73 replies to this topic

[Florian E.]

Hi,

 

i'm new here. I read a lot of stuff about aging here and elsewhere and came out with kind of a protocol/summary like this. And i'm interested to here your thoughts.

 

1. NADase

• NAD+ to NADh ratio -> Alpha lipoic acid (Natrium-R-Lipoat)
• NAD+ precursors -> Nicotinamide riboside/mononucleotide
• SIRT1/3 Activation -> Reservatrol, Honokiol

2. Senolytics

• Quercetin -> Muscle cells
• Dasatinib -> Fat cells

3. Autophagy/Mitophagy

• Honokiol/Magnolol -> Autophagy
• Pomegranate + Gorgonibacter (?) = Urolithin A = Mithophagy

4. Telomerase

• Epithalon/Endoluten

5. Mitochondrial Biogenesis

• PQQ, Q10, Vitamin C, Methylene Blue, Quercetin, MitoQ, Astaxanthin, ALCAR

6. DNA Methylation Errors

• Reset epigenetics. Maintaining differentiation -> Rapamycin (?)
• Sirt6 activation via ubiquitin ligase CHIP (?)
• mTOR/NF-κB Inhibitors (?)

 

I think the main causes for aging are somewhere between "DNA Methylation errors", Mitochondrial Biogenesis and NADase. Autophagy/Mitophagy, Senolytics and Telomerase i would use to get rid of the damage already done.

And i don't think that telomerase i such of great deal to extend lifespan and i'm a bit cautious that it maybe could also help cancer cells to survive. Regarding Quercetin i think it could be better to use a more bio-efficent form like liposomal Quercetin or EMIQ. But i read one scientific report that liposomal Quercetin has too mutagenic effects (unfortunately can't find the report anymore). I did't read this for EMIQ. But i'm not sure if EMIQ has the same effects for senolytics like regular Quercetin. For the "Urolithin A" i'm not sure what gut bacteria will produce them. Because "gordonibacter urolithinfaciens" are not enough, i read, to produce Urolithin A. They would only produce other Urolithins if some other needed bacteria.for Urolithin A is not in place.

And currently i'm reading stuff about DNA Methylation errors. Very interesting report (imho) here: https://www.ncbi.nlm...les/PMC3336960/

It seems like P53 is a very potent but also dangerous trigger.

But overall i believe every biological body structure/machine has it limits. So i'm not sure if it's possible to get much more lifespan out of the existing environment.

I'm interested to here your thoughts.

 

Finally a question concerning skin. Would you think Collarium + Methylene Blue is beneficial, damaging or useless ?

 

Best regards,

Florian

 

 

 

 

Edited by Florian Euler, 19 August 2016 - 06:54 PM.

[Never_Ending]

I think that's a good list to start with, the thing with protocols is that certain age specific components are important as well. I think that epithalon is interesting and potentially things that help the pineal function could increase the production of similar compounds since that's where it was derived from. Cycloastragenol is promising as well , however like you said telomerase is just one factor. There's really a lot of important components considering that some are more organ specific.

 

Have you tried any of the things listed ?

Also do you see any potential interactions between the compounds whether positive or negative? (since compounds will likely have some interactions which can cause changes in function and bioavailability)

Also It's interesting you bring up mitophagy , is mitophagy always beneficial or is there hopes of repairing mitochondria that have slight damage?

[Florian E.]

I think that's a good list to start with, the thing with protocols is that certain age specific components are important as well. I think that epithalon is interesting and potentially things that help the pineal function could increase the production of similar compounds since that's where it was derived from. Cycloastragenol is promising as well , however like you said telomerase is just one factor. There's really a lot of important components considering that some are more organ specific.

 

Have you tried any of the things listed ?

Also do you see any potential interactions between the compounds whether positive or negative? (since compounds will likely have some interactions which can cause changes in function and bioavailability)

Also It's interesting you bring up mitophagy , is mitophagy always beneficial or is there hopes of repairing mitochondria that have slight damage?

 

Thanks for the reply. Cycloastragenol sounds interesting. But i have to read more about it's mechanism. And, as already mentioned, i think you have to be careful with telomerase. Because (imo) if you overdose it, that could maybe help cancer cells to survive. 

