by QuestforLife, 05 July 2024 - 02:40 PM.
Posted 05 July 2024 - 07:30 PM
I will wait till I read the paper before I decide how 'potent' this TAM molecule is. Based on what I've seen before, I would be suprised if it is very potent, academic papers like to exaggerate what they have found: remember most benefits of TAM will be from mitochondrial effects rather than telomere elongation, which is not needed in most lab mice species. I will be looking for RNA HTERT levels, preferably in comparison with embryonic stem cells or cancer cells (like HELA), telomerase activity levels (ability to add telomerase repeats to a telomere like strand - again compared to HELA or ESC levels), and ability to extend the replicative lifespan of differentiated human cells like fibroblasts, ideally to several hundred population doublings.
The requirement for a synergy of a TAM with other compounds is necessary to maximise each step (RNA production, telomerase assembly, telomerase activity, etc) because nothing found so far has been remotely potent enough to do the job on its own.
I wouldn't expect the various quinoline molecules listed in the Sierra Sciences patent to be as strong as TAM818, which is a trade secret; nor is TAM818 strong enough.
Tremendously appreciated Sir
Posted Yesterday, 10:00 AM
TERT activation targets DNA methylation and multiple aging hallmarks
Many thanks to Chemically_Charmed for supplying the paper.
Background: This is a paper authored among others by Ron Depinho, famous years ago for this paper [1] where they induced (human-like) ageing in mice through telomerase deactivation and then reversed it by reactivating telomerase.
In the current paper [2] mice were genetically engineered to carry the HTERT gene plus its cis regulatory elements. This enabled researchers to see effects on this gene as it would occur in humans rather than upon the MTERT gene, which is generally active in most mice tissues but downregulated with age. Tests were carried out both on cells extracted from those mice (from the ears) and on the mice themselves.
Tests were also carried out in human cells: lung fibroblasts and Werner Syndrome fibroblasts. Presumably this allowed them to eliminate the possibility that the MTERT gene was also stimulated. I would have far preferred they used normal human cells passaged to near senescence rather than WS cells, but it is better than nothing.
Screening found a small molecule which upregulated the human telomerase gene (HTERT) in all tissues examined.
In a nutshell, what's good, what's bad?
Bad: TERT RNA upregulation was mild, maybe x2, if that
Good: TERT RNA upregulation occurred across all tissues tested
Bad: There is no comparison with HELA or any other TERT positive cell type for the extent of HTERT activation;
Bad: and there is no TRAP assay for telomerase activity; but
Good: They did show the molecule increased telomere length in human cells
Good: and reduced DNA damage foci due to short telomeres
Good: and increased proliferative ability in cells beginning to slow divisions
Bad: but that was in Werner Syndrome cells!
Good: TERT activation was VERY specific; only a couple of genes upregulated and translation in general not affected at all (means this may synergise with other approaches)
Good: The molecule has wide distribution in the body, including nervous system and brain; clearance took 3 hours (in mice)
Good: protein levels of TERT increased in PBMCs in proportion to increase in RNA levels, which is useful to know
Bad: but they looked at protein level using immunoblotting (not accurate)
Good: but they didn’t use the antibody NCL-HTERT known to be non specific to telomerase [3]
On to the effects…
Good: with only a week course of this molecule, senescence and inflammatory markers were reduced (more than halved) in old mice
Good: and this occurred across a wide range of tissues, not just blood cells
Good: and increased general markers of growth and natural killer cell activity
Good: and longer term treatment (6 months) in old mice reduced senescent cell burden
Bad: this was all injected 6mg/Kg/day
Good: The molecule had strong effects in the brain, increasing adult neurogenesis and decreasing microglia activation and inflammation. Aside: TERT seems to have particularly strong effects in the brain, as we've seen before with gotu kola extracts [4], and I speculate that this is due to high mitochondrial densities in those tissues.
