989 replies to this topic

[QuestforLife]

This is simply wrong. Epigenetic aging is due to the buildup of epimutations, while telomeric age is due to telomeric erosion. One doesn't set the other.

 

If this is wrong then why does resetting telomere length in various different cell types restore their functionality to that of young cells? Did the cells in Horvath's experiments develop other problems unrelated to their telomeres? I've seen no evidence of it. 

 

Regarding the paper you reference:

 

https://www.ncbi.nlm...les/PMC4864882/

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

‘The epigenetic clock changed over time at roughly the same rate as chronological age in both cohorts’
What did they expect? Horvath’s clock was designed to track chronological age! This does not mean it is causal to aging.
‘in a combined cohorts analysis, a one standard deviation increase in baseline epigenetic age was linked to a 25% increased mortality risk (P = 1.4 × 10−4)’
Again, what did they expect? We know mortality risk tracks with age and the Horvath clock was trained to track chronological age!
All these arguments so far are circular.

 

That is why I currently think telomere length is a marker of youthful gene expression in a particular cell type. 

[Turnbuckle]

 

Can we find any evidence of harm from ‘accelerating’ the Horvath clock by extending telomeres?
The short answer is no.

 

 

Accelerating epigenetic aging is associated with an increase in mortality.

 

Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort

https://www.ncbi.nlm...les/PMC4891876/

 

 

 

And--

 

Frailty is associated with the epigenetic clock but not with telomere length in a German cohort

https://www.ncbi.nlm...les/PMC4768341/

 

 

These are findings over the past four or five years. As far as I know, no one has yet studied accelerated epigenetic aging due specifically to taking telomerase supplements. My own experience is that it negates the age-reversal effects of stem cell stimulants.

[QuestforLife]

Accelerating epigenetic aging is associated with an increase in mortality.

 

 

And--

 

 

These are findings over the past four or five years. As far as I know, no one has yet studied accelerated epigenetic aging due specifically to taking telomerase supplements. My own experience is that it negates the age-reversal effects of stem cell stimulants.

 

As I said in post 331 above its all circular reasoning as Horvath's methylation clock was trained specifically to track chronological age. Therefore we can't be surprised that it successfully tracks increasing mortality, CDC risk and cancer, which all increase with age.

 

We can't use methylation clocks as a proxy for biological age and/or health without decoupling them from the chronological age they were designed to track.

 

One way to do this would be to use an intervention that increased health and decreased 'methylation age' and show that the change in methylation state was required for the improvement in health. Sinclair went someway to doing this by showing that TET enzymes were required for regeneration of the optic nerve in his mice. (https://www.biorxiv....0.1101/710210v1 ). But I interpret this as just that the optic nerve needs some specific progenitor cells to regenerate and it can't do this without demethylation of terminally differentiated cells, which I fully admit lengthening telomeres would not do as they do not change the identity of a cell, only its age associated gene expression. This is the same as trying to grow new teeth. You can't do it with longer telomeres, you need specific dental stem cells.

 

But this is leaving the point of this thread that lengthening telomeres is a valid intervention to reverse aging. So far we only have theoretical objections. 

Edited by QuestforLife, 21 October 2020 - 02:09 PM.

[Turnbuckle]

 

We can't use methylation clocks as a proxy for biological age and/or health without decoupling them from the chronological age they were designed to track.

 

 

 

If you were tasked by a life insurance company to set premiums, and all you had was a telomeric clock as show below (on the right), or Horvath's epigenetic clock (on the left), which would you pick?

 

https://www.wikiwand...pigenetic_clock

https://www.anti-agi...mere-lengths-2/

Attached Thumbnails

• 

Edited by Turnbuckle, 21 October 2020 - 02:41 PM.

[Iporuru]

 

If you were tasked by a life insurance company to set premiums, and all you had was a telomeric clock as show below (on the right), or Horvath's epigenetic clock (on the left), which would you pick?

