266 replies to this topic

[albedo]

Long waited preprint on this work by D Sinclair and a host of well known researchers. Good progress in the area of reprogramming:

...

 

I do not want to overdo it with this (btw, I prefer waiting for publication). However, here is a small deciphering by LEAF. You know all this already but maybe take notice of the nice diagram linked in the last paragraph of the article (several companies) which I find a useful reminder:

https://www.leafscie...-reprogramming/
 

[Harkijn]

Thansk for posting this useful article Albedo. The diagram is a much needed overview of an extending field. Interesting to note that Chromadex/ NR and it's clinical trials are not included.

Edited by Harkijn, 07 August 2019 - 11:37 AM.

[albedo]

Sorry if you have seen this already, just thought it would be good to log here too:

https://www.technolo...outh-epigenome/

Edited by albedo, 10 August 2019 - 09:46 PM.

[Bryan_S]

1st Age Reversal Results—Is it HGH or Something Else?

Nice write up on the TRIIM study. (Loss of thymus function has been linked to the collapse of the immune system that occurs typically before age 70.)

 

• human growth hormone (HGH)
• Metformin
• Vitamin D
• Zinc
• DHEA

We might have another significant target affecting our Methylation clock in the thymus, it appears thru this study small rejuvenating measures of the immune system can ward off some of the effects of aging. 

https://joshmitteldo...something-else/

[albedo]

Interesting on Oct4 ...

 

Quality of induced pluripotent stem cells is dramatically enhanced by omitting what was thought to be the most crucial reprogramming factor

https://www.scienced...304230?via=ihub

 SKM.PNG   280.7KB   0 downloads

"...Our data suggest that overexpression of Oct4 during reprogramming leads to off-target gene activation during reprogramming and epigenetic aberrations in resulting iPSCs and thereby bear major implications for further development and application of iPSC technology..."

Edited by albedo, 10 November 2019 - 02:08 PM.

[QuestforLife]

Interesting on Oct4 ...

Quality of induced pluripotent stem cells is dramatically enhanced by omitting what was thought to be the most crucial reprogramming factor

Yes very interesting. Omitting Oct4 decreased colony number but increases quality (i.e. genomic stability) in the resulting colonies.

According to Sinclair you don't need Myc (see https://www.biorxiv....0.1101/710210v1), so does that just leave us with SK?

Edited by QuestforLife, 10 November 2019 - 02:32 PM.

[Fafner55]

Wording like "unleashes" in the title “Excluding Oct4 from Yamanaka cocktail unleashes the developmental potential of iPSCs” (2019) https://www.scienced...934590919304230 may overstate the case. The text of the paper qualifies by stating

In the current study, we found that SKM can reprogram mouse somatic cells with efficiency of 30% of that for OSKM, albeit with delayed kinetics. Reprogramming in the absence of exogenous Oct4 requires high transgene expression, a non-retroviral reprogramming vector, and a high rate of cellular proliferation.

[albedo]

Do not miss latest Josh's blog, critic insight and comments, the latter often by people with good understanding. To me always a good food for thought:

https://joshmitteldo...c-age/#comments

 

Btw and related: this thread has generated interest, particularity on extracellular vesicles which I guess Bryan brought here, e.g. see:

https://www.longecit...ndpost&p=881495

 

Edited by albedo, 14 November 2019 - 08:15 PM.

[albedo]

iPSC going directly into clinic trial for heart regeneration:

https://www.technolo...ime-in-history/

[albedo]

New nice review by Belmonte's team: epigenetics at the nexus of rejuvenating interventions which induce epigenetic reprogramming, stem cell rejuvenation being a common feature:

 

Abstract | "Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing- associated disorders. Several ‘rejuvenating’ interventions have been proposed to delay ageing and the onset of age- associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non- coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age- delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes."

 

Zhang W, Qu J, Liu GH, Belmonte JCI. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol. 2020

[albedo]

In this paper (in press) authors (incl. AgeX) run an in-vitro study on supercentenarians (SC, >= 110 yo) cells reprogramming.

 

I find it interesting and encouraging, don’t you?