Regarding the list, i've tried or currently taking everything except Nicotinamide mononucleotide,Dasatinib, Epithalon and Rapamycin. And on top a short cycle of peptide bioregulators Endoluten, Ventfort and Chelohart.

I don't know if there are interactions between the substances. Currently i only take one regime at a time.

Concerning Mithophagy and mitochondrial repair/maintenance i think it could be possible to repair some mitochondria with substances from the "Mitochondrial Biogenesis" part. For example Methylene blue. See here: https://www.ncbi.nlm...pubmed/26663466

I for myself trying to do a bit more on the Mithophagy part (with ~3 glasses/day pure pomegranate juice = human dosage) because i'm a skinny person. But i'm not sure if a have all gut bacteria that is needed. I read some interesting stuff about differences between skinny and obese people, here:

https://selfhacked.c...ious-and-tired/

 

You see, obese people have too much ATP, so AMPK is not activated.  Thin people have too little ATP and AMPK is activated, which is healthy and is one of the saving graces for having shitty mitochondria.

 

I would be interested if anyone knows some SIRT6 activator supplements. Currently i only found out that Reservatrol activates SIRT1, and SIRT1 activation also leads to more SIRT6 activity. And SIRT6 is NAD+ dependend. But couldn't find a direct SIRT6 activator.

In this context i'm also very interested in the root cause(s) and counter measures for Stub1/CHIP depletion. See here for example: https://www.ncbi.nlm...pubmed/24043303

 

And finally i'm interested to hear thoughts about "reseting epigenetics". Because Rapamycin i think is not an optimal solution yet. I does not reset senescent cells for example and is only able to reset a small percentage of cells.

 

See:

https://www.ncbi.nlm...les/PMC3540161/

 

Because cell cycle progression is believed to be a key parameter for the reprogramming process, the cell cycle arrest due to cellular senescence may represent a major barrier to reprogramming.

 

I'm still young (30). So maybe after doing some auto-/mitophagy and senolytics, rapamycin can reset "enough" cells (?) :-) Unfortunately not i guess.

 

In the future i will also look a bit more into the sexual reproduction life cycle. Maybe there are some important triggers as well.

Edited by Florian E., 25 August 2016 - 11:10 AM.

[Nate-2004]

AGEs:

 

Rosmarinic Acid

Carnosine with each meal.

 

I'd love to know how to get hold of some Dasatinib.

 

Also quercetin is a synolitic for endothelium cells. As far as I know, it doesn't target muscle cells but I could be wrong.

Edited by Nate-2004, 26 August 2016 - 04:51 AM.

[APBT]

 

I'd love to know how to get hold of some Dasatinib.

 

See this thread:  http://www.longecity...buy-from-nyles/

[Never_Ending]

Cycloastragenol sounds interesting. But i have to read more about it's mechanism. And, as already mentioned, i think you have to be careful with telomerase. Because (imo) if you overdose it, that could maybe help cancer cells to survive. 

 

 

(and)

 

 

And finally i'm interested to hear thoughts about "reseting epigenetics". Because Rapamycin i think is not an optimal solution yet. I does not reset senescent cells for example and is only able to reset a small percentage of cells.

 

 

I think it's unclear whether increasing telomerase activity would promote cancer cells because it seems that cancer cells already have their own mechanism of activating telomerase for use of the cancer cells. Although I think you're right that excessive doses of telomerase activators might pose issues. The question is what dose would be excessive, which I'm unsure.

 

The article you noted about reprogramming is very interesting , it seems to say that the components such as Rapamycin are able to Prepare the cells for reprogramming as well as keep them in a healthy state. And then there would need to be more extensive reprogramming factors? I assume these factors were done in labs with isolated cells. That seemed to be what the study was saying. Is there a way to do that with an actual person?

 

As a side note Pterostilbene is another compound that works similar to resveratrol.

 

 

 

 

 

Edited by Never_Ending, 26 August 2016 - 12:57 PM.

[Florian E.]

 

Cycloastragenol sounds interesting. But i have to read more about it's mechanism. And, as already mentioned, i think you have to be careful with telomerase. Because (imo) if you overdose it, that could maybe help cancer cells to survive. 

