179 replies to this topic

[platypus]

Superhumanradio discusses "Mitochondrial farming" in the latter part of this episode: 

 

http://superhumanrad...a-butyrate.html

[Tim Ventura]

I have given it one shot, Maggie, though the protocol was slightly different from what I suggested above. The first dose was 1.5 grams nicotinamide plus 20 mg elemental lithium from lithium orotate. I've had a lot of experience with niacin, taking it for years at the 3 gram level, but nicotinamide proved to be different. Within a few hours I felt a bit like I had the flu, then fell into a deep sleep for hours in the middle of the day. Which wouldn't be surprising if it were really knocking off mitochondria. The next day I took 20 mg PQQ, and then several hours later took a 3 mg dose of C60 in MCT oil. By the third day I had an unusual amount of energy. To get the best results, I expect this would have to be repeated a number of times, as it seems unlikely the cellular mechanism is capable of eliminating all bad mtDNA in one pass, as each mitochondrion has several copies and are constantly exchanging them through fission and fusion, so it's a game of percentages.

 

High doses of nicotinamide cause sleepiness, so it's possible that this was also a causal factor. Not sure exactly what sets the threshold for that, but apparently when the body reaches a certain level of excess it makes you tired. This happened with me a few months ago and I had to quit taking nicotinamide entirely to get back to a normal level of alertness.

 

ALSO: Any idea where to obtain a higher dose of PQQ than the 20mg capsules available online? It's new, so it's still expensive - I get it. But it would be nice to be able to experiment with something higher than 20mg. I did a run of that for a month, and while I felt "good", it wasn't anything I could attribute to the PQQ itself. I came away from that thinking that it would be nice to be able to try a higher dose to see if that helped. I'd like to avoid having to spend hundreds of $$$ to test that, though.

Edited by Tim Ventura, 26 February 2017 - 06:45 AM.

[Fafner55]

Experiment #5: Inducing Mitophagy with 3750 mg NR per Day

This experiment attempts to induce mitophagy by simply depolarizing mitochondria with large doses of NR without consideration of activating autophagy. 

 

For 6 days on an empty stomach take NR, 1250 mg doses 3 times per day.  No other supplements will be taken during this period.

 

2017-02-17  Day 1. Began taking the above described treatment.  Felt generally energetic and clear minded.

2017-02-18  Day 2. Awoke with a slight headache. It was gone by mid morning after coffee.  I definitely have feelings of more energy.

2017-02-19  Day 3. No headache today and good energy.

2017-02-20  Day 4. I have felt cold off and on today. Exercise capacity has not been impaired.  I have been clear minded and productive at work.

2017-02-21  Day 5. I have felt cold off and on today, shivering at times at the normally comfortable temperatures I keep my home and office. Exercise was more difficult than usual.

2017-02-22  Day 6. This is the last day of the treatment. I felt slightly cold off and on today. Exercise was no more difficult than yesterday.

2017-02-23  Day 7. I am unusually alert and energetic today.

2017-02-24  Day 8. Exercise came easier today than usual.

2017-02-25  Day 9. My energy level continues to be high and my muscles feel much more toned than usual.

2017-02-26  Day 10. My muscles are more toned  and my daily exercise routine continues to get easier.

 

This experience is consistent with inducing mitophagy and upgrading mitochondrial population.

[Fafner55]

 

Experiment #5: Inducing Mitophagy with 3750 mg NR per Day

This experiment attempts to induce mitophagy by simply depolarizing mitochondria with large doses of NR without consideration of activating autophagy. 

 

For 6 days on an empty stomach take NR, 1250 mg doses 3 times per day.  No other supplements will be taken during this period.

 

2017-02-17  Day 1. Began taking the above described treatment.  Felt generally energetic and clear minded.

2017-02-18  Day 2. Awoke with a slight headache. It was gone by mid morning after coffee.  I definitely have feelings of more energy.

2017-02-19  Day 3. No headache today and good energy.

2017-02-20  Day 4. I have felt cold off and on today. Exercise capacity has not been impaired.  I have been clear minded and productive at work.