 

I find particularly interesting OSKM reprogramming efficiency were not impaired by (very) old age or premature aging and telomere length was reset in all cases though as I understand not that consistently for supercentenarians, the latter maybe having specialties different from other classes of age, even centenarians. I also wonder to which extent these results tell us about a "continuity of aging" starting very early (I think I owe this concept to Blagosklonny). Moreover, they have shown a differentiated gene expression between the SC mesenchymal progenitor cells and control, possibly associated to glucose metabolism and fat regulation pathways which links to dietary/caloric restriction.  It is kind of connecting many dots in aging …

 

Lee et al, 2020, Induced pluripotency and spontaneous reversal of cellular aging in supercentenarian donor cells

 

“Supercentenarians (110-year-old, SC) are a uniquely informative population not only because they surpass centenarians in age, but because they appear to age more slowly with fewer incidences of chronic age-related disease than centenarians. We reprogramed donor B-lymphoblastoid cell lines (LCL) derived from a 114-year-old (SC), a 43-year-old healthy disease-free control (HDC) and an 8-year-old with a rapid aging disease (Hutchinson-Gilford progeria syndrome (HGPS)) and compared SC-iPSC to HDC-iPSC and HGPS-iPSCs. Reprogramming to pluripotency was confirmed by pluripotency marker expression and differentiation to 3 germ-layers. Each iPSC clone differentiated efficiently to mesenchymal progenitor cells (MPC) as determined by surface marker expression and RNAseq analysis. We identified supercentenarian and HGPS associated gene expression patterns in the differentiated MPC lines that were not evident in the parental iPSC lines. Importantly, telomere length resetting occurred in iPSC from all donors albeit at a lower incidence in supercentenarian iPSCs. These data indicate the potential to use reprogramming to reset both developmental state and cellular age in the “oldest of the old.” We anticipate that supercentenarian iPSC and their differentiated derivatives will be valuable tools for studying the underlying mechanisms of extreme longevity and disease resistance.”

 

[albedo]

In this paper (in press) authors (incl. AgeX) run an in-vitro study on supercentenarians (SC, >= 110 yo) cells reprogramming.

....

I find particularly interesting OSKM reprogramming efficiency were not impaired by (very) old age or premature aging and telomere length was reset in all cases though as I understand not that consistently for supercentenarians, the latter maybe having specialties different from other classes of age, even centenarians. I also wonder to which extent these results tell us about a "continuity of aging" starting very early (I think I owe this concept to Blagosklonny). Moreover, they have shown a differentiated gene expression between the SC mesenchymal progenitor cells and control, possibly associated to glucose metabolism and fat regulation pathways which links to dietary/caloric restriction.  It is kind of connecting many dots in aging …

...

 

More and in more learned words synthetically and directly from AgeX:

• Cells of 114-year-old converted to young pluripotent stem cells
• Evidence of reversal of the telomere aging clock in a supercentenarian
• Supports hypothesis of no upper age limit for reprogramming cellular aging
• Introduces possibility of identifying the underlying biology of extreme human lifespan and healthspan

https://investors.ag...ls/default.aspx

 

[albedo]

In this paper (in press) authors (incl. AgeX) run an in-vitro study on supercentenarians (SC, >= 110 yo) cells reprogramming.

...

Lee et al, 2020, Induced pluripotency and spontaneous reversal of cellular aging in supercentenarian donor cells

...

 

A short review of the paper in lay terms by LEAF:

https://www.lifespan...enarians-cells/

[albedo]

"...We propose that autologous or cell-banked transplantable progenitors derived from tankyrase inhibitor-regulated N-hiPSC will more effectively reverse the epigenetic pathology that drives diseases such as diabetes. In future clinical studies, multiple cell types (e.g., vascular endothelium, pericytes, retinal neurons, glia, and retinal pigmented epithelium) could all potentially be differentiated from the same autologous or HLA-compatible, banked patient-specific hiPSC line for a comprehensive repair of ischemic vascular and macular degenerative disease. The further optimization of tankyrase/PARP-inhibited human naïve pluripotent stem cells in defined, clinical-grade conditions may significantly advance regenerative medicine..."

Park, T.S., Zimmerlin, L., Evans-Moses, R. et al. Vascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina. Nat Commun 11, 1195 (2020). https://doi.org/10.1...467-020-14764-5

[albedo]

A nice (conceptual / translational) and quick read....

