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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/

 



#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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#253 albedo

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Posted 22 January 2023 - 10:17 AM

I guess you all have seen this already from the Sinclair's lab. I still need to read the paper though:

 

https://hms.harvard....ion-can-reverse

 

Yang JH, Hayano M, Griffin PT, et al. Loss of epigenetic information as a cause of mammalian aging. Cell. 2023;186(2):305-326.e27.

 

Highlights
  • Cellular responses to double-stranded DNA breaks erode the epigenetic landscape
  • This loss of epigenetic information accelerates the hallmarks of aging
  • These changes are reversible by epigenetic reprogramming
  • By manipulating the epigenome, aging can be driven forward and backward
Summary

 

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called “ICE” (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.
 
Attached File  Sinclair 2023.jpg   64.13KB   0 downloads
 

 


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#254 albedo

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Posted 24 January 2023 - 10:29 PM

It is a bit dated but I always listen carefully to Aubrey, here commenting on the Information Theory of Aging and the eyesight results quoted in the paper I just posted. Right or wrong but always welcome his laser sharp analysis of results in this space:

 

"The information theory and the eyesight result are not quite so closely intertwined as you may be thinking. The information theory, in its broadest sense, is the claim that the main determinant of the age at which we start to exhibit the chronic progressive pathologies of late life is the lifelong accumulation of epigenetic noise. Stated like that, the information theory is neither new (it was first put forward in 1982 by Richard Cutler, who named it the dysdifferentiation theory) nor, in all probability, correct, any more than any other “theory of aging” is correct: the more likely state of affairs is that there is no such single main determinant, but rather that several types of lifelong accumulating damage contribute substantially but no contribution exceeds 50%. (You might get another impression from David’s recent book - but, well, he’s not the only scientist who makes certain choices about what to emphasise.) The next question is mechanistic, i.e., how does that epigenetic noise arise? David’s key idea is that the main mechanism is that the process of repairing genetic (as opposed to epigenetic) damage, such as double-strand breaks, causes an accumulation of epigenetic damage as a bystander phenomenon: first of all the epigenetic state (methylation, in particular) in the vicinity of the genetic lesion is lost when bases are replaced, and secondly the repair process entails the temporary redistribution of DNA protection proteins from elsewhere in the genome, thus exposing those other areas to accelerated damage. That’s a highly plausible and valid theory. So is the theory of Andrei Gudkov, that the DNA damage is mostly caused by retrotranspsons. Not only that, those two theories are linked, because retrotransposon activation is itself caused by epigenetic damage. But honestly the mechanism doesn’t much matter, as I’ll explain.

So, what about the (very impressive) eyesight result? It really tests (and validates) a different theory, namely that partially removing epigenetic noise is beneficial. Note the difference: there’s no reference to the mechanism by which the noise was created in the first place, nor to whether epigenetic noise contributes more to aging than all other types of damage combined. A lot of confusion arises when people fail to make this sort of distinction - when they conflate theories about how aging happens with theories about how it can be mitigated. Indeed, it could be argued that the main thing I did by introducing SENS was to highlight the importance of keeping the two distinct.

So far so good. But the thing is, the specific method of removal of the epigenetic noise is rather critical to what is really being shown. What’s actually being shown is a very much stronger result than I wrote above, namely that whacking the entire genome with a a stupefyingly indiscriminate and non-selective baseball bat called OSKM (or in David’s case only OSK) can do more good than harm if you do it just right. The point here is that such interventions don’t have a way to distinguish between epigenetic marks that are noise and marks that are signal, i.e. are acting to make the cell do what it’s supposed to do. All it can do is remove some proportion of those marks, of both types. So what we are showing when we do this and get a desirable result is that the differentiated epigenetic state is really robust and redundant, such that we can blitz quite a lot of it and the cell still knows what sort of cell it is. Plus, the fact that the cells become more regenerative means that the marks that define what sort of tissue the cell is part of are even more robust than the marks that narrow it down to its terminally differentiated state.

So, what’s not to like? Well, as so often in aging, that comes down to one word: cancer. David’s main reason for using OSK rather than OSKM is that M is c-Myc, an oncogene. The fudamental issue here is that every adult, let alone middle-aged or older adult, is chock full of cells that have already acquired most of the mutations needed to turn them into cancer cells, and the only reason they haven’t acquired all such mutations is that mutation is stochastic - a numbers game. And that can also be thought of in terms of robustness and redundancy. A pristine cell has layer upon layer of ways to stop itself from dividing more than it’s supposed to, and these mutations progressively degrade those defences and make them more and more fragile. Not the sort of thing you would want to hit with a baseball bat, right? And what’s worse, you won’t know you’ve turned a bunch of nearly-cancer cells nto actual cancer cells until they have gone on and divided enough to become detected, which usually means someone displaying symptoms. So we can’t infer much at all about the magnitude of this problem from short-term experiments. What I’m hoping for (and yeah, I’m trying my best to make it so) is that people like David, and Belmonte (the most prominent researcher in this area), and others, will take the cancer risk more seriously than their not-necessarily-all-that-far-sighted reviewers and investors may, and devise smart ways to quantify the cancer risk of such interventions as early as possible. This won’t be easy, but it’s vital. If we hide our heads in the sand and engage in oversimplistic overoptimism about this risk, we are very likely to spend a great deal of time and money on therapeutic dead ends. I’m certainly not saying that partial reprogramming (as this is called) in general is a dead end, but I’m very much saying that it will not fulfil its potential, or at least nowhere near as soon as it could, unless we focus squarely on the cancer side-effect every step of the way."

