266 replies to this topic

[albedo]

Not yet listened to this presentation by Dr. Oliver Medvedik going deep in the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" paper (1.5 hours). I just discovered it and wished to lot it here for the benefit of everyone:

 

https://www.leafscie...-club-may-2017/

 

Great video, really going deep into the paper and every single figure. Experts I think will appreciate. Interesting comment on SENS, quite positive but he seems definitively fostering a multi-prong approach, causation (maybe) vs correlation (definitively), answered well to normal criticism of using "non-normal" mice (progeric and with the four factors inserted in wild type, when translation to human he safely bet on increasing healthspan at least (vs. lifespan). Of course IMHO and limited understanding but very much worth to follow video as educating.
 

[Bryan_S]

Most likely if we could deliver interventions to the body with specificity and ease, some of the terrible diseases of aging would already be pretty well tamed. 

 

 

I've been thinking about this. I remembered bacteria transferred capabilities between them, in fact, they do a lot of genetic transfers between them. Then I began looking at the higher lifeforms to see if there was any cell to cell communication at a genetic level. I found ARC "Brain Cells Share Information With Virus-Like Capsules" So I did more reading and it seems we have the innate capability to do this across most tissues. We think in terms of using a retrovirus but it seems we have this capability within us.

 

"Extracellular Vesicle-Associated RNA as a Carrier of Epigenetic Information" So this looks like the beginnings of a delivery method. Still need a target but it seems to me cells could be programmed to manufacture the proper EVs to reset certain chromatin sites rejuvenating the recipient cell.   "Thus, coming back to EVs, both coding and non-coding RNAs in vesicles could act as protein carriers that transport proteins from one cell to another; once in the recipient cells, these proteins may bind and modify chromatin structure and activity, acting as epigenetic players able to modify gene expression."

 

 

JMHO

 

Bryan

[albedo]

Maybe the following can help in answering:

 

Federation AJ, Bradner JE, Meissner A. The use of small molecules in somatic-cell reprogramming. Trends Cell Biol. 2014;24(3):179-87.

https://www.ncbi.nlm...les/PMC3943685/

 

small molecules - OSKM.PNG

 

"...Most small molecules identified to date that provide enhancements of somatic cell reprogramming are able to compensate for three of the four canonical factors, SKM. The identification of molecules that can substitute directly for Oct4 transduction has proved difficult, but recent progress is encouraging [77]. Earlier this year, the first successful reprogramming experiment using only small-molecule compounds was published [26], using a combination of VPA, CHIR99021, 616452 (an ALK inhibitor), tranylcypromine (an LSD1 inhibitor), forskolin (an adenylyl cyclase activator), and late treatment with the global methylation inhibitor DZNep, which leads to broad reduction in histone methylation..."

 

I continued reading on what can be tried to support inner resources by helping also the adult stem cells regeneration.

 

Several intervention are well known in the community (e.g. small molecules such rapamycin, metformin, nicotinamide riboside as well as CR ...) and this paper found on ResearchGate from the same Belmonte’s group of the “In Vivo Amelioration…” study, put these interventions, at the intersection between metabolism and reprogramming, in context. I found it encouraging:

 

« Mechanistically, due to the metabolic and epigenetic remodeling observed during cellular  reprogramming, it is possible that partial reprogramming induces the rejuvenation of stem cell populations and restores cellular metabolism and epigenetic regulation in multiple tissues …  it may be possible to regulate lifespan by directly manipulating the stem cell epigenome using metabolites or small molecules...”

 

 young SC.PNG   216.41KB   0 downloads

 

Ren, R., Ocampo, A., Liu, G. and Izpisua Belmonte, J. (2018). Regulation of Stem Cell Aging by Metabolism and Epigenetics.

[Bryan_S]

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

Edited by Bryan_S, 10 July 2018 - 06:15 PM.

[albedo]

 

.....

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?

 

.....

 

Thank you. If I understand correctly, you seem fostering a multi-paths approach to the reprogramming and this seems to me very reasonable if we want to go as quick as possible to clinical. The most effective and safe therapies will then emerge naturally. This multi-paths approach appears also when comparing the reprogramming to other approaches as in the Fig. 1 in the study "Bursts of Reprogramming: A Path to Extend Lifespan?" you have provided:

 

 bursts of reprogramming.PNG   406.15KB   0 downloads

 

Note that in the figure many features are reported as not tested (NT). Rapamycin, as an mTOR inhibitor (and its possible epigenetic effect on histone methylation?), seems so far the best tested treatment, also in line with what discovered in my previous post.

 

The cell “drugable” approach to produce OSKM let me also think about the Pharma interest and funding: e.g. a patentable inductor, a small molecule or peptite (I mean different than doxycycline or tetracycline), activating the polycistronic cassette containing the genes for the factors, would be needed. I think this is, in particular, what Youthereum is looking for to get Pharma interested.

 

Also, I expect extensions from cells to full organisms to be very challenging, so maybe an initial focus on specific organs might be effective and quicker to clinic. To some extent the study I posted previously (by Tapash Jay Sarkar and Vittorio Sebastiano: "Rejuvenation on the Road to Pluripotency") proposes an approach in that direction.

 

"...The organoid platform also provides the opportunity to look at an additional dimension of aging in addressing the rejuvenation of tissue functionality. This moves beyond the Hallmarks of Aging, which are fundamentally at the cellular level, to focus on the emergent function of specific tissues which degrades due to the hallmarks. So far, very little work has been done on assessing organoid functionality..."

Edited by albedo, 11 July 2018 - 10:51 AM.

[Bryan_S]

OK just so we don't leave everyone behind here's research to support the idea of horizontal epigenetic and genomic transfers between cells. This post is meant to help build the ideas to reach a delivery path to support something like the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" study. "The study suggests that epigenetic changes drive the aging process, and that those changes may be malleable. "We did not correct the mutation that causes premature aging in these mice," says lead investigator Juan Carlos Izpisua Belmonte, a professor in the Salk Institute of Biological Science's Gene Expression Laboratory. "We altered aging by changing the epigenome, suggesting that aging is a plastic process." But as we've read these researchers used an OSKM polycystronic cassette installed in each host cell. Humans are not equipped as such.