 

Such a great decade long series of progresses with reprogramming relying on previous work of giants as Gurdon and others !

 

Masserdotti G, Götz M. A decade of questions about the fluidity of cell identity. Nature. 2020;578(7796):522-524.

 

 decade progress in reprogramming.PNG   133.12KB   0 downloads

 routes reprogramming.PNG   308.74KB   0 downloads

[Bryan_S]

Old human cells rejuvenated with stem cell technology, research finds

 

Stanford University School of Medicine is revisiting the epigenetic research of using the Yamanaka factors to rewind many of the molecular hallmarks of aging. 

 

https://medicalxpres...-stem-cell.html

 

http://med.stanford....technology.html

[albedo]

Excellent Bryan_S, just seen. I guess this is the research publication, need to read it but post it immediately here for everyone:

Sarkar, T.J., Quarta, M., Mukherjee, S. et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun 11, 1545 (2020).

https://doi.org/10.1...467-020-15174-3

[albedo]

Excellent Bryan_S, just seen. I guess this is the research publication, need to read it but post it immediately here for everyone:

Sarkar, T.J., Quarta, M., Mukherjee, S. et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun 11, 1545 (2020).

https://doi.org/10.1...467-020-15174-3

 

I did a first pass on this great paper. Any comment? A little funny thing I have found, when comparing to the pre-print one year ago in bioRxivs, authors dropped the name they gave then to their method: Epigenetic Reprogramming of Aging (ERA). A requirement maybe in the editorial review process? However ERA slipped in the text once toward the end in the muscle SC part for sarcopenia. Wrt the latter, not only in-vitro you have amelioration of 11 different hallmarks (Fig 2) but the results using muscle SC is basically positively addressing in-vivo aging driven sarcopenia, which is functional degradation, which almost by definition is aging, right?

Btw, the Stanford communication article Bryan_S pointed to is very well written and resumes well the paper. Thank you.

 

(edit=add links)

Edited by albedo, 27 March 2020 - 09:26 PM.

[kench]

Yes, albedo, I'm surprised there isn't more discussion by now about this great paper.

Maybe a new thread/topic has been started on it, and I've missed it.

Of course, the world is pre-occupied with more urgent medical news!

 

 

[albedo]

...

Maybe a new thread/topic has been started on it, and I've missed it.

...

Thank you. The only I could find:

https://www.longecit...rapy-for-aging/

https://www.longecit...ngevity-review/

 

[albedo]

Wow!  Nice new research in Nature and also some deciphering by LEAF, addressing age-related retinophaty, which might result in blindness, by chemical reprogramming of non-pluripotent cells into transplantable rod photoreceptors. Clinical use is claimed to be very challenging but feel this is also an important step toward it.

Mahato, B., Kaya, K.D., Fan, Y. et al. Pharmacologic fibroblast reprogramming into photoreceptors restores vision. Nature (2020). https://doi.org/10.1...1586-020-2201-4

 

Photoreceptor loss is the final common endpoint in most retinopathies that lead to irreversible blindness, and there are no effective treatments to restore vision^1,2. Chemical reprogramming of fibroblasts offers an opportunity to reverse vision loss; however, the generation of sensory neuronal subtypes such as photoreceptors remains a challenge. Here we report that the administration of a set of five small molecules can chemically induce the transformation of fibroblasts into rod photoreceptor-like cells. The transplantation of these chemically induced photoreceptor-like cells (CiPCs) into the subretinal space of rod degeneration mice (homozygous for rd1, also known as Pde6b) leads to partial restoration of the pupil reflex and visual function. We show that mitonuclear communication is a key determining factor for the reprogramming of fibroblasts into CiPCs. Specifically, treatment with these five compounds leads to the translocation of AXIN2 to the mitochondria, which results in the production of reactive oxygen species, the activation of NF-κB and the upregulation of Ascl1. We anticipate that CiPCs could have therapeutic potential for restoring vision.

 

Also discussed here:

https://www.lifespan...restore-vision/

 

[albedo]

A possible link to OSK reprogramming of the recent pretty amazing (provided confirmation) results of Katcher's and Horvath's and team new research?