 

https://qr.ae/prY1I3

 


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#255 albedo

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Posted 28 January 2023 - 11:45 AM

Expect a lot of discussion on the Sinclair's paper:

 

"...It’s important to bear in mind that this is where the study ended. They didn’t show that the mice given the Yamanaka treatment looked or behaved any younger (nor, unlike the first study, did they check whether they lived longer). The study didn’t report any attempt to measure this – which might seem surprising and disappointing to readers intrigued by the claim about ageing now being fully under scientists’ control..."

 

"...The second one artificially induced ageing, but there are still big questions over exactly how it did so (Brenner and a colleague, James Timmons of Queen Mary, University of London, plan to write a critique of the second paper, so we can expect the debate to continue)...."

 

https://inews.co.uk/...excited-2101013

 

I realize there is a lot of push back (for whatever reasons) by Brenner against Sinclair though. Will see what will happen on published papers (not only opinion blogs)  as time goes on ....



#256 albedo

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Posted 09 May 2023 - 08:15 AM

Progress continues on this front, powered by Sinclair's resources, with interesting results:

 

Glimpse of success? Life Biosciences' gene therapy restores visual function in primates with eye disorder

https://www.fiercebi...-primates-naion

 



#257 albedo

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Posted 02 July 2023 - 02:29 PM

Have you a take on this debate (Peter Fedichev - Aubrey de Grey)?

 

Attached File  Fedichev - DeGrey - Entropy - Reprogramming.jpg   98.04KB   0 downloads

 

You might also see few comments on Fedichev's on Reddit, here:

ing clocks, entropy, and the limits of age-reversal : r/longevity (reddit.com)

 

Fedichev et al preprint is here:

https://www.biorxiv.....02.06.479300v1


Edited by albedo, 02 July 2023 - 03:13 PM.


#258 stephen_b

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Posted 16 July 2023 - 05:12 PM

[Moved from a different thread]

 

Chemically induced reprogramming to reverse cellular aging was published 2 days ago. It examines using small molecule cocktails to achieve the same results as complicated genetic interventions in reducing aging. There are 6 cocktails examined.

 

There are a lot of ideas in the paper. Some of the small molecules might be candidates for incorporating into this protocol. I see that alpha ketoglutarate is mentioned as increasing iPSC efficiency. Forskolin and valproic acid were mentioned as being "likely to work in the early stages of CiPSC formation", where work means "achieve age reduction without altering cell identity". 

 

In the discussion section, the authors had this to say about forskolin:

 

 

The final chemical in our most efficacious C1 cocktail, forskolin, is an activator of adenylyl cyclase that has been shown to drive reprogramming and trans differentiation, depending upon the combination of other compounds present [7475]. While the mechanism of action of forskolin in the context of rejuvenation remains to be identified, increasing cellular levels of cAMP and the triggering of signal cascades that are critical for adaptations in cell identity may be key.

 

 


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#259 albedo

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Posted 09 January 2024 - 04:28 PM

You have likely seen this in Nature, but just in case ... (great paper)

 

Lu YR, Tian X, Sinclair DA. The information theory of aging. Nat Aging. 2023;3(12):1486-1499.
https://pubmed.ncbi....h.gov/38102202/

Attached File  ITOA.png   248.34KB   0 downloads


Edited by albedo, 09 January 2024 - 04:45 PM.

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#260 albedo

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Posted 17 January 2024 - 11:49 AM

I learned about the importance of vesicles in reprogramming by Bryan_S in this thread early on ... :)

Here is another important application in aging and mitochondria:

https://www.quantama..._eid=d585a1e10e

"Biologists discovered that mitochondria in different tissues talk to each other to repair injured cells. When their signal fails, the biological clock starts winding down."

 



#261 kurt9

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Posted 17 January 2024 - 05:47 PM

The key is to replicate the self-repair process without the germline.


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#262 albedo

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Posted 06 February 2024 - 08:51 AM

"The induction of cellular reprogramming via expression of the transcription factors Oct4, Sox2, Klf4 and c‐Myc (OSKM) can drive dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. However, the benefits of long-term in vivo reprogramming are limited by detrimental side‐effects. Here, using complementary genetic approaches, we demonstrated that continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction resulting in decreased body weight and contributing to premature death (within 1 week). By generating a transgenic reprogrammable mouse strain, avoiding OSKM expression in both liver and intestine, we reduced the early lethality and adverse effects associated with in vivo reprogramming and induced a decrease in organismal biological age. This reprogramming mouse strain, which allows longer-term continuous induction of OSKM with attenuated toxicity, can help better understand rejuvenation, regeneration and toxicity during in vivo reprogramming." (red mine)

 

Parras A, Vílchez-Acosta A, Desdín-Micó G, et al. In vivo reprogramming leads to premature death linked to hepatic and intestinal failure. Nat Aging. 2023;3(12):1509-1520.
https://www.nature.c...587-023-00528-5

 

 


Edited by albedo, 06 February 2024 - 09:23 AM.

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