266 replies to this topic

[albedo]

Do not miss, if interested also to the theoretical discussion between the "programmed" vs. "damage" based theories of aging we touched earlier in this thread, the recent discussion going on in the Josh Mitteldorf's (clearly on the "programmed" side) blog titled "Aubrey and Me" where exceptionally Aubrey de Grey (on the "damage" side) is also contributing. It plays a role in the context of what is being discussed here not only for the science per se but also with reference to the research funding priorities.

 

https://joshmitteldo...0/08/aubrey-me/

 

[albedo]

Very impressed how the metylation age, as measured by the various methylation clocks, is robustly and completely reset (as you expect) when you induce pluripotency:

 

 iPS epigenetic reset of mage.PNG   228.54KB   0 downloads

 

(min ~36:40)

[HighDesertWizard]

 The outer quote from the A Heat Shock Protein-Related Switch Initiates the Aging Process in Humans thread...
 
 The inner quote from upthread...
 

This, my first non-opening-non-admin-non-question-answer post with evidence to support the conjecture...
 
I'd forgotten all about this until today. I'd forgotten that, more than a year ago, in another thread, I noticed Butyrate induced PSCs...
 
 

Studies about Butyrate and its relevance to reprogramming... I haven't looked at these in any detail. Just throwing them into the mix for discussion.
 
2010, Butyrate Greatly Enhances Derivation of Human Induced Pluripotent Stem Cells by Promoting Epigenetic Remodeling and the Expression of Pluripotency-Associated Genes
 
2013, Sodium Butyrate Promotes Generation of Human Induced Pluripotent Stem Cells Through Induction of the miR302/367 Cluster
 
2014, Sodium Butyrate Efficiently Converts Fully Reprogrammed Induced Pluripotent Stem Cells from Mouse Partially Reprogrammed Cells

 
So it turns out that Butyrate impacts HSP 70 Expression...
 
To be clear about this... I'm confused by the science posted below. Some of it runs counter to what I was expecting... But all that means is that I'm missing important knowledge...
 
1997 - Modulation of heat-shock protein 70 (HSP70) gene expression by sodium butyrate in U-937 promonocytic cells: relationships with differentiation and apoptosis
 
 

From the abstract

 

The administration of sodium butyrate at 0.75 mM induced the functional differentiation of U-937 human promonocytic leukemia cells with negligible cell mortality. However, the drug rapidly caused cell death with characteristics of apoptosis when used at concentrations of 5 mM and above. In addition, butyrate stimulated the expression of the stress-responsive heat-shock protein 70 (HSP70) gene when applied at both differentiation-inducing and apoptosis-inducing concentrations.[/size]

 

2003 - Amelioration of dextran sulfate colitis by butyrate: role of heat shock protein 70 and NF-kappaB
 
2005 - Retinoid- and sodium-butyrate– induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology
 
The conceptual net finding of this post...
 
At least one substance has been found implicated in profound Human IPSC processes. IPSCs, because they have been implicated in Rejuvenation are also implicated in Aging (and a switch?). And that same substance has been found impactful on HSP 70.
 
To get a better understanding of what's going on, see the link to Vincent Giuliano's Sept 2018 blog post referenced in the conjecture thread. 
The possibility of Falsifying the conjecture this thread opened with yesterday just got smaller...
 

 

[YOLF]

Was he saying that it's a fast evolving field, or was he waiting five weeks to conclude some endpoints? Cuz it's about five weeks now... If the later, we need to start bugging him...

Sinclair made a blog post today about rewinding epigentics:

https://www.linkedin...-sinclair-ph-d-

 

 

So then, what do I think about how cellular reprogramming research might change the field of aging science and the future of human health?

 

Ask me in five weeks.

 

 

[albedo]

 
....So it turns out that Butyrate impacts HSP 70 Expression...

 

....At least one substance has been found implicated in profound Human IPSC processes. IPSCs, because they have been implicated in Rejuvenation are also implicated in Aging (and a switch?). And that same substance has been found impactful on HSP 70....