 

 

(and)

 

 

And finally i'm interested to hear thoughts about "reseting epigenetics". Because Rapamycin i think is not an optimal solution yet. I does not reset senescent cells for example and is only able to reset a small percentage of cells.

 

 

I think it's unclear whether increasing telomerase activity would promote cancer cells because it seems that cancer cells already have their own mechanism of activating telomerase for use of the cancer cells. Although I think you're right that excessive doses of telomerase activators might pose issues. The question is what dose would be excessive, which I'm unsure.

 

The article you noted about reprogramming is very interesting , it seems to say that the components such as Rapamycin are able to Prepare the cells for reprogramming as well as keep them in a healthy state. And then there would need to be more extensive reprogramming factors? I assume these factors were done in labs with isolated cells. That seemed to be what the study was saying. Is there a way to do that with an actual person?

 

As a side note Pterostilbene is another compound that works similar to resveratrol.

 

 

There were no extensive tests on humans.

See this table here from the article: https://www.ncbi.nlm...40161/table/T1/

 

I tried to find out a little bit more about rapamycin and epigenetics. It seems rapamycin (as mTOR inhibitor) has a good synergy with honokiol for cancer treatment, because honokiol suppresses PLD activity in several human cancer cell lines including 786-O cells. See: https://www.ncbi.nlm...les/PMC2778016/

But unfortunately rapamycin also seems to destabilise sugar levels by targeting mTORC2. See: http://phenomena.nat...sk-of-diabetes/

 

And concerning reprogramming of epigenetics there are also a lot of question marks (DNA damage remains, etc.). See this graphic:

 

 

Maybe a proper maintenance regime for Telomerase, Autophagy, Senolytics together with CHEC-9 peptide to activate HSP70 for tackling protein aggregation would increase the efficiency (?)

But what about DNA mutations?

 

 

And some interesting quotes from https://www.ncbi.nlm...les/PMC3336960/

 

 

Clearly, inhibiting single signaling pathways (NF-κB and mTOR) is sufficient to restore some features of youthful cells, but the number of transcriptional regulators that need to be modulated to result in full rejuvenation is unknown. Third, is the youthful state or the aged state dominant? It would be interesting to determine which epigenetic and transcriptional profile is more robust in experiments of fusion of young and old cells.

.

.

.

It should be noted that reprogramming of the epigenome to a youthful state in an aged cell has inherent risks and uncertainties. For example, the increase in proliferative activity of aged stem cells and progenitors by heterochronic parabiosis may increase the risk of developing malignancies among cells that have acquired genomic mutations during normal aging but then acquire increased proliferative potential by this rejuvenating intervention. Clearly, any therapeutic goal of cell or tissue rejuvenation would aim to restore a “young adult” state from an elderly state, not rewinding the aging clock back to embryonic or even postnatal developmental stages when growth and morphogenesis are paramount and the systemic milieu is very different from that in the adult. The challenge would be to reset the aging clock back to the appropriate adult stage. Another challenge is the coordination of reprogramming among different cell types in multicellular organisms. As such, the most feasible near-term applications of any type of rejuvenating intervention for therapeutic purposes would be those that could be administered in a temporally and spatially controlled manner (e.g., to a specific site of wound repair or tissue injury for a limited time).

.

.

.

 

Clearly, epigenetic changes are both responsive to and effectors of the aging process. With DNA damage and environmental stresses like inflammation leading to changes in chromatin, the epigenome clearly adapts to age-related changes in the genome and the local milieu. Perhaps the epigenome is a general sensor of cellular dysfunction, sensing metabolic and proteomic changes that accompany aging as well. However, the epigenome is also an effector of the aging process, enforcing different patterns of gene expression in old cells and young cells and, in many cases, resulting in cellular phenotypes associated with aging such as senescence and metaplasia (Martin, 2009). In that sense, the epigenome is rather like a lens through which genomic information is filtered (Figure 3), a lens that deteriorates with age because of both loss of integrity of genomic information and direct environmental stresses within and outside of the cell. Within the “epigenome as lens” metaphor, the process of rejuvenation is the restoration of a youthful state by actions on the epigenomic lens (Figure 3). The loss of integrity of the genomic information remains, but the rejuvenating interventions are sufficient to overcome and possibly reverse at least some of the age-related epigenetic changes. Similarly, an altered epigenome and gene expression programs may also be able to reverse or compensate for some age-dependent biochemical changes, such as protein aggregation, macromolecular oxidation, and glycation, to maintain cellular functions 

 

 

 

 

So, in summary...

