51 replies to this topic

[Rib Jig]

does he stand alone in age reversing research field as the leading authority?   
who else has the same gravitas when it comes to age reversing advances?
what is latest on Tally Health biological age testing?
does David Sinclair seek human volunteers?  details? 

 

[johnhemming]

I wouldn't say he stands alone.  He is good at PR, but the idea that aging is all about methylation is clearly wrong as heterochronic parabiosis would not work if it were. I am running some experiments at the moment based upon my own theories which I think probably will give a strong steer in a particular direction.  However, methylation is consequential not a primary cause.

[Rib Jig]

> the idea that aging is all about methylation is clearly wrong as heterochronic parabiosis would not work if it were.

 

This means little to lay people.

David Sinclair has REVERSED aging in mice:
https://www.cnn.com/...ness/index.html

Mice, as in, mammals, as in, sort of like humans.  Lay people understand that.     

Has anyone else indisputably reversed aging in higher life forms?
Or has anyone at least replicated David Sinclair's results?
And don't report reducing wrinkles with wrinkle cream...

[johnhemming]

What happened with the mice is that he dedifferentiated a number of cells which then redifferentiated.

 

The problem with aging is a question of cells not differentiating properly.  

[Turnbuckle]

I wouldn't say he stands alone.  He is good at PR, but the idea that aging is all about methylation is clearly wrong as heterochronic parabiosis would not work if it were. I am running some experiments at the moment based upon my own theories which I think probably will give a strong steer in a particular direction.  However, methylation is consequential not a primary cause.

 

Heterochronic parabiosis appears to work by rejuvenating stem cells in the older recipient. Having more active stem cells means more replacement of epigenetically old cells by epigenetically young cells and a decline in epigenetic age.

 

In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. 

https://pubmed.ncbi....h.gov/35613617/

 

[kurt9]

Heterochronic parabiosis appears to work by rejuvenating stem cells in the older recipient. Having more active stem cells means more replacement of epigenetically old cells by epigenetically young cells and a decline in epigenetic age.

 

If so, then your protocol (which I can easily do by ordering stuff off of the internet) should work just as well, if not better, than anything David Sinclair is doing. David Sinclair is one of many people doing the "cellular reprogramming" thing these days.

[johnhemming]

Heterochronic parabiosis appears to work by rejuvenating stem cells in the older recipient. Having more active stem cells means more replacement of epigenetically old cells by epigenetically young cells and a decline in epigenetic age.

 

ie the methylation changes are an effect of sorting out the functioning of stem cells.

If so, then your protocol (which I can easily do by ordering stuff off of the internet) should work just as well, if not better, than anything David Sinclair is doing. David Sinclair is one of many people doing the "cellular reprogramming" thing these days.

 

It may even work better as the cellular reprogramming assumes that the cells will differentiate properly which does not always happen (and IMO is a more important element of aging than methylation changes).

[Turnbuckle]

ie the methylation changes are an effect of sorting out the functioning of stem cells.

 

 

 

Stem cells (SCs) have little methylation compared to somatic cells. An SC is a tabula rasa that is programmed de novo during differentiation, when the SC becomes a new SC and a new somatic cell. Thus the epigenetic age of the new somatic cell is very low and the average age of the organism is reduced. Since the numbers of functional SCs steadily decline with time, the numbers of aged out cells that aren't replaced increases, and the average epigenetic age increases. This is not inevitable, however. Increasing the number of functional SCs can reverse it, along with aging itself.

Edited by Turnbuckle, 10 June 2022 - 06:10 PM.

[Turnbuckle]

If so, then your protocol (which I can easily do by ordering stuff off of the internet) should work just as well, if not better, than anything David Sinclair is doing. David Sinclair is one of many people doing the "cellular reprogramming" thing these days.

 

Precisely. No need for blood transfusions or factors that could increase the risk of cancer. Besides, proliferating existing SCs is far easier than reprograming somatic cells, and this has been demonstrated in humans. The process works by taking control of mitochondria, which determine SC fate.

Edited by Turnbuckle, 10 June 2022 - 06:34 PM.

[kurt9]

It would seem so as I think bioenergetics and, by extension, mitochondria (in the case of eukaryotes) are at the root of aging.

 

BTW, Nick Lane is coming out with a new book on bioenergetics.

 

https://nick-lane.ne...life-and-death/

 

 

[Rib Jig]

this thread & similar are populated by home scientist recycling cells

& supplement devotees...?

 

but isn't that apart from clear AGE REVERSAL success of live mammals?

where are the peers of DAVID SINCLAIR & what have they accomplished...?
                             

 

 

[Turnbuckle]

this thread & similar are populated by home scientist recycling cells

& supplement devotees...?

