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Can Epigenetic ageing be ignored and rejuvenation still be achieved

epigenetic ageing

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#1 sholay75

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Posted 23 August 2019 - 06:31 AM


Can Epigenetic ageing be ignored and rejuvenation still be achieved

 

Epigenetic aging a phenomena in which one third of the CpG sites reveal age-associated DNAm changes, of which 60% become hypomethylated and 40% hypermethylated upon aging, starts from the fetal stage.
 
'the DNAm aging clock and the developmental stage typically correlate with the gestational age, these clocks can be decoupled in some cases and likely represent two independent timing mechanisms'
 
The study from Aging cell https://onlinelibrar...1111/acel.12897
in which 1 and 3 year old donors received Epigenetically aged blood cells from aged donors, there was no affect on development and neither did growth affect Epigenetic age of the received donor cells.
 
The studies about the link between Epigenetic Clocks for Aging and Senescence indicate Epigenetic ageing is distinct from senescence-mediated ageing and replicative senescence and aging evoke characteristic modifications in the DNA methylation (DNAm) pattern, but at different sites in the genome.
These studies coupled with partial reprogramming research hint that Epigenetically aged cells may be progressively dysfunctional, but they are distinct from senescent cells and may not be harmful.
 
Could it be that Epigenetic aging of the cell in aged tissue, which leads to dysfunction, is because of the gradual decline of growth factors in the body.
This Epigenetic aging or rather progressive change in Dnam on various CPG sites, which constitute various aging clocks, have no affect on growth in a young environment i.e the cell which acquires these Dnam changes, continues to divide and function appropriately in presence of growth factors. The various studies mentioned above show that cells with accelerated deposition of these Dnam changes as in Down's syndrome, or cells with an aged Dnam profile transfused to a young environment do not hamper development and the body effectively ignores these Cpg Dnam marks.
 
If there is merit in the above argument then, by introducing young blood plasma in a aged body and maintaining the level of growth factors which correspond to levels in the young, the dysfunction of the aged cell can be reversed. The cell can keep acquiring these Cpg changes, the body will have rejuvenated  in spite of them.
 


#2 Researchgrounded

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Posted 23 August 2019 - 06:17 PM

Interesting hypothesis. Nice compilation of recent work better characterizing the nature of epigenetic change.

Sure, if in addition to the hypothesis being correct, said infusion recapitulated a youthful environment - and a far reaching one reaching the pertinent cells, tissues, and organ systems - rendering the epigenetic change harmless. It is also not clear whether under what circumstances epigenetic change is deleterious or a marker of damage and/or compensatory.

Though it makes for an attractive and enticing narrative, that is a big if, and this theory compels evidence to have empirical credence beyond conjuring biological plausibility, compatibility with what we know now, and a healthy dose of optimistic speculation.

Indeed, right now even whether young plasma itself ( not to be confused with parabiosis) provides a material net risk/gain quotient - via addition of youthful factors and/or dilution of old factors - has yet to be convincingly established. The good news is with the relentless march of science, we will know the answer one way or another with time.

Edited by researchgrounded, 25 August 2019 - 05:57 PM.


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#3 sholay75

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Posted 24 August 2019 - 05:00 AM

Yes this is optimistic speculation, but these studies raise a big question on the theory of epigenetic aging, we do not know what these Dnam changes mean and a lot of questions remain to be answered.



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#4 sholay75

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Posted 24 August 2019 - 05:56 AM

Consider some facts

 

1 progressive epigenetic changes on certain cpg sites track age very convincingly and progressively make the cell dysfunctional.

2 These Dnam changes are reversed by partial reprogramming, which introduces certain combination of Mrna's and the cell is rejuvenated.

3 These very same Dnam changes progress exponentially during growth and in certain special cases start from higher base or are highly accelerated compared to normal and cells function and divide normally without development being hampered.

 

some questions

1 Are these Dnam changes on cpg sites which constitute the epigenetic clock making the cells dysfunctional or is

progressive loss of growth factors in a maturing body giving rise to dysfunctional behavior.

