11 replies to this topic

[sub7]

Hey Quest,

 

Is this kind of gene therapy aimed at extending telomeres something we have seen before (ex is this what Liz Parish had done?) or does this constitute a novel approach?

 

https://pubmed.ncbi....h.gov/39660787/

[QuestforLife]

Looks interesting Sub thanks, I'll give it a proper read when I get chance.

 

Just from a quick skim, this looks similar to what Blasco did when her team made mice with longer telomeres from birth (and they lived longer and were healthier than normal). The one doubt about that, voiced by some here, were that the method she used, whereby ESCs were passaged for longer before making the mice, in order to generate the ESCs with longer telomeres, meant she was doing a sort of embryo selection that might account for the improved health outcomes. Bear in mind this was years ago and I am relying on memory...

 

Here they inserted a new TERT gene into ESCs and selected mice born with the new TERT transgene: these mice had longer telomeres and were healthier and lived longer and this benefits seemed to persist through several generations. So, it seems highly likely those benefits are coming from longer telomeres/more telomerase or downstream consequences of that (like higher glutathione and SOD). 

 

So this study is a proof of the benefits of telomerase study, not a practical intervention that might be used on humans. 

 

EDIT: always bear in mind that mice are not even expected to benefit that much from increased telomerase compared to humans.

Edited by QuestforLife, 19 December 2024 - 09:17 AM.

[sub7]

 

 

EDIT: always bear in mind that mice are not even expected to benefit that much from increased telomerase compared to humans.

 

 

 

 

Hmmm, this is very interesting to note. While I have you here Sir, allow me to ask the following too:
Bill Andrew said something very interesting. He basically noted that inserting the telomerase gene into your nuclear DNA through a viral vector was not a good option, because you'd have no control over where the gene would land, and obviously it could land in the middle of a critical gene and render it dysfunctional.

That is why using the method employed by Liz Parish was a better idea. There, you are inserting something (not exactly sure what to call this) into the cytoplasm and leave the nuclear DNA untouched. What exactly is it that you deliver into the cytoplasm? an mRNA? Only that would actually be able to insruct the Ribosome to make a protein, no?  And are you able to push the ribosomes to make the required protein just once or is it possible to have that "gene fragment" (for the lack of a better term) stay there and keep instructing the ribosome to make more and more of the required protein?

If my understanding as presented above is partially accurate, is the above still our only somewhat-feasible tool at our disposal?

Many thanks as usual

[QuestforLife]

Gene therapy like what Liz has done basically uses bacterial DNA to express the desired protein from the cytoplasm. It is temporary (in theory) as it cannot divide and go both ways if the cell divides, and may not last forever in the cytoplasm, as presumably there is some sort of clearance going on. In practice, such things can and do insert into the genome occasionally, which is why gene therapy can be risky. RNA therapy works similarly, in that you insert RNA into the cytoplasm that is then is made by your own ribosomes (into the desired protein). The recent covid vaccines were gene therapy, in fact. 

 

As you heard from Bill, he would only use gene therapy as a last resort. But he is still interested in using it to prove the benefits of longer telomeres, he just wants to use small molecules to get there, ideally. 

 

I think a better option (than gene therapy) might be exosomes carrying the telomerase protein, or perhaps telomerase RNA. A small molecule would be best of course, but only if we can find one that turns on hTERT (the gene we all already have). 

Edited by QuestforLife, 19 December 2024 - 12:57 PM.

[sub7]

 

I think a better option (than gene therapy) might be exosomes carrying the telomerase protein

 

this sounds so wonderful

 

likely more feasible than messing with RNA

 

thanks a ton Sir

[alphachn]

Gene therapy like what Liz has done basically uses bacterial DNA to express the desired protein from the cytoplasm. It is temporary (in theory) as it cannot divide and go both ways if the cell divides, and may not last forever in the cytoplasm, as presumably there is some sort of clearance going on. In practice, such things can and do insert into the genome occasionally, which is why gene therapy can be risky. RNA therapy works similarly, in that you insert RNA into the cytoplasm that is then is made by your own ribosomes (into the desired protein). The recent covid vaccines were gene therapy, in fact. 

 

As you heard from Bill, he would only use gene therapy as a last resort. But he is still interested in using it to prove the benefits of longer telomeres, he just wants to use small molecules to get there, ideally. 