 

Let's literally start at the beginning to show how nature may provide answers on how to proceed:

 

"Bacteria and Humans Have Been Swapping DNA for Millennia" 

 

 

"This DNA-sharing process, known as horizontal or lateral gene transfer (LGT), is now understood to occur by the direct movement of DNA between two organisms. Almost all bacterial genomes show evidence of past LGT events, and the phenomenon is known to have profound effects on microbial biology, from spreading antibiotic resistance genes to creating new pathways for degrading chemicals. But LGT is not limited to bacteria. Scientists now recognize that microbes transfer DNA to the plants, fungi, and animals they infect or reside in, and conversely, human long interspersed elements (LINEs) have been found in bacterial genomes."

 

So bacteria do it, and not with just their own species. In fact, all species have been conducting this mixing experiment for a very long time.

 

Credit; The figure above is taken from Doolittle's Scientific American article "Uprooting the Tree of Life" (February 2000). © Scientific American

 

Horizontal Gene Transfer in mammalian cells. Have any of us wondered why research with Chimeras has stalled as a source of human organs?  Chimeras are a mix of cells from two species that can grow into an adult organism. Sure there are press releases on progress but this technology but its opened up the possibility of creating cross-species pathogens and diseases that today only exist in one species but not another. Many diseases don't cross from one species to the other but Chimeras can produce diseases that are adapted to both. Why? Because of the Horizontal Gene Transfer within mammalian cells, some cells become hybrids of both species.

 

Some reading on "gypsy retrotransposons" is helpful in reckoning this epigenetic and genetic transfer topic. In the case of Chimeras, we are inviting genetic cross-talk at a very intimate level.

 

See article: "Pig-human chimeras contain cell surprise"

"The adult pigs that had received human stem cells as fetuses were found to have pig cells, human cells and the hybrid cells in their blood and organs." “What we found was completely unexpected. We found that the human and pig cells had totally fused in the animals’ bodies,” said Jeffrey Platt, director of the Mayo Clinic Transplantation Biology Program."

 

OK, so we are beginning to get the picture if two species share the same extracellular environment and each are exposed to the same nuclear messaging RNA (epigenetic messaging) in some cases, DNA and other information can be shared between cells. Here is where we begin to look at extracellular vesicles as the big information carriers.

 

Now, these pathways seem to have been conserved ancient transfer methods that took on new roles as life evolved. In fact, as demonstrated in the article "Brain Cells Share Information With Virus-Like Capsules"

 

"So our neurons use a viral-like gene to transmit genetic information between each other in an oddly virus-like way that, until now, we had no idea about. “Why the hell do neurons want to do this?” Shepherd says. “We don’t know.” One wild possibility is that neurons are using Arc (and its cargo) to influence each other. One cell could use Arc to deliver RNA that changes the genes that are activated in a neighboring cell. Again, “that’s very similar to what a virus does—changing the state of a cell to make its own genes,” says Shepherd."

 

The truth is, today we hardly understand the cargo that is moving between neurons.

 

So what purpose can this serve? In the above example, it looks to be long-term memory or the strengthening of neural pathways. Next, let's think about the immune system.

 

“Small talk” in the innate immune system via RNA-containing extracellular vesicles

 

 

"Extracellular vesicles comprise a highly refined system of intercellular communication, which is widely employed by immune cells. EV are unique carriers of information, since signaling molecules and molecules that mediate selective targeting of the transferred messages are combined within a single particle. This allows for tailor-made delivery of molecular messages to designated recipient cells. Different types of short and long non-coding RNA sequences can be present in EV and, at least in vitro, can be functionally transferred to recipient cells. EV-mediated RNA transfer by either innate immune cells or non-immune cells can influence innate (antimicrobial) immune responses."

 

OK, now we are at the point of illustrating how this can be used to modify our epigenetic profile and a host of other applications.

 

 

See: Focus on Extracellular Vesicles: Development of Extracellular Vesicle-Based Therapeutic Systems The potential is now beginning to be fathomed. "Research aimed at developing extracellular vesicles (EVs) for clinical applications. APC: Antigen presenting cell; DCs: Dendritic cells; iDCs: Immature dendritic cells; DDS: Drug delivery system; GVHD: Graft-versus-host disease; MSCs: Mesenchymal stem cells."

 

In many ways, our posts here at Longecity help promote the intermingling of ideas. As far as this topic goes "Bursts of Reprogramming: A Path to Extend Lifespan?" 

there are many supporting research programs that will contribute to the eventual clinical trials. As said before we still need the appropriate epigenetic targets.

 

 

As always JMHO

 

Bryan

Edited by Bryan_S, 11 July 2018 - 09:37 PM.

[albedo]

 

OK just so we don't leave everyone behind here's research to support the idea of horizontal epigenetic and genomic transfers between cells. This post is meant to help build the ideas to reach a delivery path to support something like the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" study......

...

 

Wow, that is good, you seem having wrote this for me as I for one was starting to get lost and this post helped :-) I start to get what you are heading to. 

 

I went back to the "Laterally confined growth of cells induces nuclear reprogramming in the absence of exogenous biochemical factors" paper and realize “…Collectively, our results highlight an important generic property of somatic cells that, when grown in laterally confined conditions, acquire stemness. Such mechanical reprogramming of somatic cells demonstrated here has important implications in tissue regeneration and disease models…”.