See also here:

 

"...It will be interesting to see if reprogramming factors, such as OSK, are induced in the tissues of treated animals. This might explain the ability to reset age. Maybe it's a different set of genes for each organ. We will see....! 23/n end..."

https://twitter.com/...912961730191363

[albedo]

Sorry if this has been reported already but, reading it again, it is so well written that I better log it here again:

 

Zhang W, Qu J, Liu GH, Belmonte JCI. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol. 2020;21(3):137-150.

https://doi.org/10.1...1580-019-0204-5

 

"Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing-associated disorders. Several 'rejuvenating' interventions have been proposed to delay ageing and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes."

 

 

[Bryan_S]

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

 

https://www.aging-us...cle/103418/text

 

Irina & Michael Conboy – Resetting Aged Blood to Restore Youth

https://www.lifespan...michael-conboy/

 

Out With the Old Blood

https://joshmitteldo...-the-old-blood/

 

 

 

JMHO Irina & Michael Conboy have been busy! What they propose are standard prescribable medical procedures. Oh and human trials next.

Edited by Bryan_S, 15 June 2020 - 10:24 PM.

[albedo]

Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

 

https://www.aging-us...cle/103418/text

 

Irina & Michael Conboy – Resetting Aged Blood to Restore Youth

https://www.lifespan...michael-conboy/

 

Out With the Old Blood

https://joshmitteldo...-the-old-blood/

 

 

 

JMHO Irina & Michael Conboy have been busy! What they propose are standard prescribable medical procedures. Oh and human trials next.

 

Yes Bryan_S. With the results (still to be peer-reviewed and better understood) by Horvath and Katcher, the progresses at Alkahest and now this work at the Conboy's lab it looks like something very interesting is going on in relation to blood and blood factors, yet using different paths and approaches. And you are right writing "standard prescribable medical procedures", that is incredible and exciting...

 

[Harkijn]

Perhaps slightly OT:   did you see this newspaper article?

https://www.sciencen...nefits-exercise

[albedo]

Reading the article on Dr Church in the last LEF magazine I wonder if what I emphasize in bold in the following excerpt (p. 52) is basically what Bryan brought in this thread when discussing EV (extracellular vesicles) as a promising technology which can be used in reprogramming, right?

 

"...Dr. Church: If our idea is correct, we should be able to impact all of them at the same time when we target the core causes of aging. When you’re rejuvenatin cells, you’re also boosting all their repair mechanisms. It’s possible that certain negative biological changes are rather permanent and hard to restore, but they would be incredibly drastic. The challenge for the near future is using artificial intelligence to design “delivery shuttles” that carry gene therapy where you want it to go. But if we can convince the cells that they’re young by giving them a dose of youth-promoting genes, their own repair factory should kick in and restore lots of damage from aging. Trying to convince every cell in the body is very difficult. Some life-extending, non-gene therapies are trying. We believe that youth-promoting hormones and other biological factors shared from cell to cell hold the key. Using gene therapy, even if we hit just a few cells, they’ll amp up hormone production, diffuse them throughout the body, and immediately amplify the gene therapy’s initial effect..."

https://www.lifeexte...55df6391fda0ec2
 

[Bryan_S]

Reading the article on Dr Church in the last LEF magazine I wonder if what I emphasize in bold in the following excerpt (p. 52) is basically what Bryan brought in this thread when discussing EV (extracellular vesicles) as a promising technology which can be used in reprogramming, right?

 

"...Dr. Church: If our idea is correct, we should be able to impact all of them at the same time when we target the core causes of aging. When you’re rejuvenatin cells, you’re also boosting all their repair mechanisms. It’s possible that certain negative biological changes are rather permanent and hard to restore, but they would be incredibly drastic. The challenge for the near future is using artificial intelligence to design “delivery shuttles” that carry gene therapy where you want it to go. But if we can convince the cells that they’re young by giving them a dose of youth-promoting genes, their own repair factory should kick in and restore lots of damage from aging. Trying to convince every cell in the body is very difficult. Some life-extending, non-gene therapies are trying. We believe that youth-promoting hormones and other biological factors shared from cell to cell hold the key. Using gene therapy, even if we hit just a few cells, they’ll amp up hormone production, diffuse them throughout the body, and immediately amplify the gene therapy’s initial effect..."

https://www.lifeexte...55df6391fda0ec2
 

 

Thanks Albedo,

 

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming is where we started this thread. So we will attempt to stay on this path for this thread, but as new epigenetic targets are identified, maybe we don't need to reboot our epigenetics as deeply as in this experiment. At all times, we need to maintain cell identity and this is the worry. Then we need viable delivery methods for these therapies because we can not directly replicate this proof of concept experiment on humans.