 

https://www.wikiwand...pigenetic_clock

https://www.anti-agi...mere-lengths-2/

 

 

Interesting fragment from the first link you gave:

 

Relationship to a cause of biological aging

It is not yet known what exactly is measured by DNA methylation age. Horvath hypothesized that DNA methylation age measures the cumulative effect of an epigenetic maintenance system but details are unknown. The fact that DNA methylation age of blood predicts all-cause mortality in later life^{[15][16][17][18]} has been used to argue that it relates to a process that causes aging.^[19] However, if a particular CpG played a direct causal role in the aging process, the mortality it created would make it less likely to be observed in older individuals, making the site less likely to have been chosen as a predictor; the 353 clock CpGs therefore likely have no causal effect whatsoever.^[20] Rather, the epigenetic clock captures an emergent property of the epigenome.

(...) At the molecular level, DNAm age is a proximal readout of a collection of innate aging processes that conspire with other, independent root causes of ageing to the detriment of tissue function.

 

[Turnbuckle]

Interesting fragment from the first link you gave:

 

Relationship to a cause of biological aging

It is not yet known what exactly is measured by DNA methylation age. Horvath hypothesized that DNA methylation age measures the cumulative effect of an epigenetic maintenance system but details are unknown. The fact that DNA methylation age of blood predicts all-cause mortality in later life^{[15][16][17][18]} has been used to argue that it relates to a process that causes aging.^[19] However, if a particular CpG played a direct causal role in the aging process, the mortality it created would make it less likely to be observed in older individuals, making the site less likely to have been chosen as a predictor; the 353 clock CpGs therefore likely have no causal effect whatsoever.^[20] Rather, the epigenetic clock captures an emergent property of the epigenome.

(...) At the molecular level, DNAm age is a proximal readout of a collection of innate aging processes that conspire with other, independent root causes of ageing to the detriment of tissue function.

 

 

There are far more GpGs regions that these 353. Over 28 thousand, in fact. And some of the newer epigenetic tests just use three. They are selected not because they are important in themselves, but because they tend to mutate with age more consistently. If you were looking for a correlation with a specific disease, you would not use this clock. Instead you would look at specific regions known to impact that disease. And you would have to look more closely at specific cell types. There are 200 different cell types with different baseline epigenetic programming. It's epigenetics that determine cell type, after all, and epimutations tend to scramble the programming. Individual cells might be perfectly happy making the wrong mix of proteins, but the organ they reside in will become dysfunctional.

Edited by Turnbuckle, 21 October 2020 - 04:26 PM.

[QuestforLife]

However, if a particular CpG played a direct causal role in the aging process, the mortality it created would make it less likely to be observed in older individuals, making the site less likely to have been chosen as a predictor; the 353 clock CpGs therefore likely have no causal effect whatsoever.^[20] Rather, the epigenetic clock captures an emergent property of the epigenome.

Saying these CpG methylation changes are detrimental is a bit like saying being a centenarian is associated with increased risk of dying because everyone else is already dead.

Edited by QuestforLife, 21 October 2020 - 04:40 PM.

[Castiel]

Extending telomeres restores youthful gene expression. Extending telomeres allows continual proliferation (see Castiel’s comments for some references using cell lines and using tissue). Here is an in vivo example readers of this thread will be familiar with:
https://pubmed.ncbi....h.gov/26214555/

As I pointed out in my last post, replicative senescence stops the Horvath Clock (even though we know senescent cells continue to be metabolically active)
https://www.ncbi.nlm...les/PMC6224244/

We also see this in vivo when users of sartans, despite their improved health, have ‘age acceleration’ (AA) according to the Horvath clock.
https://www.ncbi.nlm...les/PMC6286862/

Can we find any evidence of harm from ‘accelerating’ the Horvath clock by extending telomeres?
The short answer is no.
There is a theoretical concern that we might increase cancer from keeping cell lines proliferating endlessly, for example if random genomic instability caused them to lose epigenetic control of their cellular identity. But cells with long telomeres have better genomic stability than cells with short telomeres (https://www.ncbi.nlm...les/PMC2842081/). Nevertheless, it might not be pertinent to allow cells to proliferative forever (with active telomerase) unless we have a cast iron anti-cancer mechanism, such as employed by mole rats (they have stronger contact inhibition using hyaluronic acid, see: https://www.nature.c...467-020-16050-w).
The likes of Bill Andrews advocate turning on telomerase in all human cells. Perhaps he is right. I am more cautious, Given the choice I would lengthen my bone marrow stem cells to the length they had when I was 20 and then let them differentiate out to renew my body, shortening naturally. I would repeat this process every 10 years. I don’t think it would be a problem if you ended up lengthening all the telomeres in your body in this way, so long as they could then shorten naturally. This is the aim of occasional gene therapy treatments advocated by Michael Fossel (https://telocyte.com/media) and Liz Parrish.