 

 

Yes HighDesertWizard, I found a list of compounds shown to collaborate with OSKM to facilitate the iPSC reprogramming in my previous post in this thread (see the picture and the quote from the paper below) and sodium butyrate (NaB) is part of it in the category of epigenetic modifiers (HDAC inhibitors): it is next to valproic acid (VPA, a drug very known to treat epilepsy) which has a larger effect.

 

"...HDAC inhibitors have been widely used in biological studies and in clinical oncology for several indications [38]. A subset of these compounds has also been used in studies for stem-cell reprogramming (Table 1). The most extensively studied HDAC inhibitor in the context of reprogramming is valproic acid (VPA). VPA dramatically increases rates of reprogramming by up to 12% when used in combination with OSKM [31]. Even with removal of the oncogenic c-Myc from reprogramming, rates for OSK+VPA were reported to be higher than OSKM. Notably, VPA could also promote reprogramming, although at lower efficiency, with just OK transduction alone. Finally, the authors also reported two related HDAC inhibitors –SAHA and trichostatin A (TSA) – to be active in reprogramming, although to a lesser extent [39]. Sodium butyrate is another nonspecific HDAC inhibitor in the same class as VPA used in human reprogramming. When used together with OSKM, sodium butyrate showed higher reprogramming rates than VPA treatment in mesenchymal stem cells [40]...."

 

 small molecules - OSKM.PNG   89.68KB   0 downloads

 

You post goes, it seem to me, along the same lines I realized on the interplay between inflamation (as a stressor response) - senescence - OSKM induction and I too referred to the Giuliano's blog. You too point to a stress induced responder, the heat-shock-protein HSP70, so it looks coherent, IMHO.

[albedo]

From Dr David Sinclair in the two days ago AMA session at Reddit:

 

"We have made good progress on cellular reprogramming in vivo. Discoveries coming in rapidly. Have figured out a much safer approach than OSKM, in mice at least. Credit to Yuancheng Lu in our lab, and members of Zhigang He's lab at Harvard, Benedikt Brommer, Chen Wang and Songlin Zhou. Will release more info when I can."

 

I guess something to also follow closely. Any idea from your side?

[albedo]

Just seen and probably good to log it here also following the interesting point on EVs technology Bryan brought to this thread:

 

“Cellular dust” provides new hope for regenerative medicine"

"While stem cells have the most therapeutic potential, the benefits of regenerative medicine may best be mobilised using extracellular vesicles (EVs), also known in the past as “cellular dust” ..."

 

http://www2.cnrs.fr/...les_vdef_en.pdf

[OP2040]

From Dr David Sinclair in the two days ago AMA session at Reddit:

 

"We have made good progress on cellular reprogramming in vivo. Discoveries coming in rapidly. Have figured out a much safer approach than OSKM, in mice at least. Credit to Yuancheng Lu in our lab, and members of Zhigang He's lab at Harvard, Benedikt Brommer, Chen Wang and Songlin Zhou. Will release more info when I can."

 

I guess something to also follow closely. Any idea from your side?

 

Does anyone know what he means by "much safer approach than OSKM"?  Or is that what we're currently speculating about? 

[QuestforLife]

Does anyone know what he means by "much safer approach than OSKM"?  Or is that what we're currently speculating about? 

 

Probably unpublished data, although he later linked to this paper in his Twitter feed.

 

https://www.nature.c...598-018-32645-2

[OP2040]

Probably unpublished data, although he later linked to this paper in his Twitter feed.

 

https://www.nature.c...598-018-32645-2

 

Thanks QfL, that sure looks like it could be it, and very interesting even if not.

 

The delivery issue is the only thing holding back reprogramming.  Once that is addressed even a little it will be off to the races.

 

I am curious whether reprogramming is tissue specific.  In the Belmonte study, they were able to express OSKM presumably in every single tissue, regardless of the state of differentiation.  And it had dramatically beneficial effects in multiple tissues and overall health.  Before that study, I would have presumed that a differentiated cardiomyocyte is a hugely different beast from a differentiated skin cell, just to provide an example.  If it is what it looks like, it is very good news of course, but perplexing. 

[QuestforLife]

I am curious whether reprogramming is tissue specific.

It shouldn't matter as so long as OSKM factors are only expressed for a short time no de-differentiation occurs. All cells remain in their somatic identities, albeit younger. I suspect they might be more stem like so more metabolically flexible, but this hasn't been characterized to my knowledge.