Good: The molecular benefits in the brain also extended to actual benefits in old mice, including cognitive tests, balance and strength when injected with the substance 3 times/week.
Stepping back
Unlike with TAM818 no medicinal chemistry was done, they simply worked with the best molecule they found from screening. So, this molecule is unlikely to represent the best possible. Having said that, its molecular action was incredibly precise, with no side effects.
I am disappointed they didn't do more and better measurements of the extent of telomerase activation; I assume it was because the increase in levels were so mild. Nevertheless the benefits were real. Again, I speculate most of these effects were through non canonical mitochondrial benefits rather than through lengthening telomeres.
The study could be taken most usefully as a proof of the benefits of mild telomerase activation, rather than this being a super molecule, and secondarily that HTERT RNA upregulation does seem to feed through to actual telomerase production.
Other molecules like TAM818 do not have this level of evidence behind them, and other compounds like gotu kola extracts have a plethora of effects, some good, some bad. We do have evidence for the effects of TA-65 on mice, and they are not as promising as these results. So overall I'd say we have strong evidence for good effects with this molecule rather than weak evidence for very good effects (TAM818) or strong evidence for weak effects (TA-65). So, this paper is a step forward.
The big question is bioavailability. It is a small molecule and it gets everywhere once it is injected. Is it orally bioavailable? I suspect so because of its low molecular weight and the fact it is fat soluble.
References
[1] Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadiñanos J, Horner JW, Maratos-Flier E, Depinho RA. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011 Jan 6;469(7328):102-6. doi: 10.1038/nature09603. Epub 2010 Nov 28. PMID: 21113150; PMCID: PMC3057569.
[2] Shim HS, Iaconelli J, Shang X, Li J, Lan ZD, Jiang S, Nutsch K, Beyer BA, Lairson LL, Boutin AT, Bollong MJ, Schultz PG, DePinho RA. TERT activation targets DNA methylation and multiple aging hallmarks. Cell. 2024 Jun 21:S0092-8674(24)00592-0. doi: 10.1016/j.cell.2024.05.048. Epub ahead of print. PMID: 38908367.
[4] Tsoukalas D, Buga AM, Docea AO, Sarandi E, Mitrut R, Renieri E, Spandidos DA, Rogoveanu I, Cercelaru L, Niculescu M, Tsatsakis A, Calina D. Reversal of brain aging by targeting telomerase: A nutraceutical approach. Int J Mol Med. 2021 Nov;48(5):199. doi: 10.3892/ijmm.2021.5032. Epub 2021 Sep 13. PMID: 34515324; PMCID: PMC8448543.
Edited by QuestforLife, Yesterday, 10:04 AM.
Posted Yesterday, 02:51 PM
TERT activation targets DNA methylation and multiple aging hallmarks
Many thanks to Chemically_Charmed for supplying the paper.
Background: This is a paper authored among others by Ron Depinho, famous years ago for this paper [1] where they induced (human-like) ageing in mice through telomerase deactivation and then reversed it by reactivating telomerase.
In the current paper [2] mice were genetically engineered to carry the HTERT gene plus its cis regulatory elements. This enabled researchers to see effects on this gene as it would occur in humans rather than upon the MTERT gene, which is generally active in most mice tissues but downregulated with age. Tests were carried out both on cells extracted from those mice (from the ears) and on the mice themselves.
Tests were also carried out in human cells: lung fibroblasts and Werner Syndrome fibroblasts. Presumably this allowed them to eliminate the possibility that the MTERT gene was also stimulated. I would have far preferred they used normal human cells passaged to near senescence rather than WS cells, but it is better than nothing.
Screening found a small molecule which upregulated the human telomerase gene (HTERT) in all tissues examined.
In a nutshell, what's good, what's bad?
