266 replies to this topic

[Oakman]

http://www.nytimes.c...least.html?_r=0

 

http://www.cell.com/...8674(16)31664-6

 

---

 

• • •

    Partial reprogramming erases cellular markers of aging in mouse and human cells

  • •

    Induction of OSKM in progeria mice ameliorates signs of aging and extends lifespan

  • •

    In vivo reprogramming improves regeneration in 12-month-old wild-type mice

  Summary

  Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.

[albedo]

Interesting. I immediately wondered about the SENS position and here are some initial critical comments from their repair perspective:  https://www.fightagi...-to-adult-mice/

[albedo]

Looks like they do not induce cancer: "... Although previous studies have indicated that expression of the Yamanaka factors in vivo can lead to cancer development or teratoma formation (Abad et al., 2013; Ohnishi et al., 2014), here, we demonstrate that tumor formation can be avoided by short-term induction of OSKM. Cyclic induction of OSKM in vivo ameliorated hallmarks of aging ..."

[Oakman]

What seems esp. efficient here, is that the therapy only need to be applied occasionally, and as you mention, this potentially avoids cancers.

[Bryan_S]

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.

Edited by Bryan_S, 09 April 2017 - 07:45 AM.

[albedo]

I agree Bryan. There is also the large complexity of epigenetics. Let's not forget that epigenetics is also tissue/cell dependent which adds to the complexity of resetting the epigenome, e.g. see:

 

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.

https://www.ncbi.nlm...pubmed/18031808

Edited by albedo, 09 April 2017 - 11:01 AM.

[Oakman]

It seems (of course) there's more to this than easy manipulation of gene expression to extend lifespan, and so the difficulty of using this effect. The following explanation of the research is far more cautious in how this may work in practice, ergo the lack of follow through may be because of those ramifications.

 

http://blogs.science...nation-for-real

[Bryan_S]

http://sitn.hms.harv...e-age-reversal/

 

It could really be this simple. Perhaps not this exact approach. JMHO

 

I think what they have is a proof of concept. They need to put wild type mice thru the riggers and see how long they live. Then how many times you can hit the reset button.

Edited by Bryan_S, 09 April 2017 - 11:23 PM.

[alc]

Interesting. I immediately wondered about the SENS position and here are some initial critical comments from their repair perspective:  https://www.fightagi...-to-adult-mice/

 

that guy/girl (fightaging), michael rae from sens and couple other individuals that post here on this forum, put a lot of effort in attacking everybody that show different solutions that are viable and more efficient that their ideas, on rejuvenation.

 

if you spend some time reading some posts of michael rae there you realize that his understanding of certain things is minimal, and at best to the level of a layman. but he+fightagingguy/girl comments on everything and anything.

 

they are ok as "rejuvenation crusaders", but in recent years as we see science moving on, I (and few other researchers  that I discuss things in this field) downgraded sens rating to "mediocre". personally I'm not involved directly in any rejuvenation research, but I have couple friends that work in serious teams.

 

no offense, but sens rather than spending time to try learn and understand what is not working in their nicely described theories, they spend a lot of energy in pooh-pooh-ing others serious researchers work.

 

they attack Izpisua's work , they attack Sinclair's work, they attack Calico's work, they attack George Church's work,  ... they attack everybody's work ... we will see in couple years when these teams that they attack continuously, will start to have concrete results, we'll see them ...

 

@fightagingguy/girl & @michaelrae - I know you read these comments because you are what? "guardians" (lol), I'll see your comments in near future when these teams will show results.

head on.
 

[Bryan_S]

they attack Izpisua's work , they attack Sinclair's work, they attack Calico's work, they attack George Church's work,  ... they attack everybody's work ... we will see in couple years when these teams that they attack continuously, will start to have concrete results, we'll see them ...

 

@fightagingguy/girl & @michaelrae - I know you read these comments because you are what? "guardians" (lol), I'll see your comments in near future when these teams will show results.

head on.
 

 

 

I wouldn't give it much thought. The theory of Epigenetic dysregulation as a driver of mammalian aging is rather new. Things take time to penetrate and old ideas are difficult to discard until there is overwhelming evidence to pull you into a new path. For me it was Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects that set the stage showing us you could reset the clock. The problem however was you couldn't do this to an entire organism. In reality you still can't but the concept was demonstrated. If I remember correctly the LAKI mice were crossed to mice carrying an OSKM polycystronic cassette (4F) and a rota trans-activator (Carey et al., 2010), thereby generating LAKI 4F mice that could accept the "partial reprogramming." So these mice, as far as I know, were breed for this experiment and this approach wouldn't work on us. Still a great proof of concept.