2 partial reprogramming factors reverse the dnam age/changes, but it could also be reversing Dnam on thousands of other Cpg sites and those could be reason for the rejuvenation.

3 If aging is co related  to these progressive Dnam changes, but so is growth. How do we conclude epigenetic age needs to be reversed for rejuvenation.



#5 Turnbuckle

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Posted 24 August 2019 - 01:29 PM

Epigenetically aged cells may be progressively dysfunctional, but they are distinct from senescent cells and may not be harmful.

 

Yes this is optimistic speculation, but these studies raise a big question on the theory of epigenetic aging, we do not know what these Dnam changes mean and a lot of questions remain to be answered.

 

The first statement contradictions itself. What is dysfunctional if not harmful?

 

And we know what DNAm changes mean. The 200 cell types of the body are distinguished by their epigenetic programing. Scramble that programing enough and you end up with nothing. 



#6 sholay75

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Posted 24 August 2019 - 01:46 PM

The first statement contradictions itself. What is dysfunctional if not harmful?

 

And we know what DNAm changes mean. The 200 cell types of the body are distinguished by their epigenetic programing. Scramble that programing enough and you end up with nothing. 

A dysfunctional cell is not harmful in the sense it is not a senescent cell. A dysfunctional cell has progressive Dnam changes at various cpg sites with age, which do not allow it to function optimally, and the cell is not targeted for elimination by the body.

but this very same cell with an aged Dnam signature or an accelerated acquisition of Dnam changes divides and functions perfectly well in a young environment as shown in the studies in the 1st post.



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#7 Turnbuckle

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Posted 24 August 2019 - 02:54 PM

A dysfunctional cell is not harmful in the sense it is not a senescent cell. A dysfunctional cell has progressive Dnam changes at various cpg sites with age, which do not allow it to function optimally, and the cell is not targeted for elimination by the body.

but this very same cell with an aged Dnam signature or an accelerated acquisition of Dnam changes divides and functions perfectly well in a young environment as shown in the studies in the 1st post.

 

 

Epigenetically old cells typically become senescent because their telomeres run down, not because they are dysfunctional. As for the last thing you said about an epigenetically old cell functioning perfectly well in a young environment, could you point out exactly where you found that? Because a dysfunctional cell will still be dysfunctional. You can't erase epigenetic age by transplantation of old cells into a young body.


Edited by Turnbuckle, 24 August 2019 - 03:05 PM.


#8 sholay75

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Posted 24 August 2019 - 03:24 PM

Epigenetically old cells typically become senescent because their telomeres run down, not because they are dysfunctional. As for the last thing you said about an epigenetically old cell functioning perfectly well in a young environment, could you point out exactly where you found that? Because a dysfunctional cell will still be dysfunctional. You can't erase epigenetic age by transplantation of old cells into a young body.

In this study from aging cell https://onlinelibrar...1111/acel.12897 describes that the DNAm age of donor blood is not influenced by the environment of the recipient's body, whether younger or older. In this study a followup is done 1 and 3 years old recipients for 17 years, who received  aged donor blood stem cells. the fact that the study did not report any problem with growth for these young patients led me to the conclusion that an epigenetically aged cell functions and divides normally in a young environment .

 

 

In this study https://www.nature.c...598-019-39919-3 the epigenetic clock is significantly accelerated in fetal retina from Down syndrome samples, though the developmental clock does not show major changes and remains correlated with gestational age.  



#9 sholay75

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Posted 24 August 2019 - 03:32 PM

Epigenetically old cells typically become senescent because their telomeres run down, not because they are dysfunctional. As for the last thing you said about an epigenetically old cell functioning perfectly well in a young environment, could you point out exactly where you found that? Because a dysfunctional cell will still be dysfunctional. You can't erase epigenetic age by transplantation of old cells into a young body.

