2284 replies to this topic

[timedilation]

I've read through this entire thread, and I have to say it's one of the more interesting posts I've seen in the longevity space.  This protocol (+variations on it) seems like a very promising route to fight many mitochondrial sources of age-related deterioration.

 

I was hoping to bring up a few related considerations I don't think have seen too much discussion:

 

1) I am pretty convinced that this protocol is quite good at increasing normal mtDNA in the body.  Increased mtDNA will increase ATP production and output, which is good.  However, would the increased ATP production also increase ROS production?  Or would the opposite happen, due to reduced mtDNA damage?  If the former, the solution would be simple enough, just add antioxidant supplementation after reaching the target amount of mtDNA.  Any experiences here?

 

2) Partially related, a great portion of the structure and function of mitochondria comes from proteins encoded by nuclear DNA.  Are there any variations on this protocol to repair mito-related nDNA that have been damaged or mutated?  I would assume the quantity of such nDNA damage would also be related to the amount of ROS produced during ATP production.

 

3) How much is known about how damage accumulates when ATP production is insufficient?  Restoring mitochondria will aid various processes in the body, but what about undoing the damage that was done before building them back up?  Autophagy?  Senolytics?  Interested to hear more thoughts.

[Turnbuckle]

 

2) Partially related, a great portion of the structure and function of mitochondria comes from proteins encoded by nuclear DNA.  Are there any variations on this protocol to repair mito-related nDNA that have been damaged or mutated?  I would assume the quantity of such nDNA damage would also be related to the amount of ROS produced during ATP production.

 

 

 

While most of the genes encoding for mitochondria reside in the nDNA, the 37 genes in the mtDNA are all essential for ATP production. Since they are constantly exposed to a maelstrom of free radicals, they are damaged more frequently. The mitochondrial genes in the nucleus are far better protected, and like other genes in nDNA, are more subject to epimutations than mutations to the underlying DNA code. Epimutations impact all tissue types to varying degrees, and are hypothesized to be a primary driver of aging. Getting rid of them with stem cells is the subject of another thread -- Stem cell self-renewal with C60, whereby stem cell pools are restored to more youthful levels to replaced old somatic cells with high levels of epigenetic damage.

[longcity90]

Is it correct to say that when we have an availability of nutrients / excess and therefore a LOW energy demand there is FISSION while when we fast and there is a HIGH demand for nutrients, fusion occurs?

[Turnbuckle]

Is it correct to say that when we have an availability of nutrients / excess and therefore a LOW energy demand there is FISSION while when we fast and there is a HIGH demand for nutrients, fusion occurs?

 

The availability of nutrients will tend to determine mito morphology -- 

 

Cells under a well-fed condition maintain their mitochondria in a separated (or fragmented) state, while under fasting or starved conditions, mitochondria tend to persist in a connected (or fused) state... 

https://www.ncbi.nlm...les/PMC4023882/

 

 

 

But the availability of nutrients doesn't necessarily imply a low or high energy demand. Exercise will result in a high demand in spite of availability, and the mito situation there is complex and presently a subject of research.

[Ken Mark]

Biggest longevity improvement, 10 times normal life-time, was found in worms that were genetically modified to not have mitochondrial antioxidant analogous to CoQ10 in Humans.

Is it possible that without antioxidant defence their Mito QC machinery worked overtime to clear damaged mitos, resulting in 10 fold longevity benefit?

[Turnbuckle]

Biggest longevity improvement, 10 times normal life-time, was found in worms that were genetically modified to not have mitochondrial antioxidant analogous to CoQ10 in Humans.

Is it possible that without antioxidant defence their Mito QC machinery worked overtime to clear damaged mitos, resulting in 10 fold longevity benefit?

 

 

Possibly, as it's known that Q10 deficiency can trigger mitophagy.

https://pubmed.ncbi....h.gov/21551238/

 

On the other hand, Q10 oral human supplementation has been shown to reduce mortality due to CVD. 

https://www.ncbi.nlm...les/PMC6406788/

The study went for only 5 years, not long enough to tell if it also increased longevity.