 

So now we have a strategy path based on not using the OSKM induction but what has been shown with good evidence is that in the path to pluripotency by inducing OSKM and, with a specific time controlled protocol to avoid cancerous aberrations, they tested a reversal of 7 of the 9 hallmarks (see my post). It maybe be trivial but what evidence do we have that a non-OSKM strategy does the same? It should be so though, at least intuitively, as your go from a somatic status to one of acquired stemness, but what about cancer? They write "...Importantly, we also demonstrate, by using this platform, the induction of cancer stemness properties in MCF7 cells...".  Again it looks like a multi-prong approach is needed and the new path you seem fostering might get to clinics faster for tissue/organ regeneration. However let's keep in mind we wish to fight aging in its globality and, even if we should not take that (or SENS) as a bible, we have so far the Hallmarks as a guide.

[triguy]

From the remarkable Hallmarks of Aging (2016) paper also on butyrate, integrative hallmarks and role of microbiota:

 

"...It is therefore possible—yet remains to be proven—that the positive effects of metformin in patients with type 2 diabetes are linked to an increased abundance of Escherichia spp. within the gut microbiome, resulting in the abundant production of short-chain fatty acids, such as butyrate and propionate, with beneficial activity (Canfora et al., 2015)...."

 

Butyrate.PNG

 

Integrative Hallmarks of Aging.PNG

 

López-otín C, Galluzzi L, Freije JM, Madeo F, Kroemer G. Metabolic Control of Longevity. Cell. 2016;166(4):802-21.

http://www.cell.com/...8674(16)30981-3

 

metformin interferes Wirth igf1 production.

 

igf-1 is a big part in fighting aging

 

http://journals.plos...al.pone.0061537

[Bryan_S]

Wow, that is good, you seem having wrote this for me as I for one was starting to get lost and this post helped :-) I start to get what you are heading to. 

 

It maybe be trivial but what evidence do we have that a non-OSKM strategy does the same?

 

I think there are going to be many spinoffs from this such as regenerative medicine. Shooting for longevity is going to provide research into many areas we didn't expect.

 

I think this topic is a bit thick for most of us, at least me, so your input is valuable and telling about what needs to be covered. You also ask a very important question, "what evidence do we have that a non-OSKM strategy does the same?"

 

You're asking the right questions, and you also in a roundabout way answered the same.  "...Importantly, we also demonstrate, by using this platform, the induction of cancer stemness properties in MCF7 cells..." Plus as we covered, we don't have a drug-inducible, polycistronic expression cassette that permits rapid and potent induction of OKSM of the individual factors. This approach is a nonstarter for humans, and there are cancer risks. To answer your question head-on, yes and no.

 

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

This study shows the context of the environment can induce cell plasticity and there are specific epigenetic locations being activated. I believe advances in regenerative medicine and spinoff applications to aging will emerge from this study. I never imagined a mature cell could regress and play another role. So, this is yes but not applicable to an entire organism at least where this study left off.

 

As I read the article you posted "Rejuvenation on the Road to Pluripotency" 

Other epigenetic reprograming avenues are discussed in "3.2. iPSC reprogramming vs other longevity/rejuvenation technologies" Now respectfully consider this, and I mean no disrespect because that author covered a lot of relevant topics, but the insights given here are somewhat dated. Submitted: October 27th, 2015.

 

Hard to believe 3 years is a little behind the curve, but by comparison 15-years ago this topic was moving at a relative snail's pace. Let me give you a sense of how quickly this field is emerging and this chart is in no way up to date.

 

 

Your observation of tumors and cancers from the OSKM technique is not an entirely foregone conclusion but a topic of considerable concern. It appears if a cell is overexposed to OSKM factors, prematurely terminated from exposure or is predisposed to such cancer states, (or should I say already on the fence,) increasing that cells plasticity could have an undesirable effect. So this technique appears to have the characteristics of a balancing act. The flip side, it also shows the possibility of correcting some cancer states. The OSKM technique has opened so many doors.

 

See: "Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation" 

 

I will say there have been jewels within the failures possibly explaining previously misunderstood childhood conditions. See next; "In vivo reprogramming drives Kras-induced cancer development." 

"Indeed, our previous study demonstrated that premature termination of in vivo reprogramming leads to kidney cancer development through altered epigenetic regulation. Consistent with the partial reprogramming state, these cancer cells lose kidney cell-specific molecular signatures while they partially acquire the trait of embryonic stem cells (ESCs) including self-renewing capacity. Notably, these cancers resemble Wilms’ tumor, which is the most common childhood kidney cancer. Furthermore, these cancer cells were readily reprogrammable into iPSCs that are capable of differentiating into non-cancerous kidney cells. These results raised the possibility that reprogramming-associated epigenetic regulation has a significant impact on childhood cancer development, which is also in agreement with recent observations that childhood cancers harbor relatively few genetic mutations. However, the functional significance of epigenetic regulation related to cellular reprogramming remains largely unclear in adult cancer development."

 

I see a few bright spots in the field that I think will help take on a guiding role.

 

Do you remember the UC Berkeley Conboy study? Ageing research: Blood to blood

"By splicing animals together, scientists have shown that young blood rejuvenates old tissues. Now, they are testing whether it works for humans."

After millions of dollars were dumped into this idea Conboy revised the experiment so the blood could be turned off. They would allow enough time for a 50/50 blood exchange and disconnect the mice. This eliminated the influence of shared organs which was thought to be skewing the data. As expected, the old mouse blood had a devastating effect on the young mice and on the flip side old mice hardly benefited at all. Their research team has begun to investigate what factors in the old blood that might cause the young mice to decline. I think their insights will prove to be very illuminating within the epigenetic reprogramming topic of this forum.

 

So what this new experiment appeared to indicate is the old mice were benefiting from the young mouse's organs, i.e., lungs, liver, kidneys and so on. It was also thought the old mice benefited from a dilution of the old-mouse inhibitors that adversely affected the young mice. So this is where I think this comes full circle back into this forums epigenetic topic, understanding the undesirable effects is as valuable as the positive ones and mapping those epigenetic markers needs to commence.

 

See the UC Berkeley Conboy study refuting many of the previous beliefs the media helped spawn: "A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood"

I think this is precious research.