Edited by QuestforLife, 05 November 2018 - 07:02 PM.

[HaplogroupW]

From Dr David Sinclair in the two days ago AMA session at Reddit:

 

"We have made good progress on cellular reprogramming in vivo. Discoveries coming in rapidly. Have figured out a much safer approach than OSKM, in mice at least. Credit to Yuancheng Lu in our lab, and members of Zhigang He's lab at Harvard, Benedikt Brommer, Chen Wang and Songlin Zhou. Will release more info when I can."

 

I guess something to also follow closely. Any idea from your side?

 

No inside info from me. But this tweet yesterday suggesting publication sometime in 2019:

 

https://twitter.com/...283243905105922

[OP2040]

No inside info from me. But this tweet yesterday suggesting publication sometime in 2019:

 

https://twitter.com/...283243905105922

 

This is really exciting news, I'm not sure I can wait until next year!  Epigenetic reprogramming is the missing piece we've been waiting for.  I am hoping that since it's not OSKM, it is not just a simple NAD+ redux.   We already know NAD+ is great, but we also know it is not in itself a game changer.  So it would actually be rather disappointing if they just show that NAD+ helps reprogram cells. 

[albedo]

...

I am curious whether reprogramming is tissue specific.  In the Belmonte study, they were able to express OSKM presumably in every single tissue, regardless of the state of differentiation.  And it had dramatically beneficial effects in multiple tissues and overall health.  Before that study, I would have presumed that a differentiated cardiomyocyte is a hugely different beast from a differentiated skin cell, just to provide an example.  If it is what it looks like, it is very good news of course, but perplexing. 

 

I think it is a good point to rise on reprogramming. I am not sure but it looks like there is a cell and tissue dependency of the epigenetic DNA methylation pattern which adds to the value of Belmonte's et al work on multiple tissues as you rightly say:

 

Ohgane J, Yagi S, Shiota K. Epigenetics: the DNA methylation profile of tissue-dependent and differentially methylated regions in cells. Placenta. 2008;29 Suppl A:S29-35.

[qge]

https://www.nature.c...201321/tables/2

Summary of small molecule compounds enhancing iPSC generation.

[OP2040]

https://www.nature.c...201321/tables/2

Summary of small molecule compounds enhancing iPSC generation.

 

I've used this list as a rough guide when I first saw it.  But for some reason it doesn't have Butyrate on there, which is a an HDAC inhibitor that is readily available, affordable and well studied.  Controlled, in vivo, reprogramming is the holy grail of anti-aging,  The controlled part is what is missing from small molecules.  We don't know if they get to all the right tissues, or if they will promote cancer in vulnerable tissues.  Another reason I like Butyrate, it's been studied quite a bit and is constantly being noted for various benefits the likes of which you would expect from a natural reprogramming agent.

 

The last part of the table is also interesting.  There we have Curcumin, Fisetin, Spermidine and Rapamycin, all of which act through different pathways.  We are used to thinking of these other compounds in terms of inflammation, senescent cells, autophagy and mTOT inhibition respectively.  So it is very noteworthy that they are considered to "promote OSKM-induced reprogramming" 

 

The lesson here is that the hallmarks of aging are all seemingly tied together quite tightly.  It would be interesting to explore the implications of that.  For example, are we missing a big process here, each part of knowledge poking at one part of the elephant....

[HighDesertWizard]

Getting a handle on all this is a serious multi-year, multi-person project. A serious effort to get a handle on it requires a map of the process. Multiple levels and types of abstraction would be required to correctly and adequately depict the process. The image below is how today I envision the high-level process. I'm certain it's fundamentally flawed. But creating successive drafts that trigger Investigation, Criticism, and Enhancement is the only way to make progress.

 

Thoughts?

 

Edited by HighDesertWizard, 06 December 2018 - 04:00 AM.

[OP2040]

Love the image HDW, but then I'm a big infograph person to begin with.

 

I have to say that when all is said and done, I think epigenetic reprogramming is going to end up at the top of a more pyramidal type graph.  It touches on every other hallmark and ultimately it is the only one that can explain embryonic development, animal regeneration, etc.  There will be a lot more to it of course.

