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An idea for reversing epigenetic age by demethylating agents

dna demethylation epigenetic clock demethylating agents

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#31 QuestforLife

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Posted 20 November 2019 - 04:20 PM

What’s your opinion on David Sinclair’s tweet, especially the two bolded questions at the end: „Pretty amazed by what alpha-keto glutarate, an activator of TET enzymes that demethylate DNA, can do. Here at 1% in drinking water turning white fat in healthier beige fat via Prdm16. Wonder what else is reprogrammed. Is biological age reversed?

 

There is evidence that some super quiescent, possibly pluripotent stem cells are held that way by methylation (basically they are what's left over from the embryo - stem cells that resisted differentiation), and sufficient demethylation agents might cause them to re-enter circulation.

 

https://www.ahajourn...SAHA.118.314287

 

Of course demethylating your body long term will screw you up due to effects on various vital metabolic processes like the one carbon cycle, and probably kill your liver because of the increased demand for methylating agents. So I speculate that any intentional body wide demethylation will have to be for short bursts only, unless you can somehow make it selective. 



#32 Iporuru

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Posted 20 November 2019 - 04:45 PM

There is evidence that some super quiescent, possibly pluripotent stem cells are held that way by methylation (basically they are what's left over from the embryo - stem cells that resisted differentiation), and sufficient demethylation agents might cause them to re-enter circulation.

 

https://www.ahajourn...SAHA.118.314287

 

Of course demethylating your body long term will screw you up due to effects on various vital metabolic processes like the one carbon cycle, and probably kill your liver because of the increased demand for methylating agents. So I speculate that any intentional body wide demethylation will have to be for short bursts only, unless you can somehow make it selective. 

 

Thank you for weighing in.

Sure, I was thinking of a short, treatment, up to 1 week, using a combination of the above agents. But I'm not sure if the mechanism is by 'waking up' VSELs and making them re-enter circulation. I was rather thinking of the mechanism described in Sinclair's book: "By infecting mice with reprogramming genes called Oct4, Sox2, and Klf4, the age of cells is reversed by the TET enzymes, which remove just the right methyl tags on DNA, reversing the clock of aging and allowing the cells to survive and grow like a newborn’s. How the enzymes know which tags are the youthful ones is a mystery. Solving that mystery would be the equivalent of finding Claude Shannon’s “observer,” the person who holds the the original data.
 

You can upregulate TETs by AKG, Vitamin C, retinol and some phytochemicals mentioned by TMNMK in one of the posts above - all harmless short-term


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#33 QuestforLife

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Posted 20 November 2019 - 04:57 PM

You can upregulate TETs by AKG, Vitamin C, retinol and some phytochemicals mentioned by TMNMK in one of the posts above - all harmless short-term


Experimentation is good. By all means do it and let us know how you get on.

OSK or similar is dependent on demethylases as Sinclair has shown, but that doesn't mean nothing else is going on. We don't know yet. But cells can obviously be pushed back towards a more stem like state. And some of the compounds you mention have been used in de-differentiation experiments. It may even be possible to replace OSK(M) with small molecules. See: https://www.ncbi.nlm...96/#!po=7.32759

I'm trying something along these lines by looking for natural TGF-B and Rho Kinase inhibitors. Perhaps between all of us we'll crack this.
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#34 Iporuru

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Posted 20 November 2019 - 05:25 PM

Experimentation is good. By all means do it and let us know how you get on.

OSK or similar is dependent on demethylases as Sinclair has shown, but that doesn't mean nothing else is going on. We don't know yet. But cells can obviously be pushed back towards a more stem like state. And some of the compounds you mention have been used in de-differentiation experiments. It may even be possible to replace OSK(M) with small molecules. See: https://www.ncbi.nlm...96/#!po=7.32759

I'm trying something along these lines by looking for natural TGF-B and Rho Kinase inhibitors. Perhaps between all of us we'll crack this.