 

As I've posted before, this approach is a very low-level epigenetic reboot akin to using a jackhammer as apposed to a chisel. At this point in time, IMHO we do not have all the proper epigenetic targets selected, and on that topic, research is pressing on to identify them.

 

Here is some of that ongoing research, one of which is uncovering many important factors in the cell cycle. Let's look at a recent development: NSD2 enzyme appears to prevent cellular senescence

https://medicalxpres...senescence.html

 

Recently an article appeared about belly fat as a source of chronic inflammation. Researchers discovered that eosinophil cell therapy promotes rejuvenation. Now they harvested young Eosinophil cells from genetically identical mice and gave them to the old mice, but old cells can be regressed in age with Partial Reprogramming and reintroduced into the body since we don't all have younger genetic twins. Think of it, partial reprogramming of just Eosinophil cells (a variety of white blood cells) could be one avenue. Keep in mind this is a cell-based therapeutic approach. Furthermore, if this type of approach is affective, do we need to roll the clock back for every cell type, or can we pick those cell types that are the most influential over the rest?

Age-related impairments reversed in animal model

https://www.scienced...00706140905.htm

 

On the delivery side, EV (extracellular vesicles) are an up-and-coming delivery method, one which mimics our body's own epigenetic reprograming. Messenger RNA can very discreetly target the proper gene and then be degraded and eliminated. Targeting specific tissues, if that's desired, is still in the works but progress is being made.

 

Currently, I'm collecting articles where avenues of success are being forged. Using extracellular vesicles appears to be less invasive than say using retroviruses/lentiviruses, or reprogramming cells outside the body and then reintroducing them, but the group I'm featuring made some success on two separate fronts, both needed for different approaches. At Ohio State University, they have had success using a lipid-based delivery system for messenger RNA, mimicking natural EV's and in another experiment using the same lipid-based delivery system to insert a DNA base editor to edit the DNA base pairs where needed. So different tools will likely be needed for different tasks depending on the end goal and work along these lines is progressing.

Tiny engineered therapeutic delivery system safely solves genetic problems in mice

https://phys.org/new...ly-genetic.html

 

And another noteworthy read:

RNA as a future cure for hereditary diseases

https://medicalxpres...y-diseases.html

 

Guys, a ton of publications are coming out each week. I still have my eye on Irina & Michael Conboy because blood carries EV's and other cell signaling proteins. From a treatment standpoint, since blood transfusions from our children are kind of a non-starter, let us see what the complete blood profiles reveal from childhood to old age and then determine which cell signaling products have gone into decline and need therapeutic enhancement.

 

We can't even begin to approach whole body reprogramming until we know which genes to turn on and which to turn off. As a scientific community, we are just beginning to look at treating some genetic diseases by re-training other cells to produce needed protein products. I don't think aging will be much different because we can turn some cells into factories for declining blood factors and other RNA products needed for rejuvenation. We then become our own pharmacy. So rejuvenation approaches leveraging the body's own resources will be the most cost-effective and longest-lasting IMHO.

 

Bryan

Edited by Bryan_S, 23 August 2020 - 07:32 AM.

[albedo]

Insightful as usual Bryan! Thank you. "We then become our own pharmacy" .. love it !

[albedo]

Reprograming discussed (sect 3.1) in the frame of a theoretical new (to me) framework approach called “pro-stemness” and “pro-function” which honestly, I still need to understand better. It looks to me interesting and from two veterans of aging research (Gladyshev, Zhang):

 

 stemness - funtion.PNG   208.28KB   1 downloads

 

Zhang, B, Gladyshev, VN. How can aging be reversed? Exploring rejuvenation from a damage‐based perspective. Advanced Genetics. 2020; 1:e10025. https://doi.org/10.1002/ggn2.10025