 

I think a better option (than gene therapy) might be exosomes carrying the telomerase protein, or perhaps telomerase RNA. A small molecule would be best of course, but only if we can find one that turns on hTERT (the gene we all already have). 

 

Actually, there is a small molecule  that turns on hTERT. 

[QuestforLife]

Actually, there is a small molecule that turns on hTERT.

Sufficient to reverse telomere shortening in dividing human cells?

[alphachn]

Sufficient to reverse telomere shortening in dividing human cells?

Yes, It is called TAC, and our company sells this product, but it is very expensive. Currently, we only sell it to a few people.

 

Hong Seok Shim et al., TERT activation targets DNA methylation and multiple aging hallmarks.

Cell Doi: https://doi.org/10.1...ell.2024.05.048

Edited by alphachn, 23 December 2024 - 01:18 AM.

[alphachn]

Yes, It is called TAC, and our company sells this product, but it is very expensive. Currently, we only sell it to a few people.

 

Hong Seok Shim et al., TERT activation targets DNA methylation and multiple aging hallmarks.

Cell Doi: https://doi.org/10.1...ell.2024.05.048

If everyone is interested, I can organize a group buy for TAC. With a larger quantity, we can definitely get a better price. If you're interested, please message me with the quantity you need.We guarantee the authenticity and high quality of our products. All of these products can be sent for third-party testing to verify their content.

[longevitydiary]

If everyone is interested, I can organize a group buy for TAC. With a larger quantity, we can definitely get a better price. If you're interested, please message me with the quantity you need.We guarantee the authenticity and high quality of our products. All of these products can be sent for third-party testing to verify their content.

 

 

https://www.longecit...tions/?p=933486

[QuestforLife]

Yes, It is called TAC, and our company sells this product, but it is very expensive. Currently, we only sell it to a few people.

 

Hong Seok Shim et al., TERT activation targets DNA methylation and multiple aging hallmarks.

Cell Doi: https://doi.org/10.1...ell.2024.05.048

 

And you have evidence that the TERT activation from TAC is - as I asked - Sufficient to reverse telomere shortening in dividing human cells?

 

The reference you provide certainly does not prove that. It would require either an assay for hTERT RNA levels with a comparison to a positive control such as HELA (which we know does not senesce from telomere shortening) 

OR

Evidence of TERT negative human cells considerably surpassing the hayflick limit whilst cultured with TAC.

[alphachn]

And you have evidence that the TERT activation from TAC is - as I asked - Sufficient to reverse telomere shortening in dividing human cells?

The reference you provide certainly does not prove that. It would require either an assay for hTERT RNA levels with a comparison to a positive control such as HELA (which we know does not senesce from telomere shortening)
OR
Evidence of TERT negative human cells considerably surpassing the hayflick limit whilst cultured with TAC.

TAC delays aging through two pathways: by extending telomeres and regulating gene expression.

This is the information I obtained from this paper.
In the preclinical experiments, researchers treated elderly mice (equivalent to humans over 75 years old) with TAC for 6 months. The results showed that these older mice exhibited many "youthful" characteristics, such as enhanced cognitive abilities, the generation of new neurons in the hippocampus of the brain, and an increase in certain genes related to learning, memory, and synaptic biology. Additionally, neuromuscular control was strengthened, muscle strength and coordination improved, and the common issue of sarcopenia in older animals was reversed.
Tests on samples like blood and brain tissue also revealed that the elderly mice treated with TAC significantly reduced inflammatory responses, with a decrease in various disease-related inflammatory cytokines. They also eliminated accumulated senescent cells by inhibiting the key aging factor, the p16 gene.
At the same time, safety tests indicated no significant toxicity, including cancer risk.
These significant results in slowing down aging signs are still from animal experiments. Researchers then conducted preliminary tests on human cell lines and found that TAC could increase telomere synthesis, reduce telomere DNA damage signals, and extend the proliferative potential of these cells.


“Researchers then conducted preliminary tests on human cell lines and found that TAC could increase telomere synthesis, reduce telomere DNA damage signals, and extend the proliferative potential of these cells.”


these experiments have only yielded preliminary positive results, which are not yet sufficient. More research is needed.

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Edited by alphachn, 23 December 2024 - 01:41 PM.