 

Enabling telomerase indefinitely in all humans might not be such a good idea, without altering the immune system.  But a fraction of humans are essentially immune to cancer, and they could probably benefit from such.

 

There are centenarians who like to eat lots of meat, and like it burnt black, aka full of carcinogens.  They've been eating that all their life.  There are also lifelong two pack a day smoker centenarians, lots of carcinogens in the lung. Obviously after so many decades cancerous cells must have arisen in their bodies.  Yet they're centenarians, which means we can say they probably did develop cancerous cells but survived.  How?  The most likely explanation is an immune system able to fight cancer.

Already it has been seen in some mice that there is a sort of cancer immunity present, able to naturally fight off implants of aggressive cancer cells:

 

The Mouse That Wouldn’t Die: How a Lack of Public Funding Holds Back a Promising Cancer Treatment

 "Spring 1999. “Professor Cui, this mouse didn’t get cancer. Should I get rid of him?” It was a standard experiment in Zheng Cui’s lab at Wake Forest University, North Carolina: Inject inbred mice with cancer cells, not to study cancer, but to produce antibodies for a lipid experiment. “There must have been a mistake,” said Cui, “Inject him again.” Two weeks later, still no cancer. “Try again with a higher dose!” Still no cancer. No cancer even at a million times the lethal dose. Cui decided to breed the mutant mouse."-source huffington post

https://www.huffpost...nt-di_b_5472369

 

  Research in some humans also showed similar immune cells more apt at fighting cancer, indicating that some form of super cancer immunity might be present in some humans.

Edited by Castiel, 22 October 2020 - 04:04 AM.

[naxleo]

@QuestforLife: I am really interested in understanding your argument, because I'm afraid that I don't understand the source of your doubts on DNA methylation age as a predictor of mortality which is independent of chronological age.

 

In the paper already cited by Turnbuckle (https://www.ncbi.nlm...les/PMC4891876/), researchers find that Delta_age, i.e. the difference between DNA methylation age and chronological age, predicts mortality rates in the following 5 years. The explanatory variable Delta_age, being a difference, is already cleaned up by the effects of chronological age.

 

What problems do you see in this kind of analysis?

[QuestforLife]

@QuestforLife: I am really interested in understanding your argument, because I'm afraid that I don't understand the source of your doubts on DNA methylation age as a predictor of mortality which is independent of chronological age.

 

In the paper already cited by Turnbuckle (https://www.ncbi.nlm...les/PMC4891876/), researchers find that Delta_age, i.e. the difference between DNA methylation age and chronological age, predicts mortality rates in the following 5 years. The explanatory variable Delta_age, being a difference, is already cleaned up by the effects of chronological age.

 

What problems do you see in this kind of analysis?

 

It is not that methylation clocks are not predictive, but that they are not causal. We seem to have established that quite rigorously given they could not accumulate in the elderly (and be selected for by the clock) if they were harmful. 

 

Various factors causal to both 'real aging' (whatever that is) and advancing methylation clocks have been proposed. For example a lack of stem cells (either their number and/or their short telomeres) could lead to a slowing of the replacement of somatic cells, and hence the accumulation of a greater number of methylation changes* from those cells' initial state (because of the longer time they have to exist for). This links to the argument over whether extending telomeres is good or bad - if extending telomeres in somatic cells delays replacement it will lead to greater accumulation of methylation changes during that line's extended existence - this is something that seems to occur when you activate telomerase, for example using sartans, but it is unclear if this is detrimental to health if for example, it increases the health of your arteries (see reference upthread). Then there is the reverse side of the coin - if you abstain from telomere lengthening eventually your stem cells will not be able to keep up with demand for somatic cell replacements and the methylation changes in those lines will again accumulate by the same mechanism. But there is a difference as extending telomeres will benefit stem cells too, even if replacement from that pool is slowed, whereas not extending telomeres will lead to the same fate but without the reserve. 

 

This is just a theory, but it may be what is happening.

 

* here we are hypothesising that the accumulating methylation changes on CpG locations are those that don't affect important gene expression in that cell type, so are not corrected or do not lead to cell death. 