• The older you get the more difficult it will be (and/or longer it takes) to reprogram/reset the epigenome.
• Rapamycin is not enough and/or potentially damaging (because of mTORC2)
• Not exactly clear which parts get rejuvenated and what damage will (irreversibly?) persist
• To my understanding you would have to make sure to successfully reset a big part of all the cells (?). Which is still not possible due to lack of efficiency (?)

 

But there is hope that with more sophisticated "cocktails" it could be possible to reprogram a reasonable amount of cells.

Like this for example:

"Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state."

https://www.ncbi.nlm...pubmed/22056670

 

 

 

Edited by Florian E., 27 August 2016 - 06:17 PM.

[Florian E.]

Regime Update:

Will add a little bit of Co-E1 (NADh) to my regime. Because it interacts/transfers to Co-E2 and Co-E3 ubiquitin ligase (!).

And also this CHEC-9 peptide. But not available yet for common people atm it seems.

[Florian E.]

Regime Update:

Will add a little bit of Co-E1 (NADh) to my regime. Because it interacts/transfers to Co-E2 and Co-E3 ubiquitin ligase (!).

And also this CHEC-9 peptide. But not available yet for common people atm it seems.

 

I chancel on CHEC-9.

According to this (very good) arcticle here, many hsp70 activators are proteotoxic. http://www.jbc.org/c...271/9/4805.full

It basically says that proteotoxic events lead to glutathione (GSH) depletion. Therefore more disulfide linked proteins (PSSP) aggregate and hsp70 gets activated as "last resort" to clear aggregated proteins.

It seems to me that it's not clear if there even exist a "healthy", direct hsp70 activator.

 

So, i think it's a better move to supplement with glutathione instead. It also gets declined with aging. I will add it to my regime instead.

Sublingual form of glutathione has better bioavailability according to this article: https://www.ncbi.nlm...les/PMC4536296/

But maybe there are even better forms of supplementation. Still looking.

EDIT:

The "Life Extension" formula uses "Setria Glutathione". But only 50mg. I think you should take around 500-1000mg. In the study from Setria, their glutathione were dosed for 3 month around 1000mg/day, raised glutathione levels by 50% for one month and helped increase the body’s stores of glutathione. 

Edited by Florian E., 28 August 2016 - 12:37 PM.

[Florian E.]

Glutathion should be taken together with Vitamin C for better absorption. "Pureclinica Double Strength Glutathione" formular and "ActiNovo Liposomal L-Glutathion" seem to be a good choices imo.

And maybe i also add a little bit of Superoxide Dismutase (SOD) to the mix to stabilize glutathion levels.

[Never_Ending]

I wonder if there's a way to repair damaged DNA or mutated copies, if the body have a memory of previous genetic states. Or else would these mutated states pass on to offspring etc. The epigenetic question really is interesting. Glutathione is important for the body as well like you mentioned.  When you get to the more novel chemicals safety becomes more an issue.  Agents that are proven in vitro and work in theory but not thoroughly tested are also concerning.  Has there been any studies on the transferring of the reprogramming factors onto tissues or organs (instead of small number of cells)? That would be an important step for research I assume.

Edited by Never_Ending, 28 August 2016 - 01:36 PM.

[Florian E.]

I wonder if there's a way to repair damaged DNA or mutated copies, if the body have a memory of previous genetic states. Or else would these mutated states pass on to offspring etc. The epigenetic question really is interesting. Glutathione is important for the body as well like you mentioned.  When you get to the more novel chemicals safety becomes more an issue.  Agents that are proven in vitro and work in theory but not thoroughly tested are also concerning.  Has there been any studies on the transferring of the reprogramming factors onto tissues or organs (instead of small number of cells)? That would be an important step for research I assume.

 

 

Glutathione helps to fix dna damage/mutations.

 

This example graphic shows glutathione while aging.