Epigenetically old cells are dysfunctional is being claimed by partial reprogramming researchers, not by me. 

The epigenetic changes are what, at the nuclear level, triggers this dysfunctionality of the cell. 

— Vittorio Sebastiano

turn.bio



#10 Turnbuckle

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Posted 24 August 2019 - 04:06 PM

In this study from aging cell https://onlinelibrar...1111/acel.12897 describes that the DNAm age of donor blood is not influenced by the environment of the recipient's body, whether younger or older. In this study a followup is done 1 and 3 years old recipients for 17 years, who received  aged donor blood stem cells. the fact that the study did not report any problem with growth for these young patients led me to the conclusion that an epigenetically aged cell functions and divides normally in a young environment .

 

 

In this study https://www.nature.c...598-019-39919-3 the epigenetic clock is significantly accelerated in fetal retina from Down syndrome samples, though the developmental clock does not show major changes and remains correlated with gestational age.  

 

 

Exactly. Cells have an epigenetic age that follows them, even if you put them in another body or grow them in vitro. They grow older due to mitosis and the errors inserted by the low fidelity of methyltransferase, and for other reasons, but not because the recipient body has a different age. From your first link--

 

Our data demonstrate that transplanted human hematopoietic stem cells have an intrinsic DNAm age that is unaffected by the environment in a recipient of a different age.

 

 

 

Thus in the case of transplants, old donors produce worse results--

 

Overall, older donor age is associated with worse outcomes for all the organs studied. 

https://www.ncbi.nlm...les/PMC6123500/

 

 

 

 


Edited by Turnbuckle, 24 August 2019 - 04:12 PM.


#11 sholay75

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Posted 24 August 2019 - 04:31 PM

Exactly. Cells have an epigenetic age that follows them, even if you put them in another body or grow them in vitro. They grow older due to mitosis and the errors inserted by the low fidelity of methyltransferase, and for other reasons, but not because the recipient body has a different age. From your first link--

 

 

 

Thus in the case of transplants, old donors produce worse results--

I fully agree with you on that 'Cells have an epigenetic age that follows them, even if you put them in another body or grow them in vitro'

The fact that these epigenetically aged cells transferred to a 1 and 3 year old body divided and functioned normally. this is the gist of what i am trying to say, in a young environment epigenetically aged cells function normally without their epigenetic age being reversed i.e the epigenetic age keeps advancing at a steady rate. One can speculate then if one introduces young blood plasma/cord blood cells/young stem cells, the changed environment can allow the epigenetically aged cells to function normally regardless of their increasing epigenetic age.



#12 Turnbuckle

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Posted 24 August 2019 - 04:43 PM

I fully agree with you on that 'Cells have an epigenetic age that follows them, even if you put them in another body or grow them in vitro'

The fact that these epigenetically aged cells transferred to a 1 and 3 year old body divided and functioned normally. this is the gist of what i am trying to say, in a young environment epigenetically aged cells function normally without their epigenetic age being reversed i.e the epigenetic age keeps advancing at a steady rate. One can speculate then if one introduces young blood plasma/cord blood cells/young stem cells, the changed environment can allow the epigenetically aged cells to function normally regardless of their increasing epigenetic age.

 

 

Epigenetic age only becomes a problem when you approach geriatric age.



#13 sholay75

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Posted 24 August 2019 - 05:03 PM

Epigenetic age only becomes a problem when you approach geriatric age.

I fully agree with that, and that could be due to the progressive loss of growth factors



#14 Turnbuckle

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Posted 24 August 2019 - 05:30 PM

I fully agree with that, and that could be due to the progressive loss of growth factors

 

 

And thus we come full circle...