2017-02-21  Day 5. I have felt cold off and on today, shivering at times at the normally comfortable temperatures I keep my home and office. Exercise was more difficult than usual.

2017-02-22  Day 6. This is the last day of the treatment. I felt slightly cold off and on today. Exercise was no more difficult than yesterday.

2017-02-23  Day 7. I am unusually alert and energetic today.

2017-02-24  Day 8. Exercise came easier today than usual.

2017-02-25  Day 9. My energy level continues to be high and my muscles feel much more toned than usual.

2017-02-26  Day 10. My muscles are more toned  and my daily exercise routine continues to get easier.

 

This experience is consistent with inducing mitophagy and upgrading mitochondrial population.

 

 

Followup:

2017-03-01  Day 13. My muscles remained toned and exercise remains about the same as Day 10. I am alert and have energy throughout the day into the evening.

 

 

 

[Fafner55]

At the risk of drifting off topic, I want to share my view on the importance of treating the age-related declines in mitochondria, senescent cell and stem cell populations.

 

Previously I blogged that the rate of senescence in dermal fibroblasts in aged humans is about

1. “Cellular Senescence in Aging Primates” (Herbig et al, 2006) http://www.biodados.icb.ufmg.br/cromatina/dna07/telomere.pdf
2. http://www.longecity.org/forum/topic/77368-new-class-of-drugs-senolytics-extends-healthspan/?view=findpost&p=759736

 

Senescence cells:  S(t) ≈ 1.65 exp(0.0465 t)  where t is age in years

 

And the  rate of mtDNA 497 bp deletion is

1. “Mitochondrial DNA 4977 bp deletion is a common phenomenon in hair and increases with age” (2012)  http://www.ncbi.nlm....les/PMC4362429/
2. http://www.longecity.org/forum/topic/86297-a-protocol-to-upgrade-mitochondria/?view=findpost&p=791908

 

mtDNA damage:  D(t) ≈ 0.0002 exp(0.042 t)   where t is age in years

 

Another useful equation is the rate of decline in MSC stem cells, determined from exponential regression to be

“Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation” (2013) http://www.oapublishinglondon.com/article/438

 

MSCs per marrow cells x 100,000:  MSC (t) ≈ 1.85 exp(-0.045 t)   where t is age in years

 

Now consider the rate of cell turnover in the dermis.  I could not locate the original research defining this rate but did come across the following graph http://blog.skinauthority.com/facial-cleansing-essentials-part-3-resurfacing-transformation/  which can be modeled as

 

Skin turnover in days:  ST(t)  ≈ 9.8 exp(0.0369 t)    where t is age in years

 Skin turnover rate.jpg   19.28KB   10 downloads

Now comes the interesting part - modeling skin tissue turnover using the population of stem cells.

Assuming that, to the first order, the rate of tissue turnover is inversely proportional to the number of stem cells. That is, if the rate of proliferation is constant with age and if there are half as many stem cells as at an earlier age, then the tissue turnover rate is also half. This assumption gives

Skin turnover in days modeled by stem cell decline:  SkinTbyStemC(t) ≈ C / 1.85 exp(-0.045 t)   

where t is age in years and C is a scaling constant.

Solving for a turnover rate of 90 days at the age of 60 gives

SkinTbyStemC(t) ≈ 6 exp(0.045 t)   

 

 Skin turnover rate modeled by stem cell decline.jpg   31.39KB   9 downloads

 

So, the rates of senescent cell accumulation, mtDNA damage and cellular turnover due to stem cell decline are all very similar.  There is little doubt that these rates are related. This heuristic model points to the importance of promoting a youthful rate of tissue regeneration, in part by keeping mitochondria populations, senescent cells and stem cell populations at youthful levels, if life span is to increase.

Incidentally, the exponential decline in tissue turnover (assuming regeneration declines in other tissues like it does the skin) explains why the maximum life span has not increased much over the last 100 years while there has been significant progress in extending the medium life span.  