 

 

It seems that this is caused by decline in transcriptional activity of Nrf2 and can be reversed by Alpha lipoic acid.

See here: 

http://www.pnas.org/...1/10/3381.short

 

It would be interesting if higher dose of glutathione + Alpha lipoic acid in older people will be enough to reverse accumulated dna damage.

Currently trying to find studies on this. But nothing found so far.

[Diocletian]

What about C60oo? kmoody is making good quality C60oo in his lab, will you add it on your list when it's done?

[Florian E.]

What about C60oo? kmoody is making good quality C60oo in his lab, will you add it on your list when it's done?

 

I'm personally not such a big fan of C60. Because of its toxic nature and unknown longterm effects.

And i don't know its exact mode of operation. But if you can tell me why i should use it or what problem(s) it fixes, for example "it inhibits/activates X,Y to achieve Z" than maybe i will add it to my regime.

 

 

 

Never_Ending, on 28 Aug 2016 - 03:35 PM,said:

 

 

I wonder if there's a way to repair damaged DNA..........

 

 

Concerning reversal of some accumulated DNA damage i found 3 interesting articles.

 

 

Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells

 - http://www.bloodjour...ent/118/11/2941

 

Stem cells and the impact of ROS signaling

 - http://dev.biologist...ent/141/22/4206

 

Stem cell aging: mechanisms, regulators and therapeutic opportunities  (unfortunately no full access to article)

 - http://www.nature.co...ll/nm.3651.html

 

It seems N-Acetylcystein (glutathione precursor) is able to reverse some of the damage. Maybe Glutathione will do the same.

But, the second article states "only the Lkb1−/− HSC phenotype was not rescued with N-acetyl-cysteine (NAC)"

 

And other interesting quote from this article:

 

 

Despite their quiescence, adult stem cells are empowered by an intrinsic potential to proliferate quickly in order to regenerate tissue within a limited time in response to damage or loss. This requires metabolic plasticity in order to adapt to either quiescence or to the highly proliferative state. Thus, adult stem cells such as HSCs require a delicate balance between the maintenance that prevents exhaustion of the stem cell pool and the differentiation that continually replenishes downstream lineages.

 

 

So, for the DNA repair part i will (for now) cycle a regime of Glutathione, ALA and a bit of SOD, NAC and NADh.

I hope for my age it will be enough.

 

And regarding epigenetics i'm still looking for a better alternative than rapamycin.

Edited by Florian E., 29 August 2016 - 07:06 PM.

[Florian E.]

Hmm. I just read a bit more about HSC (stem cell) self-renewal.

 

https://www.ncbi.nlm...les/PMC3185965/

https://www.ncbi.nlm...pubmed/25538040

http://www.cell.com/...6711(15)00042-9

 

 

It seems that the body balances between repair and stem cell self-renewal mode.

So questions for me are: 

- Can you increase both modes by cyclic stimulation. And will it be beneficial

- What supplement(s) will stimulate self-renewal. Both for HSCs und MSCs

- What factors (beside DNA damage) would lower self-renewal of HSCs (and MSCs)

[Never_Ending]

There's sometimes references to adult pluripotent cells (as in natural not IPSC) , does the body have a mechanism of reprogramming or are those residual? Because there exists even amounts of totipotent cells and which are known to self replicate.    I'm assuming that since regular adult stem cells are already scarce then these more versatile cells will be even more scarce.

 

http://onlinelibrary...200017/abstract

 

Also in regards to C60   I think people speculate that it acts as a good intracellular antioxidant.

Edited by Never_Ending, 30 August 2016 - 02:38 PM.

[Nate-2004]

In response to the post about glutathione, there's not a lot of evidence according to examine.com that it's of any use.  Examine is a pretty reliable source for collecting any data they can find on most supplements.

 

 

 

 

[LeeYa]

Nice Thread!

1. NADase
•NAD+ to NADh ratio -> Alpha lipoic acid (Natrium-R-Lipoat)
•NAD+ precursors -> Nicotinamide riboside/mononucleotide
•SIRT1/3 Activation -> Reservatrol, Honokiol

Don't forget the rhythm!
http://www.nature.co.../nsmb.3004.html

Selenium might be of interest:
http://www.ncbi.nlm....les/PMC4767478/

What do you think of CD38 inhibiton?


http://www.sciencedi...550413116302248

2. Senolytics
•Quercetin -> Muscle cells
•Dasatinib -> Fat cells

What about Lithium (for GSK-3 inhibition)?