 

So since these mice are bred to be genetically identical to avoid tissue rejection. My belief is the comparative epigenetic profiles of the joined, and intermittently connected mice will prove very insightful into which epigenetic locations are of interest to study. Certainly which epigenetic positions you might want to inhabit that caused tissue and organ damage to the young mice.

 

I don't think its necessary to take on a full OSKM factor approach but it does ring many of the right bells. The trick will be is how to regress the cell without losing tissue identity or leave a cell teetering between cell states. If a cell already has a tendency to move towards a cancerous state and many cancers are now being found to resemble earlier states of cell progression, this might be a huge hurdle. How can you know if the patient might be predisposed to particular cancer?

 

So I lean more towards a soft selective approach whereas the full OSKM factor approach opens too many doors of chance. I believe that in the UC Berkeley Conboy study not only were the old mice benefiting from the young mouse organs but also from constant exposure to their young extracellular vesicles and hormones helping to improve tissue regeneration and plasticity. See "Extracellular vesicles and aging" 

 

So along the murine parabiosis model here are two studies recently published.

Also see: "Long-Range Function of Secreted Small Nucleolar RNAs that Direct 2'-O-Methylation" 

 

Running title: Long-range function of secreted snoRNAs

 

So since I'm not a scholar in epigenetics like many of you, these studies take awhile to digest and hence an investment of time is required. Also once you think you have a firm grasp the next paper appears and changes the landscape. So, on the one hand, I experience some frustration, on the other as an optimist I see the rapid publication of papers to be a great thing even if I have to disregard some ideas from a previous article.

 

As always JMHO

 

 

Bryan

[albedo]

 

I think there are going to be many spinoffs from this such as regenerative medicine. Shooting for longevity is going to provide research into many areas we didn't expect.

 

I think this topic is a bit thick for most of us, at least me, so your input is valuable and telling about what needs to be covered. You also ask a very important question, "what evidence do we have that a non-OSKM strategy does the same?"

 

.....

So I lean more towards a soft selective approach whereas the full OSKM factor approach opens too many doors of chance. I believe that in the UC Berkeley Conboy study not only were the old mice benefiting from the young mouse organs but also from constant exposure to their young extracellular vesicles and hormones helping to improve tissue regeneration and plasticity. See "Extracellular vesicles and aging" 

 

...

 

The EV focus which Bryan is bringing into this thread (see also a general comment at the end of this post) is very intriguing as it looks like, again to my very limited understanding, we can have a different anti-aging strategy, again fundamentally epigenetic in nature, and exploiting inner cellular and extra cellular communication resources, without the need of exogenous factors à-la-OSKM. I think it is a different research path but equally valuable:

 

From the study you posted “Extracellular vesicles and aging" :

 

“…This review focuses on the role EVs could play in aging, their therapeutic application for extending healthspan and their potential for use as biomarkers of unhealthy aging….”

 

“… EVs are comprised of both microvesicles, released from the plasma membrane by shedding, and nanovesicles or exosomes, generated by reverse budding of multivesicular bodies (MVBs) (47,48). These different types of EVs are characterized predominantly by their size, with exosomes ranging from 30 to 100 nm and microvesicles usually being larger than 100 nm. Although their contents likely differ, both small and large EVs are enriched for a subset of diverse proteins, lipids, messenger RNAs (mRNAs), and non-coding RNAs (ncRNAs), such as miRNAs, which are derived from the parental cells…”

 

So I went naturally researching more on EVs, e.g. exosomes, in the aging process (always trying to have sort of "global" approach to aging) and discovered (2018) an interesting link  to what some considers the center of aging regulation, the hypothalamus, and epigenetic microRNA gene expression regulation mediated by exosomes, somewhat supporting that we do indeed have some positive evidence in reply to my previous post question: “what evidence do we have that a non-OSKM strategy does the same?" ("same" meaning referring to the impact of OSKM reprogramming on the Hallmarks)

 

“…It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs…”

 

Zhang Y, Kim MS, Jia B, et al.: Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature. 2018

 

Also note that here Sox2 (of the OSKM) is key while in other case the key role seems to be taken by Oct4.

 

As a general comment on this thread which is the toughest I personally recollect on LC, we are likely, surely myself, “learning by doing”, meaning that I am discovering and learning stuff at the same time, so please apologize possible gross misunderstandings, repetitions or completely wrong paths of thoughts of which, of course, I take full responsibility of !

 

[albedo]

metformin interferes Wirth igf1 production.

 

igf-1 is a big part in fighting aging

 

http://journals.plos...al.pone.0061537

 

OK but suggest to consider more broadly also an ensemble of approaches, metabolic and metabolic/epigenic oriented, as indicated in several posts, e.g. here and here

 

 small molecules - OSKM.PNG   89.68KB   0 downloads

 

Federation AJ, Bradner JE, Meissner A. The use of small molecules in somatic-cell reprogramming. Trends Cell Biol. 2014;24(3):179-87.

https://www.ncbi.nlm...les/PMC3943685/

 

 young SC.PNG   216.41KB   0 downloads

 

Ren, R., Ocampo, A., Liu, G. and Izpisua Belmonte, J. (2018). Regulation of Stem Cell Aging by Metabolism and Epigenetics.

https://www.cell.com...4131(17)30484-9

 

and in the Hallmarks (2016):

 

 hallmarks metabolism.PNG   148.69KB   0 downloads

 

López-otín C, Galluzzi L, Freije JMP, Madeo F, Kroemer G. Metabolic Control of Longevity. Cell. 2016;166(4):802-821.

https://www.cell.com...8674(16)30981-3

 

 

 

 

 

 

[Never_Ending]

-

Edited by Never_Ending, 15 July 2018 - 10:50 AM.

[albedo]

Thinking about the application of iPSC to the clinic this short paper provides a synthetic overview and many references if we want to investigate deeper.