[Turnbuckle]

It is not that methylation clocks are not predictive, but that they are not causal. We seem to have established that quite rigorously given they could not accumulate in the elderly (and be selected for by the clock) if they were harmful. 

 

 

You are saying that aging itself is not harmful, when clearly it is.

[QuestforLife]

You are saying that aging itself is not harmful, when clearly it is.

 

It is not that I don't believe aging is harmful, rather than the methylation changes associated with age are not themselves harmful.

 

It is my opinion that they are a passive reflection of a lack of cellular turnover.  

[Turnbuckle]

It is not that I don't believe aging is harmful, rather than the methylation changes associated with age are not themselves harmful.

 

It is my opinion that they are a passive reflection of a lack of cellular turnover.  

 

So the growing damage of the epigenetic code is not harmful -- the code that distinguishes the 200 cell types from one another and which is the basis of multicellular life? That's an incredible assertion. 

[RWhigham]

 

 

So the growing damage of the epigenetic code is not harmful

You seem to equate changes in gene expression with "epigenetic damage". But methylation marks are not genetic damage. Harold Katcher has shown that changes in gene expression with age are the programmed response to an signal that is carried in the blood which can be reversed by changing the signal in the blood with injections of his "Elixir" 

[QuestforLife]

So the growing damage of the epigenetic code is not harmful -- the code that distinguishes the 200 cell types from one another and which is the basis of multicellular life? That's an incredible assertion.

Methylation of CpG locations is just one form of epigenetic change. There is histone methylation or acetylation as well, which controls access to the DNA. Plus probably lots of other ways we haven't discovered yet. But the Horvath methylation clock only looks at select CpG locations. It is this that I propose is not harmful, but only correlated with age.

[Turnbuckle]

Methylation of CpG locations is just one form of epigenetic change. There is histone methylation or acetylation as well, which controls access to the DNA. Plus probably lots of other ways we haven't discovered yet. But the Horvath methylation clock only looks at select CpG locations. It is this that I propose is not harmful, but only correlated with age.

 

 

He could have looked at the epigenetic modifications to all 28 thousand genes (and all 200 cell types as well, as only about 10% of genes are used for each cell type). Instead he looked for epigenetic changes that were predictable enough in one or two cell types to produce an epigenetic clock. Others pared down his gene set to three, thus producing a cheaper test. That doesn't mean changes in these particular genes aren't harmful, and it doesn't mean that epigenetic changes in general aren't harmful. On the contrary, they detune cells for their particular purpose. Epimutations (along with the much rarer mutations to the DNA genome) are the underlying essence of aging. And the only way known to reset them endogenously is to stimulate stem cells to replace them.

 

If you consider the 200 cell types as the instruments of an orchestra and the epigenetic code as the sheet music for each instrument, the accumulation of errors in the sheet music that add or subtract notes will ultimately take the concert level symphony you had as a baby and turn it into the caterwauling of a high school band by the time you become geriatric.

Edited by Turnbuckle, 22 October 2020 - 07:19 PM.

[Turnbuckle]

You seem to equate changes in gene expression with "epigenetic damage". But methylation marks are not genetic damage. Harold Katcher has shown that changes in gene expression with age are the programmed response to an signal that is carried in the blood which can be reversed by changing the signal in the blood with injections of his "Elixir" 

 

 

Some are, and some are random and increase steadily with age. So how does Katcher's elixir (plasma from young animals) work? Most likely it contains VSELs, which are very small embryonic like cells that were recently discovered circulating in blood. In humans, they are mostly gone by age 40, so a transfusion of young blood or expanding the VSEL population you still have have are options. Epigenetic age is then reduced by replacing old cells, not by reprograming them.

Edited by Turnbuckle, 22 October 2020 - 07:36 PM.

[QuestforLife]

He could have looked at the epigenetic modifications to all 28 thousand genes (and all 200 cell types as well, as only about 10% of genes are used for each cell type). Instead he looked for epigenetic changes that were predictable enough in one or two cell types to produce an epigenetic clock. Others pared down his gene set to three, thus producing a cheaper test. That doesn't mean changes in these particular genes aren't harmful, and it doesn't mean that epigenetic changes in general aren't harmful. On the contrary, they detune cells for their particular purpose. Epimutations (along with the much rarer mutations to the DNA genome) are the underlying essence of aging.