 

Thanks for the interesting paper - I'll delve into it. I can see it mentions some of the agents I have listed in my posts upthread.

 

As for replacing OSK(M) with small molecules, you may find this fragment from Sinclair's recent paper interesting:

 

TET enzymes, TDG and the dynamics of DNA demethylation

Although the exact function of the TET proteins in ES cells needs further study, several recent publications are supportive of a role for TET in reprogramming of somatic cells to generate induced pluripotent stem cells (iPSCs). For example, at the early stage of transduction with the transcription factors Oct4, Klf4, Sox2 and c-Myc (collectively referred to as OKSM), Tet2 is recruited to the Nanog and Esrrb loci to activate their transcription. In addition, both Tet1 and Tet2 can associate with Nanog and facilitate iPSC generation in an enzymatic activity dependent manner. Remarkably, Tet1 overexpression can not only enhance reprogramming efficiency by promoting demethylation and reactivation of Oct4, but can also replace Oct4 in the iPSC reprogramming cocktail. Furthermore, beyond reprogramming mediated by OKSM, Tet1 and Tet2 seem to have distinct roles in reprogramming mediated by fusion of somatic cells to pluripotent cells.


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#35 Iporuru

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Posted 21 November 2019 - 01:09 PM

Ponce DeLeon Health launches an AKG supplement

 

This is what they say about it on their website:

 

DNA Integrity – Methylation Increases as We Age

DNA is key to vitality by making new cells in our body, and determining how those cells will ultimately function. With age comes a process called methylation. Think of this as a kind of “rust” that coats the outer portions of your DNA. Methyl groups are chemical tags, that in effect block our DNA from doing its job when it comes to making ideal copies of itself, activating and deactivating certain genes.

 

The more methylation, the more difficult it is for DNA to make a perfect, readable copy of itself. This increases the chance of passing on flawed genetic information, leading to poorly functioning cells, and contributing to aging itself.

 

In a healthy cellular maintenance process, AKG is involved in demethylation, by cleaning up and removing these DNA tags so that the correct genes continue to be expressed. With correct levels of AKG, our DNA maintains a more balanced methylation profile, assisting cells to function at optimal levels, similar to when we are younger.

 

Usually people start to feel the short-term positive effects within a few weeks. We”ve found DNA demethylation and senescent cell signal moderation usually take 6-9 months, and continues thereafter.


Edited by Iporuru, 21 November 2019 - 01:10 PM.


#36 Turnbuckle

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Posted 21 November 2019 - 03:11 PM

 With age comes a process called methylation. Think of this as a kind of “rust” that coats the outer portions of your DNA. The more methylation, the more difficult it is for DNA to make a perfect, readable copy of itself. 

 

 

Utter nonsense, of course, and doesn't reflect the research.

 

The researchers studied mice, and found that alpha-ketoglutarate increased lifespan of female mice, but not male mice --

 

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

 

In the first cohort of female mice, median lifespan and survival (age at 90th percentile mortality) were significantly extended by 16.6% and 19.7% from inception of CaAKG feeding. These findings have been repeated in the second cohort of mice: the female median lifespan and survival were significantly extended by 10.5% and 8% (Fig. 1a, b and Extended Table 1). Although, improved survival for males was not significant in both cohorts (Fig. 1d, e), median lifespan was extended for 9.6%and 12.8% from inception of treatment, respectively (Extended Table 1).

https://www.biorxiv....1/779157v1.full

 

 

If it actually did what the vendors claim, there shouldn't be a sex difference. And while the vendors (Ponce De Leon Health) claim a decrease in epigenetic age, they don't provide any data.


Edited by Turnbuckle, 21 November 2019 - 03:35 PM.