 

In sum, there are well studied challenges, both in science and regulation, which have been partially solved in the recent years with an hopefully full resolution for human transplantation leveraging the huge incoming revolution of genome editing:

 

Garreta E, Sanchez S, Lajara J, Montserrat N, Belmonte JCI. Roadblocks in the Path of iPSC to the Clinic. Curr Transplant Rep. 2018;5(1):14-18.

Edited by albedo, 16 July 2018 - 09:37 AM.

[Harkijn]

Bryan and Albedo, I am still reading your posts as well as some of your references. Thanks for your efforts!

[Bryan_S]

The EV focus which Bryan is bringing into this thread (see also a general comment at the end of this post) is very intriguing as it looks like, again to my very limited understanding, we can have a different anti-aging strategy, again fundamentally epigenetic in nature, and exploiting inner cellular and extra cellular communication resources, without the need of exogenous factors à-la-OSKM. I think it is a different research path but equally valuable:

 

albedo, Thanks for taking the time to review the papers.

 

I think as we cover the successes reached in the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" study, we have to look at the surrounding research to evaluate its possible clinical value going forward. This one proof of concept study has shown us previous hurdles can be overcome.

 

In general, iPSCs appear to be the ideal source of replacement cells for organ disease states. A patient-specific cell line isn't prone to rejection and it belongs to that individual. In the test tube environment, these cells continue to replicate and can be encouraged to become different replacement tissues. However once introduced back into the patient they don't always perform as expected and in many cases they do nothing. I'm by no means suggesting there haven't been medically significant iPSC reprograming successes or that lives haven't been saved, just that the performance of these resulting cells is impaired as we'll discuss.

 

Here is an example of the progression of a stem cell.

 

It seems as we age past reproductive maturity slowly the extracellular environment fills with growth inhibitors as opposed to promoters. Some tissues are affected more than others. As we weigh this against observed epigenetic changes this appears to be tied to reproduction. "The Expensive Germline and the Evolution of Ageing"  and the "Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction" 

 

We can regress the age of a cell to an iPSC state. However, when those reverted cells are transplanted back into an aged host patient, the iPSC is exposed to a cocktail of cell signaling inhibitors. I believe this has been one of the most significant hurdles to regenerative medicine. Here is an artical how this aging process suppresses bone marrow stromal (stem) cell proliferation, and induces stem cell senescence.

 

The changing epigenetic landscape: The Horvath clock is defined as an age estimation method based on 353 epigenetic markers on the DNA. "However, it is unlikely that the 353 clock CpGs are special or play a direct causal role in the aging process.[1] Rather, the epigenetic clock captures an emergent property of the epigenome."

 

The causal relationship between active growth promoting epigenetic markers and active inhibitor cites has not been thoroughly worked out but is in process. So at best the Horvath clock is simply an indicator of epigenetic age and change and doesn't represent the actual causation or effect of such epigenetic markers. Research into the direct relationships between cause and effect across the epigenome needs further study and mapping. 

 

This is where successful research such as the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" study comes into play. For the first time, we can examine the before and after epigenetic profiles of the cell state prior to and after exposure to the OSKM Yamanaka factors. Transcription factors Oct4 (Pou5f1), Sox2, cMyc, and Klf4.

 

Other enhancing transcription factors are known to produce cellular plasticity states. From this standpoint, a predictive method is warranted to see what the most suitable and least invasive approach might be? "Gene regulatory network"

 

"Diversity and Plasticity of Th Cell Types Predicted from Regulatory Network Modeling"

 

From these references, a library is being built. See "Hi-C analysis and genomic interactions" any futher references would be welcome.

 

How does the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" 

Succeed where other studies have failed? For one a total reversal to the iPSC state isn't achieved. If the cells were totally regressed they could lose cell identity and become any number of tissues as was seen in previous studies. Plus the cell signaling environment is changed reducing products expressed by older cells now regressed.

 

Thru periodic cyclic exposure to the Yamanaka factors, cellular plasticity is achieved by stopping short of losing cellular tissue identity.

 

As we've realized this isn't achievable within a human host because these mice were installed with an OSKM polycistronic expression cassette.

 

The questions were asking on this forum, can this type of cellular regression be implemented in a human or animal trials to prove the same results can be achieved without installing a OSKM polycistronic expression cassette in each cell of the host subject?

 

From this question, we're asking, are there other suitable ways to regress cells towards a more plastic state in vivo? From this, there appears to be a magnitude of studies that are looking at the reprograming of epigenetic markers thru extracellular vesicles.

 

As mentioned the rate of publication in epigenetics is skyrocketing and the topic is deep, the more eyes the better.

 

As always JMHO and thanks for reading.

 

Bryan

Edited by Bryan_S, 16 July 2018 - 07:27 PM.

[YOLF]

Really surprised not to see a lot of comments on this.

 

Are any further studies moving forward as I would expect? Epigenetically how much of the epigenome is reset? Obviously the tissues retain their cell identity but what about subtle programing for tissue types controlling immunity or epigenetically passed down traits from your parents. Many of these traits are learned, retained and passed down to the next generation.

 

Virus and bacterial disease response aside are immune responses to gut and skin microbiota adversely affected? God so many questions.

 

I've looked across our forums and this topic didn't last long in discussion. Hopefully its replicated with some attention to the nuances as I've described above.

 

Interesting to say the least but bleeding edge with a little data for health span or age progression.

I would think that as the yamanaka factors, or 4F, were discovered by looking at the chemical forces at play in the environment of reproductive cells such as embryos, that this would not be a problem. Whatever epigenetics you inherited would very likely be spared. There might be some small exceptions as a whole organism is much more complicated compared to an embryo, but I imagine that even if disrupted, whatever it was that lead to to those changes would restore them. Homeostasis being what it is, is this time, to our benefit.

[YOLF]

 

 

And also here an interesting company  (Youthereum Genetics) working to apply the OSKM technology:

 

http://www.youthereum.io/

 

(edit: links)

Looks interesting. How many people are actually treating their pets? Is it the same as the human 4F/OSKM?