 

One thing I think is changing fast is the concept that stem cells are this unique, specific set of cells that just sit there waiting to regenerate.  The new model should be more about "stemness" in which almost any cell can exhibit stemness given the right gene expression and circumstances.  This is a hugely important shift in mindset because it means we no longer have to go searching endlessly for stem cells.  We can reprogram somatic cells in vivo.  In animal regeneration, there is almost never a stem cell niche that does the job of creating a whole new limb or retina.  Rather all kinds of somatic cells are de-differentiated to do the job.

 

So the new idea that is just coming into view is that of opening up chromatin so that genes that do the job of de-differentiation and regeneration can be temporarily expressed in order to renew tissues.  I'm not sure stem cells are even needed. 

 

Just to provide an example of this, retinal regeneration was accomplished in mice this way.  Chromatin was opened up with an HDAC inhibitor (Trichostatin A).  This allowed for muller glial cells to de-differentiate with some reprogramming factors. and and a whole signaling cascade allowed for retinal regeneration.  Adult mice should not be able to do this, but as many studies are showing us, most vertebrate animals have basically the same set of genes but they are expressed differently. 

 

My point is that at the end of the day this may end up being much simpler than it seems right now.  After all, it's silly to think that millions of stochastic processes coordinate horizontally to grow a new human.  It has to be a top-down programming process.  If it were my map I would just add a section for removing epigenetic marks, or whatever terminology expresses that best.  That has to be done before reprogramming factors can start the tissue regeneration process.

[albedo]

I've used this list as a rough guide when I first saw it.  But for some reason it doesn't have Butyrate on there, which is a an HDAC inhibitor that is readily available, affordable and well studied.  Controlled, in vivo, reprogramming is the holy grail of anti-aging,  The controlled part is what is missing from small molecules.  We don't know if they get to all the right tissues, or if they will promote cancer in vulnerable tissues.  Another reason I like Butyrate, it's been studied quite a bit and is constantly being noted for various benefits the likes of which you would expect from a natural reprogramming agent....

 

It is a good point also touched at the beginning of this thread (see posts by HDW) and well supported, e.g.:

 

"...In another study, Blau and colleagues reported that sodium butyrate, a histone deacetylase inhibitor, induces both mouse ESCs and human ESCs to enter a distinct self-renewal state that may represent an intermediate between ESCs and EpiSCs (Ware et al., 2009). While supporting ESC self-renewal across species, butyrate elicited differential gene expression patterns and reduced the transcriptional differences between mouse ESCs and human ESCs. Therefore, ectopic expression of genetic factor(s) or small-molecule treatment is sufficient to alter states of pluripotency...."

 

Feng B, Ng JH, Heng JC, Ng HH. Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell. 2009;4(4):301-12.

 

 

..

The lesson here is that the hallmarks of aging are all seemingly tied together quite tightly.  It would be interesting to explore the implications of that.  For example, are we missing a big process here, each part of knowledge poking at one part of the elephant....

 

Good point, I hypothesize linked to the emerging evidence of biomarkers of aging and biological age, such as the DNA methylation, capturing overall underlying aging process and complexities.

[HaplogroupW]

On the topic of butyrate as an Oct4 upregulator there's this, fairly recently:

 

https://www.cell.com...2765(18)30605-1

 

BHB is produced endogenously and continuously at millimolar levels if you eat ketogenically or fast.

 

Edited by HaplogroupW, 09 December 2018 - 08:46 AM.

[albedo]

Age X (Drs Michael West and Aubrey de Grey): a company to watch in our space. You might find it interesting, e.g. look at the videos:

 

"The Future of Human Aging" (mainly min 33:35 on) and

"Discussion of iTR Publication"

 

https://www.agexinc....tations-videos/

[Bryan_S]

Love the image HDW, but then I'm a big infograph person to begin with.

 

I have to say that when all is said and done, I think epigenetic reprogramming is going to end up at the top of a more pyramidal type graph.  It touches on every other hallmark and ultimately it is the only one that can explain embryonic development, animal regeneration, etc.  There will be a lot more to it of course.

