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Implanting an immortalized bone marrow AND a thymus to replace old cells by immortalized young cells

htert bone marrow stem cells thymus immune system telomerase immortalized cells senescence cells replacement implanting bone marrow yamanaka factors

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#1 VicenteSilvaNeyra

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Posted 24 September 2020 - 10:15 PM


I am working on algorithms to let computers help us to achieve indefinite life extension. 
I have come out with the next idea and I would like to meet people interested in collaborating with myself and other people to explore different approaches to accomplish rejuvenation and immortality. 
 

Immortalized human cells can be created with complementary DNA (cDNA) to code for the hTERT protein to induce telomerase activity (along with other methods)

 

Simonsen, JL, Rosada, C, Serakinci, N, et al have extended the lifespan proliferation of human bone marrow.

"The transduced cells have now undergone more than 260 population doublings (PD) and continue to proliferate, whereas control cells underwent senescence-associated proliferation arrest after 26 PD"

 

On the other hand, there are several approaches for thymus regeneration (Valentin P. Shichkin & Mariastefania Antica 2020) and artificial thymic organoids (reference below)

 

What would be the challenges of implanting an immortalized bone marrow AND a thymus in animals?

 

I think that by doing this, the immune system would get rid of senescence cells to be replaced by new immortalized cells created in the immortalized bone marrow. In this way, the longer Hayflick limit of immortalized cells would keep regenerated organs and tissue healthier for longer, including the thymus itself, which in turns would continue killing senescence cells to extend youth and lifespan of the whole body.

 

What if we partially express Yamanaka factors (along with other factors) to rejuvenate cells first and then express telomerase activity to make them both younger and “immortal”?

 

When we get old, both bone marrow and thymus stop working, then, by replacing old cells with younger cells with higher telomerase activity might lead to both rejuvenation and indefinite lifespan. 

 

Is anybody already working on a similar approach?

What happens when immortalized cells are put inside an old animal?

What is the risk of doing this?

What is missing to get this done?

 

The procedure of implanting a bone marrow would be done once, because it would generate immortal cells that could replace the old cells of the body, whereas injecting vectors would only work partially. 

 

In case you are interested, what would be the best days and times for having a quick chat on skype to discuss this and other ideas?

 

Vicente

 

Skype:    

fider_69@hotmail.com

 

LinkedIn

https://www.linkedin...neyra-67990118/

 

References:
 

Simonsen, JL, Rosada, C, Serakinci, N, et al. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol. 2002;20(6):592–596

https://pubmed.ncbi....h.gov/12042863/

 

Valentin P. Shichkin & Mariastefania Antica. Thymus Regeneration and Future Challenges

file:///C:/Users/Mi%20Pc/Downloads/Shichkin-Antica2020_Article_ThymusRegenerationAndFutureCha.pdf

 

Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia

https://ashpublicati...sent-a-reliable

Attached Files


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#2 VicenteSilvaNeyra

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Posted 04 October 2020 - 03:25 PM

Employing vectors to produce mutations using CRISPr has a low impact on the human body. There is scientific literature about the small percentage of cells that get benefit from this technique.

Another possibility is creating a bone marrow which generates immortalized stem cells inside a body, which might mean that the new cells with higher telomerase activity will be replacing senescence cells with the help of the immune system. 

 

Old people have lost both the thymus and the production of stem cells. 

 

If we live a maximum lifespan of 120 years with a Hayflick limit of 40-60 divisions, then if the cells of our organs, tissue and blood can divide around 200 times, it might mean that the whole body would age at a very slow rate. 

 

These are some of the experiments that could be carried out:

- Create several clones of a single mouse embryo.

- Half of the embryos are immortalized through hTERT mutation, tumor suppressors genes, any other method or a combination of them. 

- The other half of the mice are genetically modified to age faster.

- When the second set gets old, they receive the bone marrow of the mice that have a higher Hayflick limit. Because all mice are clones, then the immune system should accept the immortalized bone marrow.

 

Questions:

- Will the old mice get younger and extend their lifespan?

- Is the thymus regenerated when there is a source of stem cells?

- What would happen if both thymus and bone marrow from immortalized mice are implanted in the older ones? would they be rejuvenated?

- Instead of immortalized mice, would it be possible to produce embryos and mice without a brain and nervous system? so that the immortalized set of mice provides the older clones with a source of bone marrow, thymus and other immortalized organs?.

- Is it possible to create human bodies without brains? so these brainless clones of people are made of immortalized cells and their bone marrow can be implanted in the old people who need them? 

- Which of these experiments have been already carried out?

 

I would appreciate it if we collaborate by sharing relevant information that positively gets us closer to the goal of immortality and rejuvenation.

 

Thanks for appreciating life and health more than anything else.

 

Vicente

silvaneyra (at) gmail . com



#3 VicenteSilvaNeyra

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Posted 11 October 2020 - 08:51 PM

How can we minimize the risk of stem cell infusion?

 

What is the main cause of the risk involved in stem cell infusion?

 

How can we make the whole process more efficient?

 

Anyone interested in splitting the work of doing research?

 

Possibly, we can build a team and make progress on this subject.