[YOLF]

This is a great follow-up study.  There have been recent musings about the supposed inverse relationship between telomere length and epigenetic aging as measured by Horvath's clock.  If you combine this study with the original one, and Blasco's follow-up study on telomeres, it appears that this may not be an issue.

 

In other words, all of the potential rejuvenation therapies based on the Hallmarks are moving in the same direction.  And furthermore, it's becoming clear that epigenetic reprogramming like this is at  the very top of the hierarchy.  Changing this one hallmark would likely radically change most/all of the others as well.  Sounds tantalizingly close to a magic bullet.  That and the fears of cancer have been somewhat allayed, at least for now.

 

A proper delivery mechanisms is probably not coming anytime soon, which is unfortunate.  That may be one reason this isn't getting the attention it deserves.  It is probably more powerful and relevant than any other possible intervention, but it seems like it's a ways off, which dampens enthusiasm here.  Compare that with senolytics, which are becoming highly actionable and therefore immensely popular.

I think the approach is what needs to change on the delivery vector front. Stop looking for a single delivery vector and start attaching these things to everything and anything and do some high throughput screening. Or just stick it in a capsule that is timed for whatever part of the gut will be able to absorb it. Delivery shouldn't be this hard... it's been done a thousand times for a thousand drugs and a thousand supps. Creating a delivery vector is as old as aspirin:

 

 

In 1853, chemist Charles Frédéric Gerhardt treated sodium salicylate with acetyl chloride to produce acetylsalicylic acid for the first time;^[8]:46–48

 

Edited by YOLF, 16 July 2018 - 09:25 PM.

[albedo]

...

 

It seems as we age past reproductive maturity slowly the extracellular environment fills with growth inhibitors as opposed to promoters. Some tissues are affected more than others. As we weigh this against observed epigenetic changes this appears to be tied to reproduction. "The Expensive Germline and the Evolution of Ageing"  and the "Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction" 

 

...

 

Can this be another way of restating Dr. Judith Campisi’s insight (I hope I do not distort too much he great work!) that possibly aging, in its telomeres shortening declination, might be evolved as a protective response to cancer? (e.g. see here). And we have a kind of balance between the good and bad cell plasticity during reprogramming as rightly mentioned by OP2040 in his post on the Dr. Maria Blasco’s study: “…These findings place telomeres as important players in cellular plasticity both during in vivo reprogramming and in pathological conditions associated with increased plasticity, such as cancer….”

 

 

...

We can regress the age of a cell to an iPSC state. However, when those reverted cells are transplanted back into an aged host patient, the iPSC is exposed to a cocktail of cell signaling inhibitors. I believe this has been one of the most significant hurdles to regenerative medicine. Here is an artical how this aging process suppresses bone marrow stromal (stem) cell proliferation, and induces stem cell senescence.

...

 

Yes I think so. This is related to your growth inhibitor environment, as you mention previously in your post. There is some logic I guess as that inhibition might protect against iPSC defects. The Belmonte’s paper Roadblocks in the Path of iPSC to the Clinic posted above, indicated this clearly “…in most of the cases the same scientists that made extensive progress in the iPSC field have been the ones questioning their translation into the clinic over the last 10 years. In this regard, genetic mutations and chromosomal aberrations detected in iPSCs generated from different cell sources and utilizing different methodologies have raised concerns about their tumorigenic potential…”

 

 

...

 

The changing epigenetic landscape: The Horvath clock is defined as an age estimation method based on 353 epigenetic markers on the DNA. "However, it is unlikely that the 353 clock CpGs are special or play a direct causal role in the aging process.[1] Rather, the epigenetic clock captures an emergent property of the epigenome."

....

 

As well as I think there is a lot of debate on this, I am intrigued by this a lot and posted this here too. I feel it cannot be that simple and I tend to agree with the CpGs DNA methylation captuting the epigenome characteristics rather than being causative. But image if we find a sort of single target of aging, a master regulation, a single target to tackle, that is why I was excited by discovering two times in this thread (here and here) the role of hypothalamus.

[albedo]

Looks interesting. How many people are actually treating their pets? Is it the same as the human 4F/OSKM?

 

I believe these factors are conserved. I think Youthereum wishes to develop a pets treatment in their R&D roadmap as both a proof of concept and as an initial business model. They are searching investors and likely no treatment has initiated yet. They seems having no in house facilities and rather wish to act as a pool of experts and IP holders collaborating with academia and industry. But I have no further insight. Please check their web site.
 

[albedo]

 

...

Other enhancing transcription factors are known to produce cellular plasticity states. From this standpoint, a predictive method is warranted to see what the most suitable and least invasive approach might be? "Gene regulatory network"

 

"Diversity and Plasticity of Th Cell Types Predicted from Regulatory Network Modeling"

 

From these references, a library is being built. See "Hi-C analysis and genomic interactions" any futher references would be welcome.

 

...

 

Great finding!  I am always amazed at these researchers attacking courageously and front face such a daunting task as enlightening the gene regulatory network. Please note the last library link does not open.

[Bryan_S]

Great finding!  I am always amazed at these researchers attacking courageously and front face such a daunting task as enlightening the gene regulatory network. Please note the last library link does not open.

 

Sorry, the link was bad.

 

https://www.ncbi.nlm...les/PMC4347522/

 

https://www.research..._fig2_225276207

 

Here is an example depending on whats asked about interrelations. There is a lot more to the Hi-C Analysis and tools.

 

[albedo]

To release a bit from papers reading, I thought useful (at least for my log) extracting from a nice interview at LEAF with Dr. Steve Horvath some parts particularly related to this thread:

• On the DNA methylation “causative” vs. “biomarker” role ….

Does your clock represent aging?