3. Autophagy/Mitophagy
•Honokiol/Magnolol -> Autophagy
•Pomegranate + Gorgonibacter (?) = Urolithin A = Mithophagy

Most important is (periodic)fasting!
You may consider spermidine, trehalose, fucoxanthin, allspice.

[Florian E.]

In response to the post about glutathione, there's not a lot of evidence according to examine.com that it's of any use.  Examine is a pretty reliable source for collecting any data they can find on most supplements.

 

 

You're right. There is currently not much scientific evidence that dosing Glutathione is beneficial. To what i've read, at the end of the last century it was often used by the "alternative medicine" community. But scientifically there was no evidence that it is bioavailable orally.

The "alternative medicince" community claims that now there is more and more research that it is indeed bioavailable orally.

I'm not so sure about this yet. Dosing a little bit of NAC or other things to restore healthy homocystein levels could be enough.

Anyway, i've read lot's of reports that link reduced glutathione levels with aging and more damage.

For example:

https://www.ncbi.nlm.../pubmed/8641567

"The oxidized to reduced glutathione ratio rises with aging..."

or

https://www.ncbi.nlm...les/PMC2821140/

 

So for me, i will (in addition to homocystein maintenance) cycle a bit of liposomal glutathione to work around the bioavailability problem, in the hope that it will help to refill my depots.

 

 

 

 

Don't forget the rhythm!
http://www.nature.co.../nsmb.3004.html

Selenium might be of interest:
http://www.ncbi.nlm....les/PMC4767478/

 

 

Thanks for the links.

Second one is a very good report !

On my research over the last days on stem cells i also run over this report which corresponds with this:

http://science.scien...science.aaf2693

 

And concerning stem cells in general i also found these:

"The aged niche disrupts muscle stem cell quiescence"

http://www.nature.co...ature11438.html

 -> "Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. "

https://www.ncbi.nlm...les/PMC2548288/

 

At the moment i'm trying to make sense of all this FGF, Spry, Spred interaction.

As well as the connection to Wnt/β-catenin,PTEN/PI3K/Akt.

"Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion"

https://www.ncbi.nlm...les/PMC3185965/

 

And on MEK/ERK,Nanog,LIF,STAT:

"ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal"

http://www.sciencedi...873506114000373

 

--> Quote from report. Regarding GSK3 inhibition, what you wrote on senolytics:

"...the Wnt pathway by 6-bromoindirubin-3-oxime (BIO), a specific inhibitor of GSK3"

So i will do my research on lithium...

 

And it seems proper working Nrf2 is important:

"Nrf2 is required to maintain the self-renewal of glioma stem cells"

http://bmccancer.bio...471-2407-13-380

 

Unfortunately i'm a bit lost in the stem cell jungle as you see. So, any help is welcome !

 

For the epigenetic "reset" part in my last post, i now think that it's probably not a good idea to try to rejuvenate senescent cells.

Because i believe (and to what i've read) even if you are able to do so, the cells would have rather instable DNA. That's why they got "deactivated" in the first place (i guess).

 

 

 

What do you think of CD38 inhibiton?

 

 

I also stumbled over CD38 while researching half a year ago, and read a lot of stuff about it. But it was or is relatively new, so i'm still a bit cautious about possible side effects.

The only CD38 inhibitor i currently know of is Darzalex. 

And if i search "Google Scholar" for it, i can't find any report what it will do on "healthy" subjects.

Do you have more information about studies on CD38 inhibition ?

 

 

 

 

 

Most important is (periodic)fasting!
You may consider spermidine, trehalose, fucoxanthin, allspice.

 

I already do more fasting than the average. And i rarely take honokiol. Because i consider Autophagy definetly not the most important part in the whole regime. But as mentioned earlier, i for myself do a bit more on Mitophagy with pomegranate juice. And i will do my research on the supps you posted.

Edited by Florian E., 05 September 2016 - 07:53 PM.