 

but isn't that apart from clear AGE REVERSAL success of live mammals?

where are the peers of DAVID SINCLAIR & what have they accomplished...?
                             

 

 

My own epigenetic age dropped by 28 years, and I am, presumably, a mammal.

[johnhemming]

The Epigenetic age is an effect rather than a cause.  Hence just changing it is like clocking a car.

[Turnbuckle]

The Epigenetic age is an effect rather than a cause.  Hence just changing it is like clocking a car.

 

 

Epigenetic age is a measure of how screwed up your epigenetic codes are. The more screwed up they are, the more your cells produce the wrong balance of proteins and the more dysfunctional the organs in which they reside.

[johnhemming]

Epigenetic age is a measure of how screwed up your epigenetic codes are. The more screwed up they are, the more your cells produce the wrong balance of proteins and the more dysfunctional the organs in which they reside.

The Epigenetic Age is calculated by looking at methylation of the Epigenome. However, acetylation of the Epigenome also matters in terms of proteins and neither of those are the basic cause of aging although they are part of seeing the consequences.

[Turnbuckle]

The Epigenetic Age is calculated by looking at methylation of the Epigenome. However, acetylation of the Epigenome also matters in terms of proteins and neither of those are the basic cause of aging although they are part of seeing the consequences.

 

 

There are at least 11 distinct chemical modifications that comprise the epigenome, however, methylation is the most important. Without the epigenome, there would be nothing to distinguish the 200 cell types from one another as the underlying DNA is the same for all. Unfortunately, this epigenetic code is far more unstable than the underlying genetic code, and has no repair mechanism, apart from removal of old cells and replacement by new cells with freshly minted codes. Old cells cannot detect when their epigenome is screwed up, thus all cells have an inbuilt use-by date -- the telomeric clock -- that ultimately turns on the cell's suicide program and which also releases paracrine factors that instruct nearby stem cells to replace the suiciding cells (though this is not universal). Replacement is a huge job, as more than 300 billion cells are replaced daily. This process would keep things in a steady state except that viable stem cell numbers decline throughout life. If the decline in SCs can be reversed, then epigenetic aging can also be reversed. So stem cells are the key to age reversal, while epigenetic age is the best measure of success.

Attached Files

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Edited by Turnbuckle, 11 June 2022 - 04:46 PM.

[johnhemming]

I would agree that both methylation and acetylation are important.  I am of the view that problems with acetylation are more significant and I think later this year I may have experimental evidence to prove this.

Edited by johnhemming, 11 June 2022 - 06:38 PM.

[Rib Jig]

My own epigenetic age dropped by 28 years...

 

As layman, I understand epigenetic to mean how your DNA is "employed, what sequences are read", right?

If willing, & asking anyone who has epigenetically lowered their age:

 

X -- Y = 28y, X = ?  Y = ?

 

what specific measurable characteristics have dropped in age & by how much?
e.g., pre & post eyesight measurements, pre & post hearing measurements

 

reporting anything that can be reduced by exercise, e.g., heart rate, blood pressure, muscle, etc.,

causes lack of clarity in epigenetic claims, UNLESS one did NO exercising pre & post epigenetic measurements, right??

thank in advance for any reality-based data...       

 

& would still like to hear names of others besides David Sinclair on the front lines of epigenetic breakthroughs

supported by irrefutable evidence...

Edited by Rib Jig, 11 June 2022 - 06:48 PM.

[johnhemming]

I agree it is a good idea to identify measurable physical characteristics linked to age based deterioration that have improved.

 

My main problem with this is that I did not measure enough when I started the process. I am, however, now doing a lot more measurement.

[Rib Jig]

My main problem with this is that I did not measure enough when I started the process. I am, however, now doing a lot more measurement.

 

Then your reports & claims are anecdotal, not scientific.

And that no one else is presenting proper scientific data

on their self-administered supplementing, makes their

criticism of true scientists like David Sinclair...hilariously hypocritical.         

[Edit_XYZ]

There are at least 11 distinct chemical modifications that comprise the epigenome, however, methylation is the most important. Without the epigenome, there would be nothing to distinguish the 200 cell types from one another as the underlying DNA is the same for all. Unfortunately, this epigenetic code is far more unstable than the underlying genetic code, and has no repair mechanism, apart from removal of old cells and replacement by new cells with freshly minted codes. Old cells cannot detect when their epigenome is screwed up, thus all cells have an inbuilt use-by date -- the telomeric clock -- that ultimately turns on the cell's suicide program and which also releases paracrine factors that instruct nearby stem cells to replace the suiciding cells (though this is not universal). Replacement is a huge job, as more than 300 billion cells are replaced daily. This process would keep things in a steady state except that viable stem cell numbers decline throughout life. If the decline in SCs can be reversed, then epigenetic aging can also be reversed. So stem cells are the key to age reversal, while epigenetic age is the best measure of success.