 

One thing I think is changing fast is the concept that stem cells are this unique, specific set of cells that just sit there waiting to regenerate.  The new model should be more about "stemness" in which almost any cell can exhibit stemness given the right gene expression and circumstances.  This is a hugely important shift in mindset because it means we no longer have to go searching endlessly for stem cells.  We can reprogram somatic cells in vivo.  In animal regeneration, there is almost never a stem cell niche that does the job of creating a whole new limb or retina.  Rather all kinds of somatic cells are de-differentiated to do the job.

 

So the new idea that is just coming into view is that of opening up chromatin so that genes that do the job of de-differentiation and regeneration can be temporarily expressed in order to renew tissues.  I'm not sure stem cells are even needed. 

 

Just to provide an example of this, retinal regeneration was accomplished in mice this way.  Chromatin was opened up with an HDAC inhibitor (Trichostatin A).  This allowed for muller glial cells to de-differentiate with some reprogramming factors. and and a whole signaling cascade allowed for retinal regeneration.  Adult mice should not be able to do this, but as many studies are showing us, most vertebrate animals have basically the same set of genes but they are expressed differently. 

 

My point is that at the end of the day this may end up being much simpler than it seems right now.  After all, it's silly to think that millions of stochastic processes coordinate horizontally to grow a new human.  It has to be a top-down programming process.  If it were my map I would just add a section for removing epigenetic marks, or whatever terminology expresses that best.  That has to be done before reprogramming factors can start the tissue regeneration process.

 

I'm thinking along those lines as well. I'm also watching the tech surrounding the reprogramming of white blood cells to combat cancers. Like bloodhounds, they can be told to look for specific proteins due to senescence or injury.  I'm envisioning a team of cells that could be taught to seek out areas of inflammation and damage tasked with delivering specific reprogramming factors or growth factors to help complete the healing and rejuvenation to areas of need.

 

JMHO

 

Bryan

[albedo]

@Bryan, glad you are back

 

I wonder if anyone here knows if there are progresses with Belmonte's team at Salk testing the in-vivo reprogramming on WT mice (vs the progeric). I think it is an important step, searched the web but found nothing. Tempted to contact the authors...

 

[Bryan_S]

@Bryan, glad you are back

 

I wonder if anyone here knows if there are progresses with Belmonte's team at Salk testing the in-vivo reprogramming on WT mice (vs the progeric). I think it is an important step, searched the web but found nothing. Tempted to contact the authors...

 

Here is a list of publications from Belmonte's team.

https://www.cell.com...date&startPage=

 

https://www.ncbi.nlm...onte JC[Author]

Edited by Bryan_S, 16 December 2018 - 01:37 PM.

[QuestforLife]

I think we are not far away from in vivo reprogramming using commonly available drugs and supplements. I've been researching in my Alternative Methods to Lengthen Telomeres thread all about ROCK inhibition, which remodels the cytoskeleton and helps progenitor cells to increase their number. Turns out this is a pleitrophic effect of statins. And it might be possible to combine this with the apoptosis products of senolytics to produce temporarily immortalised cells.

https://ajp.amjpatho...e/S0002-9440(13)00594-4/fulltext

In this paper the apoptosis products were provided by irradiated (senescent) feeder cells.

The correlation between apoptosis of irradiated feeder cells and the release of feeder factors that promote conditional immortalization suggests that irradiation induces these factors and/or that the factors are released from dying cells.

Another possibility is to use an mTOR inhibitor (like rapamycin) in the place of senescent cells, as was done here when reprogramming glioblastoma cells back into healthy neurons.
https://jeccr.biomed...3046-018-0857-5

We screened a kinase inhibitor library and found that a combination of two inhibitors, Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR), could substitute for transcription factors and convert human GBM cells into neural-like cells. The induced neural cells were subsequently trans-differentiated into functional neurons. The induced neurons lost their tumorigenicity and reverted to the ‘normal state’.

If you've followed my Topic you'll know I carried out a low dose statin-sartan protocol for 1 month and experienced benefits.

https://www.longecit...es/#entry863515

I'm now realising I've barely scratched the surface of what's possible.

Edited by QuestforLife, 20 December 2018 - 11:54 AM.