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#37 dlewis1453

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Posted 21 November 2019 - 03:39 PM

SCs can age as well. They can suffer telomere shortening, DNA mutations, and to the extent they have epigenetic marks, they could suffer epigenetic aging, though this would be considerably more restricted than with somatic cells. VSELs would have the least problem with epigenetic aging, as their epigenetic coding as pluripotent cells would minimal. Thus the stem cell pools may not decline in absolute numbers with chronological aging, but the numbers of viable SCs will decline. 

 

 

My feeling is that the biggest problem is the build up of the non-dividing fraction of the SC pools. Insofar as there are homeostatic mechanisms to maintain SC pool size, increasing SC numbers from viable SCs will, at a minimum, reduce the number of non-dividing SCs by those homeostatic mechanisms, and thus return the pools to a more youthful state.

 

Thanks Turnbuckle, your responses are always enlightening. 



#38 OP2040

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Posted 21 November 2019 - 05:35 PM

2.5 years is peanuts. I saw an 11 year drop by enlarging endogenous stem cell pools and using them to replace senescent cells (using mito fusion and a UCP2 blocker).  Another approach is reprogramming, taking cells back to a pluripotent state with Yamanaka factors. In one trial, mice lived 33-50% longer. See this 4 minute video from Youthereum Genetics. In both cases cells are getting de novo programing.

 

 

Can you procide a source for the 11 year thing?  Or is it the Youthereum video you posted?  If it is, then the argument will be made that something like that won't be accessible or clear for another 50 years and it makes no sense to wait for it unless you are 15 years old.



#39 Turnbuckle

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Posted 21 November 2019 - 06:05 PM

Can you procide a source for the 11 year thing?  Or is it the Youthereum video you posted?  If it is, then the argument will be made that something like that won't be accessible or clear for another 50 years and it makes no sense to wait for it unless you are 15 years old.

 

This 11 year drop was not gained by reprogramming. This was by endogenous expansion of stem cell pools, which can be easily achieved by flicking a couple of switches on SC mitochondria. One is biasing mito morphology to fusion (to achieve proliferation over differentiation) and the other is blocking mito UCP2 pores (to banish quiescence). See the thread -- https://www.longecit...newal-with-c60/


Edited by Turnbuckle, 21 November 2019 - 06:20 PM.


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#40 Iporuru

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Posted 21 November 2019 - 07:54 PM

This 11 year drop was not gained by reprogramming. This was by endogenous expansion of stem cell pools, which can be easily achieved by flicking a couple of switches on SC mitochondria. One is biasing mito morphology to fusion (to achieve proliferation over differentiation) and the other is blocking mito UCP2 pores (to banish quiescence). See the thread -- https://www.longecit...newal-with-c60/

 

Did you show your before and after (anonymized) test results somewhere in that thread?



#41 dlewis1453

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Posted 22 November 2019 - 01:43 PM

Did you show your before and after (anonymized) test results somewhere in that thread?


Yes the test results are included as image attachments somewhere in that long thread.

#42 Iporuru

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Posted 22 November 2019 - 03:44 PM

Yes the test results are included as image attachments somewhere in that long thread.

 

I don't think there were images attached, just Turnbuckle's description of the results



#43 Turnbuckle

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Posted 22 November 2019 - 05:47 PM

I discussed these epigenetic tests in the thread Reversing the Clocks. I used Osiris Green (which no longer exists, but measured three sites) and myDNAge (which looks at "methylation patterns of over 2,000 loci"). On one occasion when I submitted tests from the two companies on the same day, I found the results the same within the error bars. 

 

To summarize: I took a baseline test in early 2018, and noted a decline of 11.2 years after three months of treatment (four months after the baseline). I then began adding telomerase stimulants with each treatment, assuming that stem cells would be most impacted and the effect on somatic cells would be minimal. This was wrong, as most of the dividing is by transit amplifying cells (TACs). Extending their telomeres would prevent the utilization of stem cells and result in older somatic cells, not younger. And in fact I saw over the next few tests that my epigenetic age was increasing. Thus I discontinued the telomerase stimulants and saw my epigenetic age stabilize and then begin to fall again (but slower than before). My last test was with myDNAge in June, and they reported that I measured younger than 96% of people my age. I will be taking another test soon.