If aging is the effect of SC depletion, then the question is, why are SC numbers going down?

I think it is due to methylation drift in the SCs.

 

Of note is that the cells do have a mechanism for reversing epigenetic drift - Sinclair also confirmed it, by reversing epigenetic drift in cells with yamanaka factors.

 

As you probably know, aging - the slow decay of the body - begins is almost all species of animals after sexual maturity is achieved. That is the point at which the epigenetic drift correcting mechanism begins to gradually shut down.

Of note are the exceptions. For example, hydra vulgaris, that normally reproduces asexually and doesn't age. Until it encounters adverse environments, develops sexual organs, reproducing sexually, and begins to age:

https://longevitylet...-hydra-animals/

[Turnbuckle]

If aging is the effect of SC depletion, then the question is, why are SC numbers going down?

I think it is due to methylation drift in the SCs.

 

Of note is that the cells do have a mechanism for reversing epigenetic drift - Sinclair also confirmed it, by reversing epigenetic drift in cells with yamanaka factors.

 

As you probably know, aging - the slow decay of the body - begins is almost all species of animals after sexual maturity is achieved. That is the point at which the epigenetic drift correcting mechanism begins to gradually shut down.

Of note are the exceptions. For example, hydra vulgaris, that normally reproduces asexually and doesn't age. Until it encounters adverse environments, develops sexual organs, reproducing sexually, and begins to age:

https://longevitylet...-hydra-animals/

 

SCs don't have much methylation. They are methylated de novo during differentiation to achieve one of 200 different cell types -- or subset thereof depending on the pluripotency of the particular SC. And Yamanaka factors don't reverse epigenetic drift per se. They create substantially unmethylated stem cells out of somatic cells, and those stem cells, once differentiated into new stem cells, have de novo and thus pristine epigenetic coding. This is not a known innate function of somatic cells, however, at least in humans. It's true that retro viruses may be used to insert certain SC proteins into somatic cells, converting them into stem cells, but that is a very artificial situation. 

 

As for sexual aging, there are many animals that die after sex, or shortly thereafter. They live fast and die fast. This is programmed, but humans don't have such programming. That human aging can be reversed with stem cells clearly points to the decline of functional SCs as the source.

[johnhemming]

As for sexual aging, there are many animals that die after sex, or shortly thereafter. They live fast and die fast. This is programmed, but humans don't have such programming. That human aging can be reversed with stem cells clearly points to the decline of functional SCs as the source.

 

Any hypothesis as to the root cause of aging has to fit all the known facts.  One known fact is that heterochronic parabiosis shares out the aging between two animals whatever their chronological age.  Also plasma replacement has a rejuvenating effect. This points to a blood borne factor as having some relevance (I think it is interleukin-10).  It does not fit with methylation being part of the root cause.

 

I agree with you that a failure of differentiation is part of the root cause.  There is also a question about availability of stem cells and what affects variations in numbers.

[Turnbuckle]

Any hypothesis as to the root cause of aging has to fit all the known facts.  One known fact is that heterochronic parabiosis shares out the aging between two animals whatever their chronological age.  Also plasma replacement has a rejuvenating effect. This points to a blood borne factor as having some relevance (I think it is interleukin-10).  It does not fit with methylation being part of the root cause.

 

 

It absolutely fits. See: Heterochronic parabiosis induces stem cell revitalization and systemic rejuvenation across aged tissues

 

The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. 

https://pubmed.ncbi....h.gov/35613617/

 

 

When you rejuvenate stem cells in an old animal with blood born factors, you are restoring maintenance and increasing the replacement of aged out cells, thus lowering epigenetic age with young cells having de novo programming. And the reverse seems possible as well, if stem cell activity were harmed by old blood, then the level or replacement would drop and the epigenetic age would increase. There is also the likelihood of transferring VSELs, which are very small blood-born embryonic-like SCs. The old animal would thus see an increase in VSELs while a young animal would see a decrease.

 

This parabiosis approach would also be expected to increase stem cell numbers if fusion was used, and to result in long term depletion if not.

 

In any case, there is no known way that any blood-born factor can decrease epigenetic age without going through SCs. The cells themselves can fix errors in the genetic code, but cannot fix errors in the epigenetic code.

[johnhemming]

It absolutely fits.

 

When you rejuvenate stem cells in an old animal with blood born factors, you are restoring maintenance and increasing the replacement of aged out cells, thus lowering epigenetic age with young cells having de novo programming. And the reverse seems possible as well, if stem cell activity were harmed by old blood, then the level or replacement would drop and the epigenetic age would increase. There is also the likelihood of transferring VSELs, which are very small blood-born embryonic-like SCs. The old animal would thus see an increase in VSELs while a young animal would see a decrease.