[HighDesertWizard]

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.

 

Bryan... Thanks for the thoughtful insight about the meaning of the experiment result throughout this thread.

 

About impacts of the Partial Reprogramming...

• Blasco and her team published a study on the heels of the Salk team, confirming its result, but also focusing on the Telomerase Expression and Telomere Length impacts.
  • Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis

Highlights

 

-- Telomeres are elongated during in vivo reprogramming in a telomerase-dependent manner

-- Telomeric protein TRF1 is highly overexpressed during in vivo reprogramming

-- TRF1 is upregulated during acinar-to-ductal transdifferentiation

 

Summary

 

Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length. Moreover, TRF1 inhibition reduced in vivo reprogramming efficiency. Importantly, we extend the finding of TRF1 upregulation to pathological tissue dedifferentiation associated with neoplasias, in particular during pancreatic acinar-to-ductal metaplasia, a process that involves transdifferentiation of adult acinar cells into ductal-like cells due to K-Ras oncogene expression. 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.

 

• Seems to me this is in line with the expectation set earlier last year that Epigenetic Clock implicated age ought to roughly approximate Telomere Length implicated age.

The epigenetic clock and telomere length are independently associated with chronological age and mortality

 

Background: Telomere length and DNA methylation have been proposed as biological clock measures that track chronological age. Whether they change in tandem, or contribute independently to the prediction of chronological age, is not known.

 

Methods: We address these points using data from two Scottish cohorts: the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936). Telomere length and epigenetic clock estimates from DNA methylation were measured in 920 LBC1936 participants (ages 70, 73 and 76 years) and in 414 LBC1921 participants (ages 79, 87 and 90 years).

 

Results: The epigenetic clock changed over time at roughly the same rate as chronological age in both cohorts. Telomere length decreased at 48–67 base pairs per year on average. Weak, non-significant correlations were found between epigenetic clock estimates and telomere length. Telomere length explained 6.6% of the variance in age in LBC1921, the epigenetic clock explained 10.0%, and combined they explained 17.3% (all P < 1 × 10 −7 ). Corresponding figures for the LBC1936 cohort were 14.3%, 11.7% and 19.5% (all P < 1 × 10 −12 ). In a combined cohorts analysis, the respective estimates were 2.8%, 28.5% and 29.5%. Also in a combined cohorts analysis, a one standard deviation increase in baseline epigenetic age was linked to a 22% increased mortality risk ( P = 2.6 × 10 −4 ) whereas, in the same model, a one standard deviation increase in baseline telomere length was independently linked to an 11% decreased mortality risk ( P = 0.06).

 

Conclusions: These results suggest that telomere length and epigenetic clock estimates are independent predictors of chronological age and mortality risk.

Edited by HighDesertWizard, 12 July 2017 - 02:17 AM.

[albedo]

A Short Interview with George Church on Genetics and the Treatment of Aging
https://www.fightagi...tment-of-aging/

Do you agree that epigenetic alterations as described in the Hallmarks of Aging are a primary driver of the aging process, and if so do you think we can safely use cell reprogramming factors OSKM (OCT4, SOX2, KLF4 and MYC) to turn back cellular aging?

Yes. Epigenetics are important drivers, but it are only part of the Hallmarks of Aging - and OSKM would, in turn, be only part of that. Other examples are factors behind heterochronic parabiosis. Efficacy may depend on the various tissue types.

[Never_Ending]

Is there a way to induce a similar effect by a molecular formula without the reprogramming vectors etc?

[albedo]

Is there a way to induce a similar effect by a molecular formula without the reprogramming vectors etc?

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   89.68KB   2 downloads

 

"...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..."

 

 

 

[HighDesertWizard]

Is there a way to induce a similar effect by a molecular formula without the reprogramming vectors etc?

 
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

[albedo]

HighDesertWizard, interesting on butyrate! I did not read the actual (paywalled) article in Science but wonder if another reason to watch for your gut health:

 

Dietary fibre helps ‘good’ bacteria win battle of the microbiome

By Tim Cutcliffe, 14-Aug-2017

Feeding beneficial gut bacteria with fibre appears to help a signalling mechanism which limits the growth of harmful pathogens, according to a new study published in Science.

http://www.nutraingr...-the-microbiome

[albedo]

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   10.82KB   0 downloads

 

 Integrative Hallmarks of Aging.PNG   136.75KB   2 downloads

 

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

[HighDesertWizard]

Sources for Butyrate other than this one?