This is a good question with two answers. One way to ask this question is to ask if methylation changes cause aging. And we honestly don’t know; there is no data. The other question to ask is if the epigenetic clock is the indicator of a biochemical process that plays a role in aging. Which I think it is; it is a biomarker of a process. There is no question that this process that underlies the clock, that if you target this process, you slow aging; this, we know.

• On the tissue dependency as mentioned in this thread and the old saying that “you are as old as you oldest organ” …

Is it true that our organs age at different speeds?

Generally, most organs age at roughly the same speed. However, for example, female breast tissue ages faster. We analyzed breast tissue from women aged 25-30, and already, their breast tissue was older than their blood. We also analyzed a woman who was 112 and looked at 30 parts of her body; it turned out that the cerebellum at the back of the brain, which helps with motion and balance, was the youngest part. I studied a lot of people over 100 and found that the cerebellum aged slower than the rest of the body.

• On the link to heterochronic parabiosis and the Mike and Irina Conboy’s research which Bryan has previously posted and also mentioned here (the link between Horvath’s clock, heterochronic parabiosis and telomeres is fascinating) ….

During your talk, you mentioned that when there is a transfusion of cells from a younger donor to an older patient, then the transfused cells will also be younger than the patient. What happens in the case when someone uses their cord blood and transfuses it into themselves when they are older, does that mean these cells would remain younger?

In principle, yes. My results indicate that it might be a good strategy to bank your own cells when you are young and use them decades later, such as using blood to replace your old blood stem cells. The problem is this blood replacement therapy is dangerous; it’s called hematopoietic stem cell therapy, and it is used for leukemia. It is a last resort because it is so dangerous and people die from it. The way the treatment happens is that you are irradiated and get chemotherapy to destroy all your blood cells, and then you have to wait a couple of weeks without any immune cells, and then you get the replacement cells, but some people die because they have no immune system.

Also, when you have blood from other people, then the body fights back; this is called graft vs host disease, which adds more complications. So, although my studies show in theory that this procedure definitely works to rejuvenate you, the side effects are the problem.

• On the OSKM factors induction and alternatives (not fully developed though) …

Can we slow down aging now?

I want to tell you that I am very optimistic and that we will have treatments against aging in a few years. I could be wrong, and I want to be cautious, but I want to tell you that I am very optimistic because we already have encouraging results. We already have treatments that have a huge effect, like the Yamanaka factors in mice, but also in human cells. If you use Yamanaka factors on human cells, it completely reverses their age. The problem is how to make them safe.

What is the danger of using Yamanaka factors?

In a word, cancer. That is the number one risk. However, there are four Yamanaka factors, and if you use four it rejuvenates the epigenetic clock, but the question now is maybe three factors are enough to rejuvenate the clock, or even one. The challenge now is to test these factors and see which of these factors work, and by not using all four, it may minimize the risk. Also there are chemical interventions that dedifferentiate cells so maybe some of these may also be able to rejuvenate the epigenetic clock.

Do you have the data from the Salk Institute, which used Yamanaka factors in mice?

I don’t have the data but I have no doubt they are working on this question. I met some of the research team, and they mentioned they want to look at that. Many people are working on Yamanaka factors, including companies; even my lab is going to apply it to human cells and mice. There are a lot of people working on this, so it’s a bit of a competition. There are also a lot of alternatives like chemical interventions that have pretty much the same effect as Yamanaka factors. It may be that one of these alternatives could be much safer and work for humans.

[albedo]

...

 

Putting theories beside, such as mutation accumulation, programmed aging etc …, I am excited by this epigenetics rejuvenation stuff as proof of concepts are being made and DNA methylation offers now a mean to check reversal of the hallmarks in a gradual manner. The rejuvenation seems can be stopped before too late for cancer to start or reversal to embryonic status happens. For the body cells integration of the factors, I would guess the most advanced technology appearing vs the more conventional and existing ones such as viral vectors, will be CRISPR.

 

...

 

In case you overlooked this recent and very interesting work on CRISPR derived technolgoy (CRISPRa), targeting endogeneus OCT4, SOX2, KLF4, MYC and LIN28A promoters, which improves substantially the efficiency of the reprogramming reportedly without introducing the genes and so mutating the genome. In this sense, I think this work goes along some of the thoughts developed in this thread:

 

"...Scientists say that for the first time they have been able to convert skin cells into pluripotent stem cells by activating the cells' own genes. The team reportedly used a type of CRISPRa gene-editing technology that does not cut DNA and can activate gene expression without mutating the genome. Up till now, reprogramming has only been possible by introducing the critical genes for the conversion, called Yamanaka factors, artificially into skin cells where they are not normally active..."

 

https://www.genengne...-cells/81255996

 

Weltner J, Balboa D, Katayama S, et al. Human pluripotent reprogramming with CRISPR activators. Nat Commun. 2018;9(1):2643.

 

"CRISPR-Cas9-based gene activation (CRISPRa) is an attractive tool for cellular reprogramming applications due to its high multiplexing capacity and direct targeting of endogenous loci. Here we present the reprogramming of primary human skin fibroblasts into induced pluripotent stem cells (iPSCs) using CRISPRa, targeting endogenous OCT4, SOX2, KLF4, MYC, and LIN28A promoters. The low basal reprogramming efficiency can be improved by an order of magnitude by additionally targeting a conserved Alu-motif enriched near genes involved in embryo genome activation (EEA-motif). This effect is mediated in part by more efficient activation of NANOG and REX1. These data demonstrate that human somatic cells can be reprogrammed into iPSCs using only CRISPRa. Furthermore, the results unravel the involvement of EEA-motif-associated mechanisms in cellular reprogramming."

 

"...We present a method for the efficient conversion of primary human fibroblasts into bona fide iPSCs based entirely on the transcriptional control of endogenous genes by CRISPRa..."