 

This parabiosis approach would also be expected to increase stem cell numbers if fusion was used, and to result in long term depletion if not.

 

In any case, there is no known way that any blood-born factor can decrease epigenetic age without going through SCs. The cells themselves can fix errors in the genetic code, but cannot fix errors in the epigenetic code.

 

I accept that parabiosis reduces epigenetic age, but that makes epigenetic age a downstream issue. The cells themselves do dynamically change the state of the epigenetic code.  They need the right conditions for that.

[Turnbuckle]

I accept that parabiosis reduces epigenetic age, but that makes epigenetic age a downstream issue. The cells themselves do dynamically change the state of the epigenetic code.  They need the right conditions for that.

 

They can't fix random errors to the code. That has to be unpacked once again from the genetic code during de novo methylation.

[johnhemming]

As we can judge a biological age from methylation patterns they are not random.

[Decimus]

Sinclair is NOT the standard-bearer. In fact perhaps the opposite in many ways. For those of us old enough to remember when he first came to light we remember how he relentlessly pushed his SIRT company in the media until he created such publicity it was bought by GSK only to flop a short time later. GSK accused him essentially of faking results in his mice studies. He disappeared for years with his reputation tarnished.

He has rebuilt himself recently, but he’s running the same methodology as before. The problem with Sinclair is he is half brilliant and half used car salesman. He always seems to push the best case scenario and there always seems to be an economic angle for him to make a lot of money or increase his own exposure. He’s a net plus because he’s good at bringing publicity to the movement but take everything he says with a truck full of salt.

To answer your question about who else, I would argue that George Church is the real deal in terms of a researcher who advocates for anti-aging and seems completely genuine in his motives. You can probably add De Grey to the list as well.

[Rib Jig]

He has rebuilt himself recently...

 

He's treated as an authority by CNN:
https://www.cnn.com/...ness/index.html

 

Do you claim a CNN writer has been irrefutably duped?

[Edit_XYZ]

SCs don't have much methylation. They are methylated de novo during differentiation to achieve one of 200 different cell types -- or subset thereof depending on the pluripotency of the particular SC. And Yamanaka factors don't reverse epigenetic drift per se. They create substantially unmethylated stem cells out of somatic cells, and those stem cells, once differentiated into new stem cells, have de novo and thus pristine epigenetic coding. This is not a known innate function of somatic cells, however, at least in humans. It's true that retro viruses may be used to insert certain SC proteins into somatic cells, converting them into stem cells, but that is a very artificial situation. 

 

As for sexual aging, there are many animals that die after sex, or shortly thereafter. They live fast and die fast. This is programmed, but humans don't have such programming. That human aging can be reversed with stem cells clearly points to the decline of functional SCs as the source.

The 4 yamanka factors do not unmethylate cells. An umethylated or even partially unmethylated cell will immediately die.

Unmethylating is akin to erasing executable programs.

 

In fact, stem cells have a very specific epigenetic coding - different from the ones of somatic cells.

The 4 yamanaka factors change the epigenetic coding of a cell from a somatic cell coding to a stem cell coding. This is a VERY precise changing of the epigenetic coding.

D. Sinclair proved that, by using only 3 of the 4 yamanaka factors, one can eliminate the epigenetic drift of a somatic cell, to the pristine epigenetic coding of said somatic cell.

This is only possible if, in every cell, the information of the epigentic codings of stem cells/somatic cells is stored in a way that substantially prevents degradation, and there is a mechanism that can precisely change the epigenetic coding of said cell to one stored - a mechanism activated by the yamanaka factors.

 

BTW, when I said that aging - the slow decay of the body - begins is almost all species of animals after sexual maturity is achieved, and that is the point at which the epigenetic drift correcting mechanism begins to gradually shut down, I was NOT referring to animals that die after procreation - such as the salmon*, where death is hormonally induced -, nor to other exceptions, such as negligible senescent species.

I am referring to the vast majority of animals - which includes humans.

 

*Speaking of which, I read a paper detailing how, after the hormonal mechanism killing the salmons was disabled, the salmons experienced the decay of the body corresponding to standard aging.

 

 

You said that aging is caused by stem cell depletion. But you did not say why said stem cells are depleting with age.

I said why - epigenetic drift in the stem cells.

Yes, during differentiation, a stem cell will change its epigenetic coding to another type of cell. But, for this, you need the stem cell to differentiate. And the more epigenetic drift in the stem cell, the harder it is to differentiate.

Edited by Edit_XYZ, 13 July 2022 - 02:16 PM.