 

Your idea is not totally wrong, however. While aging is essentially the increasing corruption of the epigenetic code (epimutations), senescent cells put out secretions (senescence-associated secretory phenotype--SASP), which create inflammation and can drive other cells to senescence, while stem cells are known to put out extracellular vesicles (EVs) that are able to

 

control inflammation, accelerate skin cell migration and proliferation, control wound scarring, improve angiogenesis, and even ameliorate signs of skin aging. 

https://www.ncbi.nlm...les/PMC6466099/

 

 

 

So one does nearly the opposite of the other. And with aging you get more senescent cell secretions as senescent cells build up, and less stem cell vesicles as stem cell pools dry up, a combination that magnifies the problem of growing epigenetic age.



#15 Never_Ending

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Posted 24 August 2019 - 08:48 PM

I think that this questions can be understood in 2 different ways (the 2nd being probably the intended meaning).

 

1. Can a certain degree of rejuvenation be achieved despite ignoring the epigenetic aging? 

Yes and clearly since the mouse parabiosis experiments have clearly showed the old mouse getting more rejuvenated without a clear focus of addressing its epigenetic aging.

 

2. Can perpetual lifespan be achieved despite ignoring epigenetic aging?

 

Almost surely not. First just to get it out of the way there's a big difference in putting a aged DNAm substance into a younger environment and visa versa (its much easier for a young body to functionally ignore a old group of cells than for a old body to follow the route of a young group of cells).

 

To answer the main point of the question, I dont think its possible to ignore epigenetic aging and just focus on cell and tissue damage while being able to extend healthy life indefinitely. Healhspan requires not just young functional groups of cells but also the genetically driven coordination of these groups of cells cohesively. By ignoring epi-aging you can still achieve good extension but not really indefinite because the body would eventually not have enough "cohesive" aspect that it needs to function properly.  This will lead to a unpredictable and sub-par mortality rate even in the best scenario and would be not well suited for extreme or near indefinite healthspan extension.  It would still be a great deal to accomplish if done and would greatly improve prospects for aging people.



#16 sholay75

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Posted 25 August 2019 - 09:13 AM

I think that this questions can be understood in 2 different ways (the 2nd being probably the intended meaning).

 

1. Can a certain degree of rejuvenation be achieved despite ignoring the epigenetic aging? 

Yes and clearly since the mouse parabiosis experiments have clearly showed the old mouse getting more rejuvenated without a clear focus of addressing its epigenetic aging.

 

2. Can perpetual lifespan be achieved despite ignoring epigenetic aging?

 

Almost surely not. First just to get it out of the way there's a big difference in putting a aged DNAm substance into a younger environment and visa versa (its much easier for a young body to functionally ignore a old group of cells than for a old body to follow the route of a young group of cells).

 

To answer the main point of the question, I dont think its possible to ignore epigenetic aging and just focus on cell and tissue damage while being able to extend healthy life indefinitely. Healhspan requires not just young functional groups of cells but also the genetically driven coordination of these groups of cells cohesively. By ignoring epi-aging you can still achieve good extension but not really indefinite because the body would eventually not have enough "cohesive" aspect that it needs to function properly.  This will lead to a unpredictable and sub-par mortality rate even in the best scenario and would be not well suited for extreme or near indefinite healthspan extension.  It would still be a great deal to accomplish if done and would greatly improve prospects for aging people.

The young body is not ignoring an old group of cells, it is using the same cells to divide and proliferate. It is using the same group of cells to populate the blood system and feed the growth of the body in a very normal way. However it is ignoring dnam changes on certain  cpg sites on those cells, which are shown to be detrimental after the body stops growing.

 

The question is why does the young environment ignore these dnam changes.

 

This study https://www.nature.c...598-019-39919-3

'the DNAm aging clock and the developmental stage typically correlate with the gestational age, these clocks can be decoupled in some cases and likely represent two independent timing mechanisms'. It is hinting that the growth clock and the aging clock are independent circuits in the cell.
 
Speculative hypothesis
what if the growth clock and the aging clock are independent and parallel mechanisms. Suppose a subset of these parallel mechanisms is targeting common genes. When both the mechanisms are active in the cell, the growth mechanism dominates and the common genes targeted function optimally. when maturity of the body is activated due to a morphological milestone, the growth mechanism in the cell gradually diminishes and the aging mechanism starts to dominate, the common genes targeted start to dysfunction.
 