 

For other effects see posts 201 and 214 of Stem cell self-renewal with C60 thread. Pages 7 & 8.


Edited by Turnbuckle, 22 November 2019 - 06:22 PM.

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#44 Nate-2004

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Posted 30 November 2019 - 03:26 PM

I discussed these epigenetic tests in the thread Reversing the Clocks. I used Osiris Green (which no longer exists, but measured three sites) and myDNAge (which looks at "methylation patterns of over 2,000 loci"). On one occasion when I submitted tests from the two companies on the same day, I found the results the same within the error bars. 

 

To summarize: I took a baseline test in early 2018, and noted a decline of 11.2 years after three months of treatment (four months after the baseline). I then began adding telomerase stimulants with each treatment, assuming that stem cells would be most impacted and the effect on somatic cells would be minimal. This was wrong, as most of the dividing is by transit amplifying cells (TACs). Extending their telomeres would prevent the utilization of stem cells and result in older somatic cells, not younger. And in fact I saw over the next few tests that my epigenetic age was increasing. Thus I discontinued the telomerase stimulants and saw my epigenetic age stabilize and then begin to fall again (but slower than before). My last test was with myDNAge in June, and they reported that I measured younger than 96% of people my age. I will be taking another test soon.

 

For other effects see posts 201 and 214 of Stem cell self-renewal with C60 thread. Pages 7 & 8.

 

Turnbuckle, what is your diet like, does it contribute to any of this huge reversal do you think? Is it just your self-renewal protocol?

 

I'm trying to drop the saturated fat in my diet as it may be at the root of why my fasting glucose is so high and why I can't seem to get control of my A1c. I realize stearic acid is the exception here but it's really hard to isolate that to any positive degree. I imagine this issue is likely countering any attempts on my part to utilize your protocol.


Edited by Nate-2004, 30 November 2019 - 03:27 PM.


#45 Turnbuckle

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Posted 30 November 2019 - 04:09 PM

Turnbuckle, what is your diet like, does it contribute to any of this huge reversal do you think? Is it just your self-renewal protocol?

 

 

 

I didn't change my diet over that period (other than the protocol brownies) so diet had nothing to do with it. As for stearic acid, I don't use it outside the protocol because fusion prevents the natural clearance of defective mitochondria. As for CVD risk, it poses minimal problems compared to other saturated fats, and is much better than trans-fats.

 

Stearic acid, a unique long-chain SFA, has emerged as a candidate to use as a substitute for TFA in food manufacturing. It has the requisite physical attributes that a solid fat imparts and seems to have little effect on important risk factors for cardiovascular disease (CVD).

 

 
 
 
You can also use sulforaphane to achieve fusion. I've used 50 mg of sulforaphane glucosinolate (Thorne brand), generally with stearic acid as the latter doesn't cross the BBB. I've considered adding myrosinase as an activator (from powdered brown mustard), but haven't tried that yet -- Supplementation of the Diet by Exogenous Myrosinase via Mustard Seeds to Increase the Bioavailability of Sulforaphane in Healthy Human Subjects after the Consumption of Cooked Broccoli.

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#46 TMNMK

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Posted 30 November 2019 - 10:37 PM

 

I do that every now & then when I'm feeling really courageous. It is so gross and causes my stomach to do backflips for a few hours. I open 4 capsules, pour them into a cup with maybe 50ml of water, add a couple teaspoons of brown mustard seed powder and swirl for awhile [.. oh I'm getting shivers just thinking about how gross it is right now ..], then swig as fast as humanly possible. Blech, what we do for hope of health.