Horvath's methylation changes aren't associated with any particular genes that I'm aware of. His clock just looks at whether methyl groups are at particular CpG sites. That is why I said they're probably the left overs - the methylation changes that didn't matter to the cells. That doesn't mean other epigenetic changes aren't important. I'm specifically criticising Horvath's clock, and probably other methylation age based clocks too.

Regarding the plasma fraction used by Katcher, I'm pretty sure it is cell free. I know VSELs are small but I don't think even they would make it through. The plasma might include exosomes from such cells. But I had the distinct impression Katcher knew exactly what factors were in it, so that would rule out such variable things as exosomes.

[Turnbuckle]

Regarding the plasma fraction used by Katcher, I'm pretty sure it is cell free. I know VSELs are small but I don't think even they would make it through. The plasma might include exosomes from such cells. But I had the distinct impression Katcher knew exactly what factors were in it, so that would rule out such variable things as exosomes.

 

I couldn't find a patent application by Katcher, but if his elixir is similar to Alkahest's, then it has no cells in it -- Blood Plasma Fractions as a Treatment for Aging-Associated Cognitive Disorders

[yz69]

Horvath's methylation changes aren't associated with any particular genes that I'm aware of. His clock just looks at whether methyl groups are at particular CpG sites. That is why I said they're probably the left overs - the methylation changes that didn't matter to the cells. That doesn't mean other epigenetic changes aren't important. I'm specifically criticising Horvath's clock, and probably other methylation age based clocks too.

Regarding the plasma fraction used by Katcher, I'm pretty sure it is cell free. I know VSELs are small but I don't think even they would make it through. The plasma might include exosomes from such cells. But I had the distinct impression Katcher knew exactly what factors were in it, so that would rule out such variable things as exosomes.

 

Actually, Horvath's clock is associated with some gene expressions,  according to this paper https://link.springe...3148-018-0481-4

 

from this table 

 

Horvath's clock acceleration is highly associated  to LDL and TC and less associated with inflammation markers like CRP, so I don't think it's fair for low carb keto folks (like me) since we all have high LDL/TC however very low TG and pretty high HDL.

 

On the other hand,  Hannum's clock favor high HDL and low TG, as well as good inflammation markers.

 

I would say Horvath's clock is only good for those on a standard American diet or plant based diet.

[Castiel]

Some are, and some are random and increase steadily with age. So how does Katcher's elixir (plasma from young animals) work? Most likely it contains VSELs, which are very small embryonic like cells that were recently discovered circulating in blood. In humans, they are mostly gone by age 40, so a transfusion of young blood or expanding the VSEL population you still have have are options. Epigenetic age is then reduced by replacing old cells, not by reprograming them.

actually some of the research, discussed in josh mitteldorf's blog's comments, suggest mere blood dilution might be just as rejuvenating.   Not blood donation, but removing cells and proteins from the blood and putting back a solution with just plain albumin, iirc.

 

There appears to be a proaging signal in the blood.  

Diluting blood plasma rejuvenates tissue, reverses aging in mice

 

 

· Young blood or factors are not needed for the rejuvenating effect; dilution of old blood is sufficient.” In humans, the composition of blood plasma can be altered in a clinical procedure called therapeutic plasma exchange, or plasmapheresis, which is currently FDA-approved in the U.S. for treating a variety of autoimmune diseases.

https://news.berkele...-aging-in-mice/

Edited by Castiel, 23 October 2020 - 04:49 AM.

[QuestforLife]

Actually, Horvath's clock is associated with some gene expressions,  according to this paper https://link.springe...3148-018-0481-4

 

from this table 

tab1.png

 

Horvath's clock acceleration is highly associated  to LDL and TC and less associated with inflammation markers like CRP, so I don't think it's fair for low carb keto folks (like me) since we all have high LDL/TC however very low TG and pretty high HDL.

 

On the other hand,  Hannum's clock favor high HDL and low TG, as well as good inflammation markers.

 

I would say Horvath's clock is only good for those on a standard American diet or plant based diet.

 

These are not links to gene expression, but weak associations (~0.11-0.17) with high confidence (p=0.0008 or lower) to blood lipid levels known to generally go up with age. Hence an association between these levels and methylation changes closely correlated with age is unsurprising. 

