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In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

genes genotype yamanaka factors partial reprogramming epigenetics stem cells juan carlos izpisua belmonte

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#241 Bryan_S

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Posted 21 December 2021 - 08:38 PM

Interesting this is coming out from Google's Calico: "Partial reprogramming restores youthful gene expression through transient identity suppression". Is it what there are now doing? I am sorry if you have already seen it but thought useful to log it here too.

 

Nice find, I'd hoped someone would look past the Yamanaka factors to skirt and avoid teratoma formation. These are resulting "tumor-like formations containing tissues belonging to all three germ layers." So this is a significant move forward in finding a method that presents less risk of cancers. If I understood him correctly, it appeared they were aiming for a precursor cell type that forms the adult cell types, meaning instead of targeting a pluripotent regression strategy (with cancer risk) they wanted to push cells back to just their previous intermediary cell type, not all the way back to their pluripotent state. I might be off just a little with that summation but they appear to be trying to find a less invasive risk methodology than with the Yamanaka factors.

 

Tip of the hat to this find.


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#242 Bryan_S

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Posted 24 December 2021 - 10:12 PM

Continued . . . 

 

https://www.biorxiv....4556v2.full.pdf


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#243 albedo

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Posted 07 January 2022 - 11:37 AM

From the Gladishev's lab. A section is dedicated to OSK/OSKM, interesting the hint to future possible research:

 

"...Therefore, a potential future effort might be to investigate intrinsic connections and differences between the reversal of cell identity and the reversal of biological age. In this regard, a key potential experiment would be to study the fundamental intersection of downstream gene expression dynamics common to OSK/OSKM expression and other interventions or biological events that cause robust reversal of aging assessed by molecular aging biomarkers. This would enable investigation of alternative reprogramming factors downstream of OSKM that only reverses the molecular aging biomarker readout and age-related cellular phenotypes, but not cell identity (Figure 3). Alternatively, it would be extremely interesting to identify genetic programs that lead only to loss of cell identity, but not biological age reversal. Furthermore, it is worth noting that reprogramming factors were originally identified by screening embryonic-specific gene expression patterns. Hence, the dynamics of biological age in embryos may provide insights into novel rejuvenation therapies..."

 

Zhang, B., Trapp, A., Kerepesi, C., & Gladyshev, V. N. (2021). Emerging rejuvenation strategies—Reducing the biological age. Aging Cell, 00, e13538. https://doi.org/10.1111/acel.13538

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#244 albedo

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Posted 21 January 2022 - 01:48 PM

Of course, I expect many of you know this already, but just in case I refer to this article in Nature Biotechnology here too:

 

Rejuvenation by controlled reprogramming is the latest gambit in anti-aging

https://www.nature.c...587-022-00002-4

 

Independently on long term clinical results benefiting all people (I personally always feel mixed when big money arrives w/t its cohort of hype, scientists flocking (inc. Barron, the top GSK exec) and other side-effects ... have seen so much of mixed results from similar initiatives ...), I admit I feel good we have been engaging in this discussion since long time. Btw, I have nothing against money, this is an area where we need much of it both private and public.


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#245 albedo

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Posted 02 February 2022 - 10:48 AM

Mounting evidence (preprint) from Manuel Serrano's group... I think Bezos's Altos Labs is recruiting him too ...

 

"The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum."

 

 

Dafni Chondronasiou, Diljeet Gill, Lluc Mosteiro, Rocio G. Urdinguio, Antonio Berenguer, Monica Aguilera, Sylvere Durand, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Abad, Daniel E. Martin-Herranz, Camille Stephan Otto-Attolini, Neus Prats, Guido Kroemer, Mario F. Fraga, Wolf Reik, Manuel Serrano

bioRxiv 2022.01.20.477063; doi: https://doi.org/10.1...22.01.20.477063


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#246 albedo

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Posted 16 March 2022 - 09:41 AM

In case you missed it (7 march 2022):

Cellular rejuvenation therapy safely reverses signs of aging in mice

https://www.eurekale...releases/945240


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#247 albedo

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Posted 25 March 2022 - 09:52 AM

"Stem cell therapies, including stem cell transplantation and rejuvenation of stem cells in situ, are promising avenues for tackling a broad range of diseases. Stem cells can both self-renew and differentiate into other cell types, and play a significant role in the regulation of tissue homeostasis and regeneration after cell degeneration or injury. However, stem cell exhaustion or dysfunction increases with age and impedes the normal function of multiple tissues and systems. Thus, stem cell therapies could provide a solution to aging and age-associated diseases. Here, we discuss recent advances in understanding the mechanisms that regulate stem cell regeneration. We also summarize potential strategies for rejuvenating stem cells that leverage intrinsic and extrinsic factors. These approaches may pave the way toward therapeutic interventions aiming at extending both health and life span."