An example GDF11 which declines with age, suppose a subset of genes in the growth mechanism is targeting Histone corresponding to GDF11 to make the DNA of the gene accessible for transcription and a subset of genes in the aging mechanism targeting the same Histone corresponding to GDF11, but which function to reduce the transcription.
 
In this scenario growth and aging can be thought of as two mechanisms opposing each other, where one stops dominating the other takes over. Introducing the growth factors in the body just diminishes the aging mechanism and if balance can be achieved perpetual lifespan might be possible.
 
Speculative hypothesis ends


#17 Never_Ending

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Posted 25 August 2019 - 11:09 AM

 

The young body is not ignoring an old group of cells, it is using the same cells to divide and proliferate. It is using the same group of cells to populate the blood system and feed the growth of the body in a very normal way. However it is ignoring dnam changes on certain  cpg sites on those cells, which are shown to be detrimental after the body stops growing.

 

The question is why does the young environment ignore these dnam changes.

 

This study https://www.nature.c...598-019-39919-3

'the DNAm aging clock and the developmental stage typically correlate with the gestational age, these clocks can be decoupled in some cases and likely represent two independent timing mechanisms'. It is hinting that the growth clock and the aging clock are independent circuits in the cell.
 
Speculative hypothesis
what if the growth clock and the aging clock are independent and parallel mechanisms. Suppose a subset of these parallel mechanisms is targeting common genes. When both the mechanisms are active in the cell, the growth mechanism dominates and the common genes targeted function optimally. when maturity of the body is activated due to a morphological milestone, the growth mechanism in the cell gradually diminishes and the aging mechanism starts to dominate, the common genes targeted start to dysfunction.
 
An example GDF11 which declines with age, suppose a subset of genes in the growth mechanism is targeting Histone corresponding to GDF11 to make the DNA of the gene accessible for transcription and a subset of genes in the aging mechanism targeting the same Histone corresponding to GDF11, but which function to reduce the transcription.
 
In this scenario growth and aging can be thought of as two mechanisms opposing each other, where one stops dominating the other takes over. Introducing the growth factors in the body just diminishes the aging mechanism and if balance can be achieved perpetual lifespan might be possible.
 
Speculative hypothesis ends

 

 

I think someone linked this one before but i couldn't find it again. This one: https://www.ncbi.nlm...pubmed/30332397

 

I think growth or more so development counters the senescence aspect of aging. But have have to notice that this is a senescence stage (1-21 roughly) that is meant to be countered by growth and development. The cohesive requirement that i mentioned earlier is in fully abundance at this stage. Compare this to an elderly that is already running very aged DNAm in that case things like GDF and other hormones as well as purely senescence focused therapies will not address enough.

 

On the positive note if we look at how developtmental clock influences the body its through things like growth factors hormones ... I believe the the epigenetic age or DNAm also influences the body through signalling molecules (likely more elusive ones) but still it means that we might be able to get the effects of targeting epi-aging without a completely direct approach.



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#18 QuestforLife

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Posted 29 August 2019 - 10:21 AM

 

 

The question is why does the young environment ignore these dnam changes.

 

 

 

 

The young body is not ignoring anything. DnaM age is just a measure of how far the cell lines have drifted from the initial stem cell 'template'. Have a lot of cells dividing, or even not dividing but being very metabolically active, and you will inevitable get methylation drift. 

 

This probably interacts with telomere loss and failure of tissue maintenance later in life when the cells adapt with their own 'intentional' methylation (gene expression) changes. 

 

Exactly when epigenetic methylation changes become harmful is difficult to say at this point, but it probably doesn't matter until old age when it indicates that replacement from stem compartments is failing, in contrast to young people who happen to have longer telomeres than their peers so need replacement from their stem cells less often (which is probably beneficial).

 

Not many people understand this distinction. 


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