 

BodyBio - Sodium Butyrate, Short Chain Fatty Acid, 600mg, 100 Vegetarian Capsules

[Never_Ending]

albedo and HighDesertWind  very interesting! I had been looking for info like this. It seems that it's easier to find molecules that work to support the reprogramming factors,  but much harder and rarer to come across molecules(and combinations) that can replace the factors. Will definitely be looking more into this.

Edited by Never_Ending, 15 August 2017 - 12:33 AM.

[HighDesertWizard]

2007

 

Motif module map reveals enforcement of aging by continual NF-κB activity

 

Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-κB. Inducible genetic blockade of NF-κB for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-κB blockade and orthogonal cell cycle interventions revealed that NF-κB controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-κB is continually required to enforce many features of aging in a tissue-specific manner.

 

 

2015

 

NF-κB activation impairs somatic cell reprogramming in ageing - full text at sci-hub
 

ABSTRACT

 

Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor–Guillermo progeria syndrome and Hutchinson–Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

 

<< Fascinating discussion of results on in-vitro human cells and in-vivo rodents. >>

 

DISCUSSION

 

Somatic cell reprogramming constitutes a paradigm of rejuvenation as it involves the complete erasure of aged marks and the restoration of homeostatic balance. The assumption that the aged state, like the differentiated state, requires active maintenance has attracted special attention towards the identification of signals and regulatory mechanisms that sustain ageing, as they may represent prominent targets of rejuvenation strategies14,45. In this regard, although the causal involvement of NF-κB in ageing has been well documented40,42–44,46, our results notably extend this view, establishing a mechanistic link between ageing and cell differentiation through NF-κB signalling. Accordingly, we demonstrate here that NF-κB hyperactivation constitutes a critical impediment to somatic cell reprogramming into iPSCs in both normal and accelerated ageing. This work has also led us to identify the upstream regulators and the main effectors involved in this process. Additionally, our data demonstrate that NF-κB regulation of chromatin-modifying factors has a remarkable impact on the establishment of this reprogramming barrier. In this regard, DOT1Lmediated methylation of Lys 79 in histone H3 represents a molecular crosstalk between ageing and differentiation control36. DOT1L then emerges as a prominent effector of NF-κB activity in ageing.

 

Furthermore, the identification of this molecular mechanism has allowed us to translate this information into a therapeutic approach, which we have successfully evaluated in progeroid animals. Thus, DOT1L inhibition extended longevity and prevented ageing-associated alterations in progeroid mice. Although we have previously demonstrated that NF-κB blockade extends longevity40 , chronic treatment with anti-inflammatory compounds in humans has some side effects that made their administration not generally assumable. However, the possibility of targeting critical effectors of NF-κB response could suppress the observed side effects. Besides, DOT1L inhibitors have been recently tested for the treatment of haematological malignancies, which opens the possibility of using these compounds to treat age-associated alterations. Globally, our results further demonstrate the utility of cell-based models of progeroid syndromes to study ageing mechanisms in general and the pathogenesis of progeria in particular. Moreover, we also provide an experimental proof-of-concept about the relevance of studying the molecular mechanisms underlying reduced reprogramming competence of aged cells to develop rejuvenationbased therapies.

 

 

 

 

 

 

I included the 2nd set of study result pics to highlight the goings on of IκBα during aging. You'll recall that, just recently, a study showed that adding IκBα stem cells to the hypothalamus increased lifespan.

 

I posted info about that study, including a survival curve here at Longecity.

 

FWIW, as you may (not) know, I've been focused on NF-kB inhibition via a specific innate mechanism for 5 to 10 years now, depending on how the years are counted. In 2017, I got blood testing done and was more than pleasantly surprised.

N = 1. Anecdotal? Yes.

 

Remember? April 2012... One, out of the blue, oddball study, about C60-OO, triggered a tsunami of discussion and experimentation at Longecity. There was no data about Humans.

 

Edited by HighDesertWizard, 15 August 2017 - 05:04 AM.

[albedo]

I have not read this recent work but to me it looks linking aging, epigenetics (via miRNAs) and brain stem cells expressing one of the OSKM factors (Sox2):

 

Zhang Y, Kim MS, Jia B, et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature. 2017;548(7665):52-57.

https://www.nature.c...ature23282.html

 

"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."

[HighDesertWizard]

I have not read this recent work but to me it looks linking aging, epigenetics (via miRNAs) and brain stem cells expressing one of the OSKM factors (Sox2):

 

Zhang Y, Kim MS, Jia B, et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature. 2017;548(7665):52-57.

https://www.nature.c...ature23282.html

 

Hi albedo... Thanks for posting more info about that 2017 study. In my last post, I screwed up the link to that important 2015 study. Here's the title again along with the correct link.