[albedo]

A nice recent review incl. different theories of aging (damage/epigenetics), an in-depth discussion of the Ocampo's et al results and a discussion on therapeutics ... it is coming!

 

Goya RG, Lehmann M, Chiavellini P, Canatelli-mallat M, Hereñú CB, Brown OA. Rejuvenation by cell reprogramming: a new horizon in gerontology. Stem Cell Res Ther. 2018;9(1):349.

[albedo]

An interesting and independent follow-on (not published yet) on the Ocampo et al. study Oakman posted in his OP. I think the follow-on is in particular made possible by the establishment of DNA methylation as a possible mean to check intervention results on the aging hallmarks and minimize risk of cancer:

 

Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity

https://www.biorxiv....0.full.pdf html

 

"Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. However, attempts to realise in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e. "younger" cells), rather than dedifferentiation, which bears the risk of cancer? Here we analyse cellular age during iPSC reprogramming and find that partial reprogramming leads to a reduction in the biological age of cells. We also find that the loss of somatic gene expression and epigenetic age follow different kinetics, suggesting that rejuvenation can be achieved with a minimised risk of cancer."

 

The nice work has been now published:

 

Olova N, Simpson DJ, Marioni RE, Chandra T. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell. 2018;:e12877.

 

"...Despite the obvious differences in reprogramming kinetics, our results also suggest that the improvements observed by Ocampo et al. in their OSKM‐inducible secondary reprogramming system might be due to epigenetic rejuvenation. It remains to be shown how stable in time the rejuvenated phenotype is in either of the systems. Further analysis is also needed regarding the effect of partial reprogramming on adult stem cells or premalignant cells, which have already shown a higher propensity of transforming to malignancy (Abad et al., 2013; Ohnishi et al., 2014). It is possible that a premalignant phenotype could be attenuated or amplified by partial reprogramming...."

[albedo]

 

Here's a research twist, and food for thought, think about this, reprogramming somatic cells in the absence of exogenous biochemical factors. This approach is a complete 180 from the OSKM method used in the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" project.

 

See: "Laterally confined growth of cells induces nuclear reprogramming in the absence of exogenous biochemical factors" 

 

What's the significance? You don't need OSKM factors. Environmental physical constraints were used in this example, not exogenous biochemical factors. Reprogramming gene promoters were progressively acetylated, while mesenchymal promoters were deacetylated by 10 days without exogenous biochemical factors.  In vivo, cells transdifferentiate into different lineages in the absence of exogenous factors, indicating that the local mechanochemical factors could be important elements and are sufficient for inducing such transitions. WHO KNEW? This opens up insight into areas of regenerative medicine. It appears somatic cells have more plasticity than previously thought given the proper environment.

 

What is promoting the epigenetic reprogramming? It appears the cells in contact with a designed physical substrate undergo cytoskeletal reorganization, which changes nuclear shape and facilitates nuclear orientation along the growth axis. From this the epigenetic landscape of the chromatin, particularly the levels of H3K9Ac, H3K4Me3, and H3K27Me3, changes with time. The increase in nuclear plasticity along with the reorganization of epigenetic and chromosome packing within the nucleus, with time leads to the rewiring of the nuclear architecture in a manner that primes the nucleus for reprogramming.

 

What's the takeaway? There is more than one way to skin a cat. As mentioned in the post above, cells communicate "Extracellular Vesicle-Associated RNA as a Carrier of Epigenetic Information."   

 

I believe if we find the right epigenetic targets we can regress a cell without installing an OSKM polycystronic cassette in each cell of a host organism we wish to regress in age. Remember in the OSKM polycystronic cassette it was installed artificially to encompass all the cells of the mouse at embryonic conception. This was the basis of the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" experiment. That way, "each cell" was drugable to produce OSKM factors. Here is another link to that experiment that asked many relevant questions Bursts of Reprogramming: A Path to Extend Lifespan?

 

We can't do that type of reprogramming to an adult human without the drug-inducible cassette. However, research like I posted yesterday and today show there are other ways to make epigenetic changes with our "default epigenetic software" we are all innately born with.

 

This research is very preliminary, but it appears you can regress cells without using the OSKM factors. It also appears cells can transmit epigenetic information to one another and here is a natural path to exploit if enough cells can be called into action.