 Human survival rates.jpg   35.72KB   7 downloads

 

[Turnbuckle]

Can the selectivity of the NAD mediated mitophagy be increased by exercise? I gave it a shot--

 

Protocol:

2g nicotinamide and 5g of ribose taken before breakfast 

2 hours later, 25 minutes on gym weight machines

Then another 1g of nicotinamide four hours after first dose

 

Result:

The weights I could lift were less than normal, and much less than with C60. Normally I never feel anything from such a short session, but this time I felt sore the next day, as if I'd spent a couple of hours working out. It's known that NAD+ temporarily promotes mito fission as part of the QC process, and small mitochondria are less efficient at producing ATP. Apart from what this is doing for mitochondrial health, this suggests one could exercise more efficiently, and with less weight and thus less potential for injury.

 

A caveat: This is my second try with this protocol. The first time I had a similar result after the first day, but I continued it for 4 days straight, adding a run on the last day. As a result I felt beaten up for a week and old knee and ankle injuries seemed to have been re-injured and bothered me for weeks. So it appears that nicotinamide magnifies the effect of exercise, and pushing it day after day can also magnify the potential for injury.

[Fafner55]

“Mitophagy in neurodegeneration and aging” (2017) http://www.sciencedirect.com/science/article/pii/S0197018617300955

Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ and urolithins.

[Stewart D]

Can the selectivity of the NAD mediated mitophagy be increased by exercise? I gave it a shot--

 

Protocol:

2g nicotinamide and 5g of ribose taken before breakfast 

2 hours later, 25 minutes on gym weight machines

Then another 1g of nicotinamide four hours after first dose

 

Result:

The weights I could lift were less than normal, and much less than with C60. Normally I never feel anything from such a short session, but this time I felt sore the next day, as if I'd spent a couple of hours working out. It's known that NAD+ temporarily promotes mito fission as part of the QC process, and small mitochondria are less efficient at producing ATP. Apart from what this is doing for mitochondrial health, this suggests one could exercise more efficiently, and with less weight and thus less potential for injury.

 

A caveat: This is my second try with this protocol. The first time I had a similar result after the first day, but I continued it for 4 days straight, adding a run on the last day. As a result I felt beaten up for a week and old knee and ankle injuries seemed to have been re-injured and bothered me for weeks. So it appears that nicotinamide magnifies the effect of exercise, and pushing it day after day can also magnify the potential for injury.

 

My first real post on LongeCity - hello.

 

My experiments on this have built up to taking 2.5 grams of nicotinamide for one day. 1 gram in the morning at 10am, 1 gram at 2pm and 0.5 gram at 4pm and 150mg CoQ10 at night. (I might add folate to the evening mix next time)

 

Result was a totally washed out feeling mid afternoon - a real lack of energy and unable to concentrate. A week later I noticed my aerobic level of exercise was higher and this followed a long period of low activity when I would normally go backwards. This seems to be a semi permanent change in that weeks later I still have the similar level of aerobic exercise even after periods of missing exercise sessions and is only now drifting away a little.

[Fafner55]

Since glaucoma is known to be linked to mitochondrial dysfunction, that nicotinamide prevents this disease is an indication that this low cost vitamin is effective in increasing NAM and inducing mitophagy.

“Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice” (2017) https://www.ncbi.nlm.nih.gov/pubmed/28209901?dopt=AbstractPlus

Glaucomas are neurodegenerative diseases that cause vision loss, especially in the elderly. The mechanisms initiating glaucoma and driving neuronal vulnerability during normal aging are unknown. Studying glaucoma-prone mice, we show that mitochondrial abnormalities are an early driver of neuronal dysfunction, occurring before detectable degeneration. Retinal levels of nicotinamide adenine dinucleotide (NAD+, a key molecule in energy and redox metabolism) decrease with age and render aging neurons vulnerable to disease-related insults. Oral administration of the NAD+ precursor nicotinamide (vitamin B3), and/or gene therapy (driving expression of Nmnat1, a key NAD+-producing enzyme), was protective both prophylactically and as an intervention. At the highest dose tested, 93% of eyes did not develop glaucoma. This supports therapeutic use of vitamin B3 in glaucoma and potentially other age-related neurodegenerations.