[QuestforLife]

actually some of the research, discussed in josh mitteldorf's blog's comments, suggest mere blood dilution might be just as rejuvenating.   Not blood donation, but removing cells and proteins from the blood and putting back a solution with just plain albumin, iirc.

 

There appears to be a proaging signal in the blood.  

Diluting blood plasma rejuvenates tissue, reverses aging in mice

https://news.berkele...-aging-in-mice/

 

Regarding aging or youthening factors in the blood, just look at page 1 of this thread, posts 20-22, where I talk about conditional reprogramming of normal somatic cells into progenitors ((https://www.longecit...es/#entry864097)). They start off using a ROCK inhibitor and feeder cells (which are senescent embryonic cells) and later find out they can substitute the feeder cells for just the apoptosis products produced by these cells 2 days after irradiation. Then in another later paper (it's somewhere in my thread!) they find they can do away with the radiation products by stimulating telomerase release from normal cells using a p53 isoform. 

 

So I can absolutely believe that there are inflammatory factors in the blood - and that these are probably the normal triggers for healing - but are missing some important factor (like telomerase, for instance) in old people so end up causing harm. 

 

In short I am in favour of the plasma rejuvenation being due to some sort of reprogramming of existing cells.  

[aribadabar]

   Not blood donation, but removing cells and proteins from the blood and putting back a solution with just plain albumin, iirc.

 

That sounds like awful lot of hassle for a healthy adult to go through compared to a simple blood donation if the results are same/virtually similar.

Are they?

Let's keep in mind that RBCs are typically replaced every 90-120 days and WBCs every 6 days anyways. Plasma is restored within a couple of days.
 

Edited by aribadabar, 23 October 2020 - 11:06 PM.

[Iporuru]

Yuri Deigin's article on epigenetic aging and methylation clocks, with interesting references

[Iporuru]

Yuri Deigin's article on epigenetic aging and methylation clocks, with interesting references

 

From the article:

Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo

Here we show that loss of Dnmt3a endows HSCs with immortality in vivo. The self-renewal potential of Dnmt3aKO HSCs far exceeds that of normal HSCs and the lifespan of the mice from which they were derived. Our data establish that HSCs do not have an inherently finite lifespan but that loss of Dnmt3a augments epigenetic features that enforce self-renewal and enable HSCs to be propagated indefinitely. Further examination of the mechanisms perpetuating immortality in Dnmt3aKO HSCs may provide a window for artificially extending the lifespan ofHSCs, an important biomedical application in the context of the aging human population.

[QuestforLife]

Yuri Deigin's article on epigenetic aging and methylation clocks, with interesting references

This post is my opinion and is not fully referenced. Take it in the spirit it's intended.

I like Yuri and other 'programmed aging' enthusiasts like Josh Mittledorf. But believing in programmed aging is for me something akin to believing in heaven. I'd love to believe. But that doesn't mean I do.

As this article points out there are many different epigenetic clocks, and only those mapped to chronological age like Horvath's are subject to my previous criticisms.

I agree with Yuri that Sinclair's idea of random DNA damage leading to epigenetic dysregulation is preposterous (my words not Yuri's). Upon reading Sinclair's book it was obvious to me that this would mean the resulting epigenetic changes would be random, and they're clearly not - they preferentially target genes important for repair, for example.

This is where Yuri's argument for programmed aging comes in. But I just can't make myself believe it. Repair IS costly. It is not plausible to maintain all Ants like the privileged Queen, just like we can't equally share out the wealth of Elon Musk, no matter what the Marxists claim.

I also agree there is no 'saved' epigenetically young state. But I don't agree with the following statement:

'Returning to epigenetic rejuvenation by partial reprogramming, the very fact that it is possible, and occurs smoothly, tells me that the decrease in the expression of “good” genes with age is also epigenetically programmed, and does not occur randomly due to some kind of “noise”. After all, if it were a random process, we would not have any epigenetic clocks, since the variation between people would be too large, and would only increase with age. There would also be no epigenetic rollback: after all, reprogramming is an obviously smooth process, ending with a complete loss of differentiation and the transformation of a cell into a pluripotent one.'

