LONGECITY

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

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?

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.

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.

 

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

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

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.

 

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.

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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).

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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

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.

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. 

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.

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.

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

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

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

 

 

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

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.

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.

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

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.

 

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

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

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

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

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.

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"

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...

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.

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.