 

"...In conclusion, CRISPRa reprogramming will provide a powerful tool for inducing pluripotent cells. The core method described here can be further improved by targeting known pluripotency genes and regulatory elements, as well as by screening for novel reprogramming factors and elements^23,43,44. This will pave way for the development of more comprehensive CRISPRa reprogramming strategies, which in combination with transgenic factors, RNAi, and small molecular compounds, will promote more efficient and specific reprogramming of human cells for future application..."

 

[albedo]

Let me share here an additional reading which I think is related to how this thread is developing and try connecting dots.

 

First we discussed the In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming of Belmonte’s team.

 

We then discussed different delivery paths of the factors inducing the reprogramming, both exogenous and endogenous, CRISPR or CRISPRa (endogeneous) and viral vectors.

 

Bryan brought to our attention the works on EVs (extracellular vesicles) which largely differ in the size and so in the type of proteins and RNAs they can carry horizontally between cells.

 

Now I pop into a couple of readings on one side emphasizing the strong connection between viruses and EVs and on the other the issue of delivery.

 

“…The similarity was so striking that Margolis realized that some viruses — like HIV and other small RNA viruses — and exosomes and extracellular vesicles fall on two different extremes of the same continuum…”

 

“…Since vesicles resemble viruses, the question of course is whether the first extracellular vesicles were primitive viruses and the viruses learned from extracellular vesicles or vice versa…”

 

“…The recent explosion of research on extracellular vesicles — from 135 studies published in 2013 to 1,087 studies in 2017 — testifies to scientists’ new appreciation of their centrality to cellular functioning. Because extracellular vesicles and exosomes can pass information between cells, scientists have begun to implicate them in everything from cancer to viral infections to basic neural functioning…”

 

https://www.quantama...iruses-20180502

 

So, can EVs be THE way forward for the best and safe epigenetic message delivery system for reprogramming as Bryan seems to foster (hopefully I am not distorting his thought!)?

 

That the delivery is a big issue is in this interview with Belmonte himself and in a new paper from his team where the large size of CRISPR-Cas9 cannot be fit into a single viral vector and they have chosen to split it into two parts for cell delivery and successfully let two parts operate again together once in the cell (the results for hopefully treating epigenetically diabetes, kidney disease, muscular dystrophy and other diseases are encouraging in mice)

 

“…In this way, the technology operates epigenetically, meaning it influences gene activity without changing the DNA sequence…”

 

“…But the resulting protein—dCas9 attached to the activator switches—is too large and bulky to fit into the vehicle typically used to deliver these kinds of therapies to cells in living organisms, namely adeno-associated viruses (AAVs). The lack of an efficient delivery system makes it very difficult to use this tool in clinical applications...”

 

https://www.salk.edu...ular-dystrophy/

 

and their paper in Cell:

 

In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation

[Bryan_S]

Just completed this overview. Very interesting take on the ongoing research. I'll mention the paper has not as of yet been peer-reviewed.

 

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

https://www.biorxiv....18/03/31/292680

[albedo]

Just completed this overview. Very interesting take on the ongoing research. I'll mention the paper has not as of yet been peer-reviewed.

 

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

https://www.biorxiv....18/03/31/292680

 

Thank you Bryan to repeat this study already quoted several times in this thread (e.g. here and here and here) but honesty while I clearly understand the eAGE (Horvath's clock or similar based on DNA methylation) is a good way fwd to check rejuvenation, I still have hard to understand the uncoupling of the two dynamics of dedifferentiation and epigenetic rejuvenation. Feeling they are on something though ...

[albedo]

Bumping a bit for lack of lack of comments. I just finished reading an outstanding review article and might post later on when digested.

[Bryan_S]

Thank you Bryan to repeat this study already quoted several times in this thread (e.g. here and here and here) but honesty while I clearly understand the eAGE (Horvath's clock or similar based on DNA methylation) is a good way fwd to check rejuvenation, I still have hard to understand the uncoupling of the two dynamics of dedifferentiation and epigenetic rejuvenation. Feeling they are on something though ...

 

Sorry for the study redundancy, I've been on the road for the last week with intermittent internet, and I did not do a thorough search before posting.

 

What I find interesting as I move beyond that paper is this recently published study, Age-Related Epigenetic Derangement upon Reprogramming and Differentiation of Cells from the Elderly. They determined methylation aberrations between reprogrammed cells and hESCs and classified them into two main categories: de novo and inherited or memory (Figure 1). The former refers to DNA regions whose methylation levels are significantly different in iPSCs from both parental somatic cell line and hESCs and are specific for each newly-established-iPSC line.

 

So as we look to what might be "lost" in the In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming process it "appears" some of our fears might be asswaged by this study as the original DNAm pattern survives in an immature version of the adult counterpart. This seems to be the only study to ask these questions.

 

"5. Impact of Reprogramming-Associated Alterations in the Study of Age-Related Diseases

 

The application of the analysis of DNAm pattern in iPSCs and their derivatives indicate that while reprogramming is associated with a reversion of DNAm patterns to embryonic-like state, the differentiation process does not lead to a full re-establishment of the cellular specific DNAm-profile. These results fit with what emerges from recent reports, indicating that tissues differentiated from iPSCs do not present the same physiological and functional features of the target cells rather than they are more similar to an immature version of their adult counterpart (Figure 2) [70,71]."

 

As always JMHO

Bryan

Edited by Bryan_S, 30 July 2018 - 03:48 PM.

[OP2040]

Bumping a bit for lack of lack of comments. I just finished reading an outstanding review article and might post later on when digested.

 

Well, definitely don't stop, some of us are reading diligently.  I'm very impressed with the knowledge and enthusiasm displayed here.

 

Here's something up for discussion, assuming it hasn't already been posted:

https://www.ncbi.nlm...les/PMC5831052/

 

This research shows that the NMR has cells that are resistant to reprogramming.  As we all know by now, the NMR is a negligibly senescent animal.

 

Of course, we are counting on being able to do the reprogramming on our own cells.  But the point is that this is more evidence that epigenetic mechanisms are the glue that holds the entire aging program together.