 

NF-κB activation impairs somatic cell reprogramming in ageing.

 

 

 

More investigation has turned up these related studies. Notice that the first two study titles suggest that the contents they contain contradict each other!  

 

2012, Innate Immune Suppression Enables Frequent Transfection with RNA Encoding Reprogramming Proteins

 

2012, Activation of Innate Immunity is Required for Efficient Nuclear Reprogramming

 

2012, Surprise After the Prize: Innate Immune Signaling Required for Pluripotency

 

2014, Innate immunity and epigenetic plasticity in cellular reprogramming

Edited by HighDesertWizard, 18 August 2017 - 12:36 PM.

[albedo]

This looks very interesting, in the very elderly humans ....

 

"Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a unique opportunity to derive patient-specific stem cells with potential applications in tissue replacement therapies and without the ethical concerns of human embryonic stem cells (hESCs). However, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. Here we demonstrate, using an optimized protocol, that cellular senescence is not a limit to reprogramming and that age-related cellular physiology is reversible. Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. These results provide new insights into iPSC technology and pave the way for regenerative medicine for aged patients." (bold mine)

 

Lapasset L, Milhavet O, Prieur A, et al. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. 2011;25(21):2248-53.

 

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

 

http://www.youthereum.io/

 

(edit: links)

Edited by albedo, 11 January 2018 - 07:43 AM.

[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."

 

Edited by albedo, 16 April 2018 - 01:22 PM.

[OP2040]

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

 

 

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.

 

 

[Bryan_S]

I'm still dismayed this area hasn't generated a larger following! This appears to be the path that will win in ameliorating the causes of aging.

 

JMHO

 

Bryan

[OP2040]

I'm still dismayed this area hasn't generated a larger following! This appears to be the path that will win in ameliorating the causes of aging.

 

JMHO

 

Bryan

 

I couldn't agree more, but it's up to us to popularize it and push it forward.

 

The main roadblock is that it is still very esoteric with nothing actionable.  No one here has any idea how to make this work for anything but a transgenic mouse.  And we are all well aware of how long it takes for even the most mundane things to pass through the medical establishment.  Added to that, the safety issues for self-experimentation with this would be truly nerve wracking, though I would still do it if I was 80, because why not...

 

So the real question is how do we move the ball forward and make this something that seems real rather than just another exciting mouse study.

 

The only thing I've seen is Sodium Butyrate, but it is very debatable about whether it's health effects are attributable to it's limited programming ability.  I'd love to try this on some in vivo human tissue (maybe skin) using electrophoresis, if that's even possible.  But it seems way beyond my ability, and a bit scary.

 

Another exciting study from last year may eventually play into this.  The one where they used a chip to transfect live tissue with programming factors.   I don't see why you couldn't use that same chip did deliver OSK (not sure if you would want M) to tissue.  Good luck building the same chip that they used to nano-transfect though.  Same problem, too esoteric and unreachable for the general public at this point.

[Bryan_S]

I couldn't agree more, but it's up to us to popularize it and push it forward.

 

The main roadblock is that it is still very esoteric with nothing actionable.  No one here has any idea how to make this work for anything but a transgenic mouse.  And we are all well aware of how long it takes for even the most mundane things to pass through the medical establishment.  Added to that, the safety issues for self-experimentation with this would be truly nerve wracking, though I would still do it if I was 80, because why not...

 

So the real question is how do we move the ball forward and make this something that seems real rather than just another exciting mouse study.

 

The only thing I've seen is Sodium Butyrate, but it is very debatable about whether it's health effects are attributable to it's limited programming ability.  I'd love to try this on some in vivo human tissue (maybe skin) using electrophoresis, if that's even possible.  But it seems way beyond my ability, and a bit scary.

 

Another exciting study from last year may eventually play into this.  The one where they used a chip to transfect live tissue with programming factors.   I don't see why you couldn't use that same chip did deliver OSK (not sure if you would want M) to tissue.  Good luck building the same chip that they used to nano-transfect though.  Same problem, too esoteric and unreachable for the general public at this point.

 

Did you read: ICO will fund resetting the epigenetic aging clock to prolong human lives by over 30%

https://www.nextbigf...by-over-30.html

 

The Parabiosis experiments in mice have reinforced the idea that old cells can be rejuvenated. 

https://www.nature.c...o-blood-1.16762

 

These cell signaling proteins are a subtle methylation or demethylation nudge. I believe we'll find the OSKM factor approach (Oct4, Sox2, Klf4 and c‐Myc, abbreviated as OSKM) is more like a hammer than a decreet scalpel. I believe we'll find safer factors and better targets that don't run the risk of dismantling our cell identity.