 

Yusheng Cai, Si Wang, Jing Qu, Juan Carlos Izpisua Belmonte, Guang-Hui Liu, Rejuvenation of Tissue Stem Cells by Intrinsic and Extrinsic Factors, Stem Cells Translational Medicine, 2022;, szab012, https://doi.org/10.1093/stcltm/szab012

 

Will all this translate into clinic soon, hopefully with the money Belmonte et al. will get from Altos? Hopefully something will happen that I can consider! Particularly for "agers" as me it is a legitimate question to ponder what can be done in meantime ...... ;)


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#248 albedo

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Posted 01 April 2022 - 10:14 AM

In case you missed it. Highly enjoyable read:

 

Partial reprogramming deep dive: the good, bad, and partially unresolved

 

https://www.adanguye...l-reprogramming


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#249 albedo

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Posted 18 June 2022 - 11:56 AM

Oops ... we had suspicions right? Caution, also with the hype and big money:

 

In vivo reprogramming leads to premature death due to hepatic and intestinal failure

Alberto Parras, Alba Vílchez-Acosta, Gabriela Desdín-Micó, Calida Mrabti, Cheyenne Rechsteiner, Fabrice Battiston, Clémence Branchina, Kevin Pérez, Christine Sempoux, Alejandro Ocampo

bioRxiv 2022.05.27.493700; doi: https://doi.org/10.1...22.05.27.493700

 

 



#250 kurt9

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Posted 18 June 2022 - 03:36 PM

Oops ... we had suspicions right? Caution, also with the hype and big money:

 

In vivo reprogramming leads to premature death due to hepatic and intestinal failure

Alberto Parras, Alba Vílchez-Acosta, Gabriela Desdín-Micó, Calida Mrabti, Cheyenne Rechsteiner, Fabrice Battiston, Clémence Branchina, Kevin Pérez, Christine Sempoux, Alejandro Ocampo

bioRxiv 2022.05.27.493700; doi: https://doi.org/10.1...22.05.27.493700

 

I'm actually not surprised by this. The liver and intestinal cells replenish and replace themselves faster than any other tissue in the body. Not only would cellular reprogramming not be of much help here (the cells do not last long enough to get epigenetic damage and when they do, they are obviously replaced fast and effective enough as it is) but that cellular reprogramming may mess things up here. If cellular reprogramming were to fail, it would be expected that the failure would be with such fast replacement tissues. It appears that it did.

 

Yes, there is a lot of money and hype flowing into cellular reprogramming these days.


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#251 albedo

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Posted 02 August 2022 - 08:20 AM

Ariel VA Feinerman: Previously you have said that there are two types of epigenetic changes, reversible shift, which is a reaction to the cellular environment, and irreversible noise, which is stochastic. Now researchers claim that epigenetic changes are because of double strand breaks. This type is not shift or noise because this is stochastic and reversible using the Yamanaka factors (OSKM). Can you comment on this?

 

Aubrey de Grey: The problem is that OKSM doesn't only eliminate noise - it eliminates (very nearly) all epigenetic marks, whether noise or signal. The only reason it can be therapeutic is because doing just a little bit of that wiping of information seems to be OK - the cell can use the residual signal as a guide to rebuild the lost signal, whereas the proportion of the noise that was also removed is really gone. Sounds good! Except ... that in the body (even the young adult) there are a lot of cells that are most of the way to becoming cancerous. These cells are in what we can think of as an epigenetically fragile state: it doesn't take much to tip them over the edge, because their cell-cycle stabilisation defences are already damaged. So, all in all, I am currently quite pessimistic about the future of OKSM-based rejuvenation.

 

https://www.fightagi...ation-research/

 



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#252 albedo

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Posted 16 September 2022 - 10:46 AM

Grigorian Shamagian L, Madonna R, Taylor D, Climent AM, Prosper F, Bras-Rosario L, Bayes-Genis A, Ferdinandy P, Fernández-Avilés F, Izpisua Belmonte JC, Fuster V, Bolli R. Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine. Circ Res. 2019 Mar 15;124(6):938-951. doi: 10.1161/CIRCRESAHA.118.313795. PMID: 30870121; PMCID: PMC6442739.

https://pubmed.ncbi....h.gov/30870121/

 

The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2

 

"...we should consider regeneration as a global and balanced process, by involving the entirety of cardiac structures and cells types and by incorporating cellular rejuvenation as a new biological target..."

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