[sub7]

Do you guys have any opinion on how Pioglitazone will impact the overall wellbeing of Mitochondria?

 

Just posting one research here, but a lot of studies point to Pioglitazone's ability to increase fatty acid oxidation by mitochondria...

 

Pioglitazone Enhances Mitochondrial Biogenesis and Ribosomal Protein Biosynthesis in Skeletal Muscle in Polycystic Ovary Syndrome
https://journals.plo...al.pone.0002466

[ta5]

US Patent application 20200054061: 
Methods and compositions for rapidly decreasing epigenetic age and restoration of more youthful function

Mentions many of the same things in this thread, like stearic acid, sulforaphane, PQQ, NR, C60, etc. 

[genX]

US Patent application 20200054061: 
Methods and compositions for rapidly decreasing epigenetic age and restoration of more youthful function

Mentions many of the same things in this thread, like stearic acid, sulforaphane, PQQ, NR, C60, etc. 

 

Apparently Turnbuckle has been doxxed!

Interesting to some of the detailed explanations regarding C60 in the patent application.

 

P.S. Can one patent something which has already been disclosed publicly on Longecity?

[nadaepeu]

Apparently Turnbuckle has been doxxed!

Interesting to some of the detailed explanations regarding C60 in the patent application.

 

P.S. Can one patent something which has already been disclosed publicly on Longecity?

I guess the patent might have been submitted by Turnbuckle himself, or at least I hope so.

[ta5]

The patent includes this fun flowchart:

[stephen_b]

Any thoughts on whether biogenesis could or should be extended for longer than day 5?

[Turnbuckle]

Any thoughts on whether biogenesis could or should be extended for longer than day 5?

 

 

It's known that mito mass generally increases with aging and in certain mito diseases (eg, Kearn-Sayre syndrome), but that is likely due to the build up of defective mtDNA loops. In healthy cells there appear to be homeostatic mechanisms that limit mito mass. In any case, increasing mito mass does nothing directly to purify the population, as good and bad loops of mtDNA are duplicated at the same rate. Fission/mitophagy is where damaged loops are removed, and fusion/biogenesis serves only to get the numbers up for the next round. So I don't see any reason to extend the latter.

[CuriousMonkey]

1) Any test to know how much defective mtDNA one has? Particularly any way to know if its 100%.

2) I previously used NR at 300 mg dose and it caused major heart palpitations and shortness of breath. Any alternatives that have been used with protocol with success instead of NR/NMN?

 

Thank you in advance. 

[PAMPAGUY]

I use B3 powder. Works great and no problems.

[CuriousMonkey]

I use B3 powder. Works great and no problems.

 

Could you please tell me the dose you used? Thanks.

[PAMPAGUY]

1,000 mg daily.  Need a minimum of 1 gram to get past the liver where most of it is metabolized  Can try larger dose, and back off if you get side effects.  Great NAD precursor

[Turnbuckle]

1,000 mg daily.  Need a minimum of 1 gram to get past the liver where most of it is metabolized  Can try larger dose, and back off if you get side effects.  Great NAD precursor

 

 

It's not clear to what you are referring to. If it's NR, it is indeed broken down, but if nicotinamide or niacin, it is not. At least not that I'm aware of.

[timedilation]

What is the easiest way to take glycerol monostearate?  Can I just swallow some raw powder with a cup of water?  Do I need to mix the powder and water and heat it in the microwave?  Do I have to make hot chocolate or something like with regular stearic acid?

[Fafner55]

What is the easiest way to take glycerol monostearate?  Can I just swallow some raw powder with a cup of water?  Do I need to mix the powder and water and heat it in the microwave?  Do I have to make hot chocolate or something like with regular stearic acid?

 

I wash down the raw powder with water without problem.