 

The NAD repletion trials on mice and humans have reinforced the idea that increasing a cells energy budget increases cellular repair. I believe there is enough evidence accumulated that even cellular senescence of stem cells is a state that can be reversed when cellular repair is boosted. https://www.ncbi.nlm...les/PMC5088772/

 

What I believe will move the OSKM factor approach forward will be reliable metrics and methylation mapping with techniques like the Levine Clock. If I remember correctly, it measures 353 different methylation sites. 

 

The Levine Clock=PhenoAge reliably measures biological age, and this blog link below reviews some of the implications. This has set the stage for human testing where we can measure Methylation changes over short trial durations to see if the cellular clock has moved within the trial.

https://joshmitteldo...trials-part-ii/

 

Last year there was a nice overview written on Epigenetic Rejuvenation: https://medium.com/@...on-8c498103c353

 

One area I see that will get a big boost is in the treatment of diseases. Cancer, for instance, arises from a loss of cell identity. What if instead of trying to directly kill cancer, risking healthy tissue we come up with a way to turn back on the cells original identity or turn on the cells apoptosis genes? This research is already happening, here is one example: https://www.scienced...169409X17302351

 

So I see a convergence of tools moving this forward. We've just begun to unravel the toolkit epigenetics represents. We can now see changes at the methylation level and measure them, so we can now tell if we've moved the aging clock back. We can design molecules to interact with these methylation sites to test new compounds. So I think the time is right for this area to explode as we test and identify the proper methylation targets to address.

 

So I agree, it's up to us to popularize it and push these ideas forward.

 

As always JMHO

Bryan

 

 

[OP2040]

The Youthereum thing thing is quite interesting.  But you know how these things go.  Even an outsider company will take our lifetimes to commercialize something like this.  We've benefited more from the basic research itself, when it can be extrapolated into something useful. 

 

The best example is for senescent cells.  We say around here for years knowing exactly what needs to be done in theory.  And then finally some company like Unity comes along and all they can really do is target osteoarthristis, because "aging isn't a disease".  So 40 years from now we will have an effective therapy for osteoarthristis.  Wow, I'm so excited.  Until the FOX04-dri thing came along from someone doing basic research, there was no chance for a comprehensive senescent cell therapy in our lifetimes.  Don't get me wrong, FOX04-dri may not even work, but even if it doesn't work in humans some tweak of it should.  The same idea has panned out with NAD+ enhancers.  Sinclair's basic research is all we really needed.  The inflexible regulations and seedy price gouging companies have done absolutely nothing to move the science or end-goals forward.  It may not sound like it but I'm fairly supportive of the current system, but it's just not flexible enough to deal with aging.

[Bryan_S]

I think we'll find as we begin to identify the methylation targets, much of this will turn out to be ubiquitous with some if not all mammalian species since we share most of our DNA with them. So comparative mapping of long-lived mammals should yield results for possible targets to reset. This ground work has already begun.

 

JMHO

Bryan

 

 

The evolution of CpG density and lifespan in conserved primate and mammalian promoters

https://doi.org/10.18632/aging.101413

 

Gene promoters are evolutionarily conserved across holozoans and enriched in CpG sites, the target for DNA methylation. As animals age, the epigenetic pattern of DNA methylation degrades, with highly methylated CpG sites gradually becoming demethylated while CpG islands increase in methylation. Across vertebrates, aging is a trait that varies among species. We used this variation to determine whether promoter CpG density correlates with species’ maximum lifespan. Human promoter sequences were used to identify conserved regions in 131 mammals and a subset of 28 primate genomes. We identified approximately 1000 gene promoters (5% of the total), that significantly correlated CpG density with lifespan. The correlations were performed via the phylogenetic least squares method to account for trait similarity by common descent using phylogenetic branch lengths. Gene set enrichment analysis revealed no significantly enriched pathways or processes, consistent with the hypothesis that aging is not under positive selection. However, within both mammals and primates, 95% of the promoters showed a positive correlation between increasing CpG density and species lifespan, and two thirds were shared between the primate subset and mammalian datasets. Thus, these genes may require greater buffering capacity against age-related dysregulation of DNA methylation in longer-lived species.

 

https://www.ncbi.nlm...pubmed/29661983

 

https://twin-cities....ng-intervention

 

Long-lived rodents reveal signatures of positive selection in genes associated with lifespan

http://journals.plos...al.pgen.1007272

https://medicalxpres...ty-mammals.html

 

Edited by Bryan_S, 30 April 2018 - 02:30 PM.