Just because you can smoothly roll back the epigenetic changes that occur with age - and that those changes were not random - does not mean the process that causes them in the first place cannot be stochastic. Let me explain.

My eyes were attracted to Fig 4 from this paper Yuri quotes

https://www.cell.com...1247(19)31091-5

(See the attached pic.)

Most comments on age related changes in gene expression are on the epigenetic upregulation of inflammatory genes for example, not the downregulation of the electron transport chain in mitochondria. I did a deep dive into loss of expression into important mitochondrial genes earlier this year and I can tell you that there most certainly is an energetic trade off between ATP production and mitochondrial maintenance, a full explanation of which will have to wait for its own post. The point is that the resulting mitochondrial dysregulation can lead to mtDNA escape and autoimmunity via the STING response.

This is only one example of a non programmed aging pathway. My favourite telomeres are another. It may be a surprise to some that given my interest in telomeres I am not a 'programmer'. But telomeres too MAY be designed to trade the death of the old for the (breeding) success of the young. Nature is happy for short telomeres to kill the old with cancer or any of the other diseases of aging, in order to avoid the small chance (excessively) long telomeres in the young could lead to more of the much rarer, but deadly, childhood cancers.

Most of all programmed aging lacks a clock. This is ironic given the many methylation clocks quoted by Yuri in its support. But what is the signal that makes them tick? It still hasn't been found. Yuri suggests the germ cell signalling on sexual maturity that leads to heat shock response being downregulated in nematodes. But it's clear any kind of heat is bad for germ cells. Even saunas that make you live longer will damage your sperm count.

Here's a much simpler explanation. It is the stochastic damage of metabolism that makes epigenetic clocks tick. Old cells (without ready replacements) acquire dysfunctional mitochondria through stochastic metabolic processes and the passage of time The cell then adapts to a bad situation by making the best of it and down and upregulating various genes in the nucleus. Then (naive) scientists come along and decide the problem (and aging itself) is those adaptations.

Consider this the null hypothesis. Disprove it if you can.

Attached Thumbnails

• 

Edited by QuestforLife, 28 October 2020 - 10:21 PM.

[Castiel]

That sounds like awful lot of hassle for a healthy adult to go through compared to a simple blood donation if the results are same/virtually similar.

Are they?

Let's keep in mind that RBCs are typically replaced every 90-120 days and WBCs every 6 days anyways. Plasma is restored within a couple of days.
 

 

 

In humans, the composition of blood plasma can be altered in a clinical procedure called therapeutic plasma exchange, or plasmapheresis, which is currently FDA-approved in the U.S. for treating a variety of autoimmune diseases. The research team is currently finalizing clinical trials to determine if a modified plasma exchange in humans could be used to improve the overall health of older people and to treat age-associated diseases that include muscle wasting, neuro-degeneration, Type 2 diabetes and immune deregulation.

https://news.berkele...-aging-in-mice/

 

From my understanding blood donation while beneficial is not enough, but thankfully there is already an approved procedure that can do the dilution in humans.

[Castiel]

This post is my opinion and is not fully referenced. Take it in the spirit it's intended.

I like Yuri and other 'programmed aging' enthusiasts like Josh Mittledorf. But believing in programmed aging is for me something akin to believing in heaven. I'd love to believe. But that doesn't mean I do.

As this article points out there are many different epigenetic clocks, and only those mapped to chronological age like Horvath's are subject to my previous criticisms.

I agree with Yuri that Sinclair's idea of random DNA damage leading to epigenetic dysregulation is preposterous (my words not Yuri's). Upon reading Sinclair's book it was obvious to me that this would mean the resulting epigenetic changes would be random, and they're clearly not - they preferentially target genes important for repair, for example.

This is where Yuri's argument for programmed aging comes in. But I just can't make myself believe it. Repair IS costly. It is not plausible to maintain all Ants like the privileged Queen, just like we can't equally share out the wealth of Elon Musk, no matter what the Marxists claim.[/quote]

 

 

 

Repair is costly but not too costly, not only are there negligible senescent species, but calorie restriction results in extended lifespan.

 

Resveratrol has extended the lifespan of multiple species, insects, fishes, worms, yeast, while it failed in an initial experiment with normal mice it seems a subsequent experiment with normal mice did extend their lifespan too.