[timedilation]

I wash down the raw powder with water without problem.

 

Are we sure it is fully absorbed like that?  Just want to make sure I wouldn't be reducing the dose taking it raw.
 

Edited by timedilation, 08 January 2021 - 09:12 PM.

[Fafner55]

Are we sure it is fully absorbed like that?  Just want to make sure I wouldn't be reducing the dose taking it raw.
 

 

I haven't seen published results on bioavailability of glycerol monostearate. I simply take it without food and hope for the best.

[muntjac]

What supplements are to be used or avoided before and after the protocol? I've been running searches on the various supplements I take, and many affect mitochondrial dynamics to some extent.

 

https://www.ncbi.nlm...les/PMC3772083/

Glucosamine (GlcN) modulates molecular targets of the autophagy pathway in vitro and in vivo and the enhancement of autophagy was mainly dependent on the Akt/FoxO and mTOR pathway. These findings suggest that GlcN is an effective autophagy activator and motivate future studies on its efficacy in modifying aging-related cellular changes and supporting joint health.

 

 

[Rich D]

What is the easiest way to take glycerol monostearate?  Can I just swallow some raw powder with a cup of water?  Do I need to mix the powder and water and heat it in the microwave?  Do I have to make hot chocolate or something like with regular stearic acid?

 

I simply add it in to my oatmeal before heating it up in the microwave.

Edited by Rich D, 14 January 2021 - 12:53 AM.

[sub7]

This seems like very important news

 

https://link.springe...522-020-09907-6

 

Any way to utilize this drug in the quest for healthier mitochondria?

[sub7]

I wanted to specifically share this in a separate post, ad the risk of one of the 2 links getting "lost in the shuffle" is lower this way

 

https://www.ncbi.nlm...ts-11-02221.pdf

 

Does not appear very actionable, but still important news.... Worms without CoQ10 live 10 times longer

[muntjac]

https://www.ncbi.nlm...les/PMC6210273/

The addition of DHEA resulted in a significant decrease of the overlap coefficient between mitochondria/PINK1 and mitochondria/LC3, while PORs with DHEA pretreatment had decreased autophagosome formation. The phenomenon clearly indicated that DHEA reduced mitochondrial damage, which means that DHEA effectively reduces the occurrence of mitophagy to increase the function and quality of mitochondria. We also confirmed the cellular distribution of mitophagy using 2.5-dimensional reconstructions and intensity profiles. In the POR/DHEA group, we further confirmed that the green, red, and blue fluorescence did not fully match that of the POR group (Figure 6C). To explore whether the protective mechanism of DHEA is related to suppression of mitophagy, we assessed the mRNA expression of PINK1 and PRKN by qRT-PCR. The mRNA levels of PINK1 and PRKN significantly decreased in the CCs from the POR/DHEA group compared to those from the POR group (Figure 4D). These results verified the protective effect of DHEA in preventing autophagy associated with the mitochondrial pathway.

 

 

[Rays]

This seems like very important news

 

https://link.springe...522-020-09907-6

 

Any way to utilize this drug in the quest for healthier mitochondria?

 

The figure 1b looks impressive:

 

 Metolazone.png   511.89KB   1 downloads

 

Edited by Rays, 18 January 2021 - 11:12 AM.

[Bushi84]

i've just read into this Fission Fusion thing.

Can someone explain to me how it works? I've looked at the past pages, but don't immediately find something that tells me more. And time has the better of me lately. 

 

Fission is when the cells break down

Fusion is when they fuse back together.

 

But how does this work with fasting? On days of Fusion you don't fast?

 

[CuriousMonkey]

Does Turnbuckle explain anywhere the rationale of 3 days of fission and 2 days of fusion? My understanding is that mitophagy and mito biogenesis occur in unison so that your total pool of mitochondria remains constant. As such it doesn't make sense biochemically that increases and fission and fusion can be spilt. If I have any of this incorrect, please do explain why that is the case. Thank you in advance.