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#47 Nate-2004

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Posted 01 December 2019 - 02:03 AM

I do that every now & then when I'm feeling really courageous. It is so gross and causes my stomach to do backflips for a few hours. I open 4 capsules, pour them into a cup with maybe 50ml of water, add a couple teaspoons of brown mustard seed powder and swirl for awhile [.. oh I'm getting shivers just thinking about how gross it is right now ..], then swig as fast as humanly possible. Blech, what we do for hope of health.

 

Broccomax comes with myrosinase and plus you can even just ground up brown mustard seed and put it in capsules and take it with the other caps. Why bother converting it beforehand if the very same thing happens when chewing and swallowing broccoli sprouts?

 

I didn't change my diet over that period (other than the protocol brownies) so diet had nothing to do with it. As for stearic acid, I don't use it outside the protocol because fusion prevents the natural clearance of defective mitochondria. As for CVD risk, it poses minimal problems compared to other saturated fats, and is much better than trans-fats.

 

Has your diet always been fairly healthy though in terms of low sat fat and sugar? I realize stearic is fine, it's just that my genes, FTO in particular, apparently gives me an extra problem with saturated fat, as it somehow makes me more insulin resistant. I don't know how it works and I don't think they know yet either. It's just an association but at least I know now why I keep struggling with fasting glucose.

 

I thought sulforaphane was localized fusion though isn't it?


Edited by Nate-2004, 01 December 2019 - 02:10 AM.


#48 Turnbuckle

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Posted 01 December 2019 - 11:55 AM

 

 

I thought sulforaphane was localized fusion though isn't it?

 

 

Localized? How so? 

 

Drp1 is a protein required for fission. Without it, mitocondria will fuse. Another protein MIEF1 binds to Drp1 and prevents its activity, resulting in fusion. Sulforaphane (SFN) appears to work the same way. 

 

Our data strongly support Drp1 being negatively regulated by SFN although whether the GTPase is a direct target of acylation remains to be elucidated. Despite this knowledge gap, the function of Drp1 is clearly being compromised by SFN as both mitochondria and peroxisomes become hyperfused in response to SFN treatment and these organelles share Drp1 for their respective scission events.

https://www.ncbi.nlm...les/PMC5126150/

 

 

Obviously, SFN should not be used all the time, as fission is important to the mechanism for detecting and eliminating defective mDNA. Use of SFN with the SC protocol would be very intermittent and shouldn't interfere with mito QC.

 

And while stearic acid is stopped by the blood brain barrier (BBB), SFN is not.

 

Blood-brain barrier (BBB) is a highly selective semi-permeable membranes barrier that separates the circulating blood from the brain extracelluar fluid in the CNS. The ability to go through the BBB is essential to exert neuroprotective effects for any phytochemicals. Several researches have demonstrated that SFN can traverse the BBB and accumulate in the CNS. 

https://www.ncbi.nlm...les/PMC5880051/

 


Edited by Turnbuckle, 01 December 2019 - 12:01 PM.

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#49 QuestforLife

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Posted 02 December 2019 - 08:52 AM

 

 

To summarize: I took a baseline test in early 2018, and noted a decline of 11.2 years after three months of treatment (four months after the baseline). 

 

Was this 11 years from baseline using MyDNage or the other test that only looked at a couple of locations?



#50 TMNMK

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Posted 02 December 2019 - 04:11 PM

Broccomax comes with myrosinase and plus you can even just ground up brown mustard seed and put it in capsules and take it with the other caps. Why bother converting it beforehand if the very same thing happens when chewing and swallowing broccoli sprouts?

 

Yeah theoretically simply taking the pill works, so I often do just that. But I just feel more confident that if I do the swirling in a cup for awhile with brown mustard seed powder that SFN is being generated. It's just a confidence thing. 



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#51 BieraK

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Posted 19 December 2019 - 08:38 AM

Hi, Noob question.
Do supplements that reduce or increase the availability of methyl donors such as Nicotinic Acid AKA Niacin and TMG aka Betaine modify the state of methylation? TMG is used to donate methyl groups and reduce homocysteine, I wonder if its use increases the aging clock.
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