 

"In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" experiment. They created a "drugable path" to produce OSKM factors at each cell. Keep in mind an adult organism like humans, represents a lot of cells to address and call into action. We now know with the new research cells release "Extracellular Vesicle-Associated RNA as a Carrier of Epigenetic Information." So here is an exploitable, innate delivery system that uses the extracellular spaces to communicate epigenetic change, cell to cell, and at much greater distances via our circulatory system across an organism. So how do we leverage an intrinsic pathway to address all the cells of the body?

 

Question one: How many Extracellular Vesicle's need to be released to affect an entire organism? Can this be done with a simple injection? I don't know for sure, something tells me you need something more persistent and overwhelming than a single injection. 

 

Then there is the cost, but what if you engineered host skin cells with an Expression cassette. Within that "drugable" expression cassette with the epigenetic message you want your Extracellular vesicle's to carry. Make the host cells do the work.

 

To create cells with the Expression cassette the host individual would donate some skin cells to be infected with the expression cassette. Then, just as we treat burn victims, these cells are grafted back into the host with the epigenetic message we want to promote. 

 

So I see a two-stage approach. Stage one is the recruitment of host cells installed and waiting to release Extracellular Vesicles with our desired epigenetic message. Next, the treatment regimen begins, and the individual takes a drug engineered to activate the expression cassette to release the epigenetic message. 

 

JMHO from what I see happening in the field.

 

Bryan

 

 

Bryan seems to be on something having introduced here the EV idea.

 

The following work is supportive for the skin rejuvenation but maybe not only for the skin. Is it a poof-of-concept toward a safer rejuvenation path?

 

Ferreira ADF, Gomes DA. Stem Cell Extracellular Vesicles in Skin Repair. Bioengineering (Basel). 2018;6(1)

 

"... Furthermore, reports have suggested that purified stem cell EVs could play a role in rejuvenating skin cells. A report from Oh and colleagues indicated that EVs from iPSCs could restore the function of aged human dermal fibroblasts. The authors reported that dermal fibroblasts pretreated with iPSC EVs resisted photoaging with UVB and did not overexpress matrix-degrading enzymes MMP-1/3 but, on the contrary, displayed a high expression of collagen I, as young fibroblasts do..."

 

"...Various stem cells types and their EVs can induce angiogenesis, including adipose, bone marrow, and umbilical cord MSCs, endothelial progenitor cells, and iPSCs [93]..."

 

Look also at:

 

Adamiak, M.; Cheng, G. Induced Pluripotent Stem Cell (iPSC)-Derived Extracellular Vesicles Are Safer and more Effective for Cardiac Repair than iPSCs. Circ. Res. 2018, 122, 296–309.

[QuestforLife]

 

Ferreira ADF, Gomes DA. Stem Cell Extracellular Vesicles in Skin Repair. Bioengineering (Basel). 2018;6(1)

 

"... Furthermore, reports have suggested that purified stem cell EVs could play a role in rejuvenating skin cells. A report from Oh and colleagues indicated that EVs from iPSCs could restore the function of aged human dermal fibroblasts. The authors reported that dermal fibroblasts pretreated with iPSC EVs resisted photoaging with UVB and did not overexpress matrix-degrading enzymes MMP-1/3 but, on the contrary, displayed a high expression of collagen I, as young fibroblasts do..."

 

 

Which explains why when I took a low dose statin and sartan for a month, my skin looked better - there probably wasn't sufficient time for skin turnover, but increased numbers of circulating endothelial progenitors could provide the beneficial vesicles to skin via capillaries. The question is how to have that benefit permanently, i.e. once the progenitors re-differentiate, the benefit would be expected to be lost, and this is indeed what I experienced; after a month or two my skin was back to my normal, 40 yo skin :(

[albedo]

"...Today, we chronicle the progress of OSKM and discuss how this powerful treatment may be able to reprogram cells back into a youthful state, at least partially reversing the hallmark of epigenetic alterations and other hallmarks as well..."

 

Hitting the Reset Button on Aging Cells (by Steven Hill of LEAF)

https://www.leafscience.org/oskm/