 

Risk according to the FDA:

https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies

 

Some possible side effects:

  • Cancer
  • Administration site reactions,
  • The ability of cells to move from placement sites and change into inappropriate cell types or multiply,
  • Failure of cells to work as expected, and
  • The growth of tumors.
  • Serious infections
  • Blindness


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#4 QuestforLife

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Posted 04 November 2020 - 12:03 PM

Once you have the edited bone marrow cells, implanting is no issue as BMSC are known to home to the marrow via SDF-1 (stromal derived factor). It might be advantageous to combine this with G-CSF in order to stimulate the resident stems cells to free up some space in the marrow for the new cells to occupy (see my brief commentary on a relevant paper, here.

 

You would then have chimeric bone marrow, but if the study you reference is correct, the immortalised bone marrow stem cells would gradually replace the senescing normal BMSCs. The main dangers would be ensuring no other changes were made to the stem cells, either genetically or epigenetically to ensure they didn't have abnormal differentiation profiles (i.e. engaging in self renewal but not differentiating as required by the body), or in offering a low bar to cancerous transformation (but this could be tested in the test tube).



#5 VicenteSilvaNeyra

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Posted 04 November 2020 - 11:18 PM

Thanks for reading my post and sharing your thoughts.

 I hold a master’s degree in physics rather than a degree in biology, so please bear with me.

 

“Is this evidence that maximum lifespan is just a function of stem cell availability?

If stem cells are available during youth, I think that the best approach to achieve life extension would be to keep the levels of hormones and the function state of every system of the body which work properly during youth, including stem cell production (with long telomeres).

 

“You would then have chimeric bone marrow, but if the study you reference is correct, the immortalised bone marrow stem cells would gradually replace the senescing normal BMSCs.

Let’s consider the next thought experiment.

1.- Mice receive an infusion of immortalized stem cells.

2.- After that, they are exposed to dietary restriction and fasting.

My hypothesis:

Assuming that the process of producing immortalized stem cells is 97% efficient, then the 3% could include mutant cells which can potentially produce cancer.

It has been shown that fasting kills cancerous cells because cancer cells lack the evolutionary mechanisms to deal with lack of food.

Then, I think that the strongest cells in mice would survive after fasting, including those which remain working efficiently after 60 divisions, therefore, immortalized cells would never achieve senescence before 100 divisions whereas normal cells would be dead by then, including some defective cells in the 3% group.

Then, the percentage of our chimeric bone marrow would have more immortalized cells than normal cells after fasting.

If we repeat this alternating process of immortalized stem cell infusion followed by fasting, we would expect to gradually replace normal stem cells by cells with higher telomerase activity (hTERT immortalized cells) until the whole body of mice is made of immortalized cells (longer lifespan).

 

Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines (click here for further information)

 

Fasting to enhance Cancer treatment in models: the next steps (click for further information)

 

Do you know if similar experiments have been carried out?

Are you interested in carrying out these sorts of experiments yourself?

What would you need to do it?

We could extend the lifespan of pets after successful attempts with mice and other animals.

 

Artificial Intelligence algorithms can help us to achieve our goals. I would need to know what the challenges are by exchanging key information relevant for you and I.

 

Thanks


 



#6 VicenteSilvaNeyra

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Posted 04 November 2020 - 11:30 PM

 The main dangers would be ensuring no other changes were made to the stem cells, either genetically or epigenetically to ensure they didn't have abnormal differentiation profiles (i.e. engaging in self renewal but not differentiating as required by the body), or in offering a low bar to cancerous transformation (but this could be tested in the test tube).

 

The rest of my answer is in the previous comment above. 

Artificial Intelligence algorithms can help us to make the process of immortalization more efficient. 

Also, I read that immortalized stem cells display lower probability of spontaneous differentiation than normal stem cells.(that's what I understood from the article shown below)

 

We could adjust the procedure to deal with risk and the efficiency of immortalization, so that we minimize fatal side effects. I can help with statistics to do this automatically.

 

Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines (click here for further information)

 

Fasting to enhance Cancer treatment in models: the next steps (click for further information



#7 QuestforLife

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Posted 05 November 2020 - 01:45 PM

Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines (click here for further information)

 

Fasting to enhance Cancer treatment in models: the next steps (click for further information

 

You may or may not be aware of the following study that immortalised HSCs in vivo (in mice), as validated by serial transplantations. 

 


Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo

https://pubmed.ncbi....h.gov/29617651/

 

Dnmt3a loss of function in hematopoietic stem cells (HSCs) skews divisions toward self-renewal at the expense of differentiation. Moreover, DNMT3A mutations can be detected in the blood of aging individuals, indicating that mutant cells outcompete normal HSCs over time...

 

AND

As Dnmt3a has been suggested to regulate telomeres (Gonzalo et al., 2006) and telomere shortening limits HSC transplantability (Allsopp et al., 2003), we computationally predicted telomere length (Ding et al., 2014). Tx-12 Dnmt3a KO HSCs showed no erosion of telomere length (Figure S4E; Table S4). Cumulatively, these data suggest Dnmt3a loss of function is sufficient to bias HSC fate decisions and initiate the pre-malignant condition of CHIP but is not sufficient to drive malignant transformation.

 

This is an example of what you don't want to do, as although you've immortalised your stem cells, you've unfortunately also stopped them differentiating as they should.







Also tagged with one or more of these keywords: htert, bone marrow, stem cells, thymus, immune system, telomerase, immortalized cells, senescence cells replacement, implanting bone marrow, yamanaka factors

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