 

Not only that but humans are essentially negligible senescent for over a decade of life.    All while their brain is consuming a disproportionate amount of energy far higher than in adults, it does not age despite excessive metabolic activity related to learning function.

 

As for aging clocks, iirc, the nucleus that controls autonomous breathing reflex experiences cell loss overtime, I've heard at more advanced ages once the cell loss is significant an animal has an ever increasing probability of autonomous breathing halting while asleep without becoming alarmed.   This is behind many of the deaths of older animals, iirc.    An external alarm that woke people if they stopped breathing could probably allow healthy centenarians to break the 130 year mark.

 

Also there probably is something in the blood that causes dilution to reverse aging and rejuvenate.

 

https://www.ncbi.nlm...les/PMC2892727/

We already saw that healthier centenarians have longer telomeres.  The rate of telomere shortening is a strong predictor of species lifespan.   Mice who were made to age similar to humans with short telomeres experienced reversal of aging with telomerase therapy.

 

Telomerase therapy alone won't be enough, super cancer immunity is also necessary.  In the article I linked earlier the researchers wife developed advanced metastatic cancer that had spread throughout her body and had months to live, a cell transplant from a super cancer immune human, entirely eradicated her cancer supposedly.

 

We know negligible senescent either are telomerase positive or have alternate means of lengthening telomeres, it is probably likely they also have super cancer immunity.    

 

My position unlike Aubrey is that the longer lived a species is the fewer the number of mutations needed to take it to negligible senescence, biological immortality.    Humans are exceptionally long lived, the combination of a few nutraceuticals or drugs maybe enough to push them into biological immortality by altering gene expression enough.    Still the breathing nucleus, which I think doesn't regenerate, is a limiting factor, at advanced ages an external alarm is needed during sleep to stop potential death from natural breathing reflex stopping.   Eventually regenerative therapy will become necessary, as in a couple of centuries the nucleus will probably deplete of cells and the natural reflex won't just have a significant probability of stopping, but will cease all together requiring manual breathing at all times presumably.

Edited by Castiel, 29 October 2020 - 06:02 AM.

[Castiel]

Here's a much simpler explanation. It is the stochastic damage of metabolism that makes epigenetic clocks tick. Old cells (without ready replacements) acquire dysfunctional mitochondria through stochastic metabolic processes and the passage of time The cell then adapts to a bad situation by making the best of it and down and upregulating various genes in the nucleus. Then (naive) scientists come along and decide the problem (and aging itself) is those adaptations.

Consider this the null hypothesis. Disprove it if you can.

I don't think so.

 

It is said neural metabolic rate is similar between various species of mammal, presumably so within bowhead whales too.   The brain is 2% of body yet consumes 20% of oxygen, iirc.   10x energy of most other organs.  Most of the energy goes towards information transmission function of neurons.   If energy production was significantly compromised the neuron would stop functioning.   Yet not only have unmodified mice neurons managed to live twice as long when transplanted to rats, and human neurons have lasted over 115 years in humans, but bowhead neurons seem to last for over 200 years.   AFAIK bowhead neurons do not seem to have additional protection mechanisms, though maybe they do.

 

Mitochondrial quality I've heard is maintained via a process of mitoptosis.   This is how the neuron, even that of mice, became negligible senescent, able to have high mitochondrial function indefinitely, and some believe could last indefinitely in the right host.   I've heard mitoptosis is downregulated with aging.   Restoring mitoptosis, I once heard, can even remove negative mutations from the mitochondrial population.

 

mitoptosis paper

https://www.ncbi.nlm...les/PMC3475017/

 

 

One way telomerase therapy might restore youthful function and appearance under the microscope to old cells, even allowing them to produce young tissue, might be via restoring mitoptosis activity.

 

 

This is corroborated by studies conducted both in models of replicative senescence and in aging animals, in which the presence of abnormal mitochondria was associated with an overall shift towards more fusion events, which resulted mainly from the downregulation of fission proteins and reduced clearance of mitochondria by autophagy (Lee et al., 2007; Yoon et al., 2006).

https://www.ncbi.nlm...les/PMC2912461/

 

Again reduced clearance and reduced fission proteins in an age related manner.   Aging downregulates mitochondrial maintenance mechanisms.

Edited by Castiel, 29 October 2020 - 06:24 AM.