Bad: TERT RNA upregulation was mild, maybe x2, if that
Good: TERT RNA upregulation occurred across all tissues tested
Bad: There is no comparison with HELA or any other TERT positive cell type for the extent of HTERT activation;
Bad: and there is no TRAP assay for telomerase activity; but
Good: They did show the molecule increased telomere length in human cells
Good: and reduced DNA damage foci due to short telomeres
Good: and increased proliferative ability in cells beginning to slow divisions
Bad: but that was in Werner Syndrome cells!
Good: TERT activation was VERY specific; only a couple of genes upregulated and translation in general not affected at all (means this may synergise with other approaches)
Good: The molecule has wide distribution in the body, including nervous system and brain; clearance took 3 hours (in mice)
Good: protein levels of TERT increased in PBMCs in proportion to increase in RNA levels, which is useful to know
Bad: but they looked at protein level using immunoblotting (not accurate)
Good: but they didn’t use the antibody NCL-HTERT known to be non specific to telomerase [3]
On to the effects…
Good: with only a week course of this molecule, senescence and inflammatory markers were reduced (more than halved) in old mice
Good: and this occurred across a wide range of tissues, not just blood cells
Good: and increased general markers of growth and natural killer cell activity
Good: and longer term treatment (6 months) in old mice reduced senescent cell burden
Bad: this was all injected 6mg/Kg/day
Good: The molecule had strong effects in the brain, increasing adult neurogenesis and decreasing microglia activation and inflammation. Aside: TERT seems to have particularly strong effects in the brain, as we've seen before with gotu kola extracts [4], and I speculate that this is due to high mitochondrial densities in those tissues.
Good: The molecular benefits in the brain also extended to actual benefits in old mice, including cognitive tests, balance and strength when injected with the substance 3 times/week.
Stepping back
Unlike with TAM818 no medicinal chemistry was done, they simply worked with the best molecule they found from screening. So, this molecule is unlikely to represent the best possible. Having said that, its molecular action was incredibly precise, with no side effects.
I am disappointed they didn't do more and better measurements of the extent of telomerase activation; I assume it was because the increase in levels were so mild. Nevertheless the benefits were real. Again, I speculate most of these effects were through non canonical mitochondrial benefits rather than through lengthening telomeres.
The study could be taken most usefully as a proof of the benefits of mild telomerase activation, rather than this being a super molecule, and secondarily that HTERT RNA upregulation does seem to feed through to actual telomerase production.
Other molecules like TAM818 do not have this level of evidence behind them, and other compounds like gotu kola extracts have a plethora of effects, some good, some bad. We do have evidence for the effects of TA-65 on mice, and they are not as promising as these results. So overall I'd say we have strong evidence for good effects with this molecule rather than weak evidence for very good effects (TAM818) or strong evidence for weak effects (TA-65). So, this paper is a step forward.
The big question is bioavailability. It is a small molecule and it gets everywhere once it is injected. Is it orally bioavailable? I suspect so because of its low molecular weight and the fact it is fat soluble.
References
[1] Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadiñanos J, Horner JW, Maratos-Flier E, Depinho RA. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011 Jan 6;469(7328):102-6. doi: 10.1038/nature09603. Epub 2010 Nov 28. PMID: 21113150; PMCID: PMC3057569.
[2] Shim HS, Iaconelli J, Shang X, Li J, Lan ZD, Jiang S, Nutsch K, Beyer BA, Lairson LL, Boutin AT, Bollong MJ, Schultz PG, DePinho RA. TERT activation targets DNA methylation and multiple aging hallmarks. Cell. 2024 Jun 21:S0092-8674(24)00592-0. doi: 10.1016/j.cell.2024.05.048. Epub ahead of print. PMID: 38908367.
[4] Tsoukalas D, Buga AM, Docea AO, Sarandi E, Mitrut R, Renieri E, Spandidos DA, Rogoveanu I, Cercelaru L, Niculescu M, Tsatsakis A, Calina D. Reversal of brain aging by targeting telomerase: A nutraceutical approach. Int J Mol Med. 2021 Nov;48(5):199. doi: 10.3892/ijmm.2021.5032. Epub 2021 Sep 13. PMID: 34515324; PMCID: PMC8448543.