[Florian E.]

 

Don't forget the rhythm!

http://www.nature.co.../nsmb.3004.html

Selenium might be of interest:
http://www.ncbi.nlm....les/PMC4767478/

 

 

 

On my research over the last days on stem cells i also run over this report which corresponds with this:

http://science.scien...science.aaf2693

 

 

Ok. That was BS.(does not correspond)

But concerning a possible NADase fix i will surely look more into MSC and CD38. Safest option in past have been NAD+ precursors. So (imo) more data on MSC and CD38 treatment is needed.

And i found two more, but still experimental, CD38 inhibitors -> SAR650984 and MOR202

Edited by Florian E., 05 September 2016 - 09:05 PM.

[Nate-2004]

Apigenin and Quercetin are the most popular of CD38 inhibitors. I've not heard of the others you're talking about.

[Florian E.]

Apigenin and Quercetin are the most popular of CD38 inhibitors. I've not heard of the others you're talking about.

 

 

Thanks for the hint. Now that you mentioned it, i can remember that this CD38 feature was also one of the reasons why i added Quercetin to the regime. A year ago or so, i read this on Quercetin and also decided that the other CD38 inhibitors are too experimental. Quercetin really is a very interesting substance. Sorry, i just read too much over the last months and forgot about this CD38 property.

 

 

 

Concerning Selenium i tried to find out more about its effects. It also has good synergy with glutathione according to some reports. But proper (non-toxic) dosing + bioavailability seem to be a problem. 

[Florian E.]

I've now read a few more interesting things about stem cells...

 

 

To me it seems that (for now) SIRT6 overexpression could be a good countermeasure against stem cell degradation. But for the future better (more complex) stem cell therapies are needed.

As far as i can understand this, accumulated DNA damage leads to more and more degradation of several systems (like stem cell funtion, hGH,...) and increased expression of safety mechanisms (like P53-MAPK, hsp70, senescence, ...) is the consequence, amongst other things, to inhibit cancerous cell growth.

 

When stem cells grow old: phenotypes and mechanisms of stem cell aging (very good article imo)

http://dev.biologist...content/143/1/3

 

I think that leads us back to what we all already know...

See this graphic:

 

Senolytics and telomerase will help to "safe" stem cell function as well.

So i think the current regime is fine until there are good stem cells therapies available. 

 

Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair

http://www.cell.com/...1247(15)01145-6

 

Influences of lamin A levels on induction of pluripotent stem cells

http://bio.biologist...ntent/1/11/1118

 

There are several triggers you could play with. But it think that at the moment SIRT6 overexpression is the safest option. 

Currently trying to find out if there are also risks with SIRT6 overexpression and if it's enough to fix all the double-strand breaks (DSBs), which are the main problem.

 

Edited by Florian E., 11 September 2016 - 08:55 PM.

[LeeYa]

Fenugreek for SIRT6 upregulation:


Icariin Intervenes in Cardiac Inflammaging through Upregulation of SIRT6 Enzyme Activity and Inhibition of the NF-Kappa B Pathway
http://www.hindawi.c...2015/895976/#B5

[Florian E.]

Fenugreek for SIRT6 upregulation:


Icariin Intervenes in Cardiac Inflammaging through Upregulation of SIRT6 Enzyme Activity and Inhibition of the NF-Kappa B Pathway
http://www.hindawi.c...2015/895976/#B5

 

Thanks very much. I was also trying to find good SIRT6 stimulators.

But to be honest i still don't know what to think of this. Because as i searched for Fenugreek i found this, very good overview, of important triggers and substances:

https://healthycell....tic-Figures.pdf

 

But according to this, Fenugreek seems to have kind of an inhibitory effect on SIRT6 (?)

 

And as is searched for more information, i found this:

 

http://www.bloodjour...tent/127/9/1138 - "Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells"

Abstract:

 

 

Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD+-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM.

 

To me it seems that this alternating activation of either SIRT6 or MAPK is just another fu**ing (but clever) evolutionary trade off (?). To my understanding longer periods of SIRT6 activation would inhibit new cell growth (MAPK), which would be bad. And longer periods of MAPK activation could lead to cancerous cell growth. Plus, some cancer fighting systems only get activated in the absence/depletion of SIRT6.

 

I'm currently still trying to find out more about the exact (side)effects of "Icariin", you mentioned

 

Maybe it's only possible to fix all this externally with "exogenous stem cell therapies" etc.

In that regard  i recommend to watch this current interview with Aubrey de grey.

"Ray Kurzweil 2016 - Aubrey de Grey interviewed by Ray Kurzweil"

[LeeYa]

Actually, Icariin is an active ingredient of horny goat weed!(Icariin is not a component of fenugreek, sorry for that mistranslation).

 

Chronic SIRT6-acitvation might have some disadvantages, indeed.
For example, it seems to compete with your telomerase elongation strategy.

Alternatig both approaches could be a solution.

For example, strategies 1. + 3. + 6. on a rotating basis with 4.+ 5.
Just my two cents...

Edited by LeeYa, 14 September 2016 - 09:24 AM.

[Florian E.]

Added AC11® (for DNA repair) and Curcumin (Meriva®) to my regime after doing a bit of research (see also previous post: Epigentic-Figures.pdf)

But i'm still skeptical of how exactly DNA repair is achieved by AC11®.

 

With all that, i think you will still not be able to make a really big difference concerning aging/rejuvenation.

So i looked for existing stem cell therapies.

Looks like you can already have full body stem cell rejuvenation e.g. in India, Mexico, Philippines,... for ~10.000$ (according to a quick search on placidway.com)

I'm interested if someone here can tell more about the safety and techniques of these therapies.

But even with safe & working stem cell therapies there a still more problems to fix.

[Darryl]

The Nrf2 inducer/NF-κB inhibitor I chose is Andrographis paniculata extract, simply because the andrographolide that comprises 30% of extracts is the most potent, relatively non-toxic Nrf2 inducer found in a couple of high-throughput screens. Andrographolide is an irreversible antagonist of NF-κB, and substantial amounts get through the liver and into the systemic circulation.

 

Shaw et al, 2009. Therapeutics for neurological disorders. U.S. Patent Application 13/125,097.

Smirnova et al, 2011. Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators. Chemistry & biology, 18(6), pp.752-765.

Panossian et al, 2000. Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine, 7(5), pp.351-364.

 

I continue to follow andrographolide science esp toxicology. I haven't seen much to be wary of in my 1 or 2 capsule a day dosing.

 

As for the oral glutathione someone recommended upthread, Stephen Spindler's lab demonstrated it has no effect in long-lived mice.

 

 

 

 

 

Edited by Darryl, 22 September 2016 - 09:21 PM.

[Florian E.]

The Nrf2 inducer/NF-κB inhibitor I chose is Andrographis paniculata extract, simply because the andrographolide that comprises 30% of extracts is the most potent, relatively non-toxic Nrf2 inducer found in a couple of high-throughput screens. Andrographolide is an irreversible antagonist of NF-κB, and substantial amounts get through the liver and into the systemic circulation.

 

Shaw et al, 2009. Therapeutics for neurological disorders. U.S. Patent Application 13/125,097.

Smirnova et al, 2011. Development of Neh2-luciferase reporter and its application for high throughput screening and real-time monitoring of Nrf2 activators. Chemistry & biology, 18(6), pp.752-765.

Panossian et al, 2000. Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine, 7(5), pp.351-364.

 

I continue to follow andrographolide science esp toxicology. I haven't seen much to be wary of in my 1 or 2 capsule a day dosing.

 

As for the oral glutathione someone recommended upthread, Stephen Spindler's lab demonstrated it has no effect in long-lived mice.

 

Thanks for the information. So, would you kick Reservatrol as nrf2 activator and other NF-Kβ inhibitors ? 

The only thing about "Andrographis paniculata" that worries me a bit, is a possibly bad effect on testicles.

See (Reports on Andrographis paniculata+testicles since 2012):

https://scholar.goog...l=de&as_sdt=0,5

[LeeYa]

My favorite NRF-2 inducer is Glucosamine:

https://www.ncbi.nlm...pubmed/24714520

Resveratrol has different, sometimes even opposing effects on cellular metabolism (mostly dose-dependent) and bioavailability is hard to predict.