Nice break down. If you are interested in finding out the identity of TAM818 It wouldn't be impossible to extract it out of the cream and have the structure analyzed.
Posted Yesterday, 03:46 PM
Nice break down. If you are interested in finding out the identity of TAM818 It wouldn't be impossible to extract it out of the cream and have the structure analyzed.
Posted Yesterday, 04:37 PM
I have the tablets. Want me to send you some? The active ingredient is in a 375mg soft gel also containing: macadamia oil, walnut oil, vit D3, D-alpha tocopherol and astaxanthin.
The telomere supplement that they have doesnt look like it contains TAM818 from the website. I just see one with this:
Curcumin 1000mg, L Carnosine 500mg, Silybin 200mg, Glutathione 100mg, Astragalus 80mg, Black pepper extract 8mg, Vitamin D (10,000i.u) Also contains magnesium stearate, hypromellose and natural colouring, Vegan. Free from gluten and dairy.
Which one do you have?
Posted Yesterday, 05:46 PM
The telomere supplement that they have doesnt look like it contains TAM818 from the website. I just see one with this:
Curcumin 1000mg, L Carnosine 500mg, Silybin 200mg, Glutathione 100mg, Astragalus 80mg, Black pepper extract 8mg, Vitamin D (10,000i.u) Also contains magnesium stearate, hypromellose and natural colouring, Vegan. Free from gluten and dairy.
Which one do you have?
These: https://defytime.com...-care-capsules/
Posted Yesterday, 06:22 PM
Oh interesting. Did you feel effects or see results from it? It must be a natural molecule if its in a supplement unless he's taking some legal risks.
The amount must be small as well if the amount is less that the D-alpha-tocopherol, :Macadamia Oil, Walnut Oil, Vitamin D3, Astaxanthin, N-Carboxamide, Totarol Powder, D-alpha-tocopherol, TAM C0314818
Posted Yesterday, 06:41 PM
Oh interesting. Did you feel effects or see results from it? It must be a natural molecule if its in a supplement unless he's taking some legal risks.
The amount must be small as well if the amount is less that the D-alpha-tocopherol, :Macadamia Oil, Walnut Oil, Vitamin D3, Astaxanthin, N-Carboxamide, Totarol Powder, D-alpha-tocopherol, TAM C0314818
Some increase in exercise capacity perhaps, nothing huge.
It is NOT a natural molecule. Perhaps they get around it by selling in NZ and the far East.
Posted Yesterday, 06:42 PM
The big question is bioavailability. It is a small molecule and it gets everywhere once it is injected. Is it orally bioavailable? I suspect so because of its low molecular weight and the fact it is fat soluble.
Why is this a relevant matter? Why not just inject it?
Are you against injecting such experimental compounds? -I totally respect it, if such is the case; however, people in here inject many compounds that are "experimental" at best
Posted Yesterday, 09:20 PM
Some increase in exercise capacity perhaps, nothing huge.
It is NOT a natural molecule. Perhaps they get around it by selling in NZ and the far East.
I ask the one truth 818 chat if it was Bill Andrews selling that supplement and they said no.
"He’s an old distributor of our skincare in Korea from about 8-10 years ago. He went rogue and sadly kept using our ingredient name and Bills. There’s not much we can do unfortunately."
That supplement might not actually contain TAM818
Posted Yesterday, 09:52 PM
I ask the one truth 818 chat if it was Bill Andrews selling that supplement and they said no.
"He’s an old distributor of our skincare in Korea from about 8-10 years ago. He went rogue and sadly kept using our ingredient name and Bills. There’s not much we can do unfortunately."
That supplement might not actually contain TAM818
Posted Yesterday, 10:00 PM
Why is this a relevant matter? Why not just inject it?
Are you against injecting such experimental compounds? -I totally respect it, if such is the case; however, people in here inject many compounds that are "experimental" at best
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