[Andey]

Are there any relyable proxy to measure mitochondrial capacity/output ? It could find some use in experiments like these if we can access mitochondrial function at different stages.

 

These days I practice 2 different breathing technics - Wim Hof`s and Frolov`s (russian one), and found that my retention time correlates well beetwen those two but vary in few days intervals. When I feel myself a bit exhausted or ill my retention time is significantly lower and in the opposite I set new personal records when I feel well rested a day after a good solid night sleep.As I understand mitochodria is responsible of utilising excess CO and its activity could correlate with tolerability for this excercise.

 

 

[Turnbuckle]

My experiments on this have built up to taking 2.5 grams of nicotinamide for one day. 1 gram in the morning at 10am, 1 gram at 2pm and 0.5 gram at 4pm and 150mg CoQ10 at night. (I might add folate to the evening mix next time)

 

Result was a totally washed out feeling mid afternoon - a real lack of energy and unable to concentrate. A week later I noticed my aerobic level of exercise was higher and this followed a long period of low activity when I would normally go backwards. This seems to be a semi permanent change in that weeks later I still have the similar level of aerobic exercise even after periods of missing exercise sessions and is only now drifting away a little.

 

Thanks for posting that, Stewart. Your experience may be unusual but certainly isn't unique, as I found a long thread on it here on another site. And on this site I've seen reports of unusual fatigue popping up on NR threads. It's not surprising that some have a problem, as mitochondria are very dynamic. Each cell may have a thousand or more mitochondria that are constantly fissioning and fusing. This activity is necessary for maintaining a healthy population. Taking NAD+ precursors like nicotinamide, niacin or NR push mitochondria into fissioning and higher levels of mitophagy. Stopping the precursors should allow homoeostasis to return and for mitochondria to fuse back to their normal (and more efficient) average size. Perhaps in your case they have been slow to do so. This is purely speculation, of course, but there are supplements that promote fusion as well. In fact, dietary stearic acid [C18:0] appears to be a primary promoter of mito fusion--

 

We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinsons genes Pink or Parkin. This work identifies the metabolite C18:0 as a signaling molecule regulating mitochondrial function in response to diet.

 

https://www.ncbi.nlm...les/PMC4561519/

 

 

Stearic acid [octadecanoic acid] is common in various foods and can also be purchased as a powder. You might also supplement CoQ10, as it has been shown to inhibit fission in an animal model. (And for that reason, one might want to avoid CoQ10 when doing the NAD/exercise protocol I tried above.)

[Stewart D]

I've been taking nicotinamide for some time at 500mg levels. Just from reading about its general benefit for health, skin cancer etc. I'm fair skinned and live in Australia.....so anything that helps with skin cancer is a good thing.

 

But - This thread in particular got me experimenting with it. I've tried taking 1-1.5 grams at once - it does't have a huge effect - but I do notice something. Its taking multiple amounts over a day that causes the large deficit and the later benefit. The amount I posted about before is the amount that caused a flu like symptoms with later increase in strength and energy. 

 

There seems to a threshold that you need to cross but then you also need to stay there.....for some hours. 

 

I'm late 40's in decent but not super great shape which I think is an important detail in this story. 

[stefan_001]

Estimated Dose of NR Needed to Induce Mitophagy

• 
  "Nicotinamide enhances mitochondria quality through autophagy activation in human cells" (2009) http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2009.00487.x/full
• 
  “Novel NAD+ metabolomic technologies and their applications to Nicotinamide Riboside interventions” (2016) http://ir.uiowa.edu/etd/3203/ (Ph.D. thesis)
• 
  “GENERALLY RECOGNIZED AS SAFE (GRAS) DETERMINATION FOR NIAGEN ™ (NICOTINAMIDE RIBOSIDE CHLORIDE)“ (2015-12) http://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm505226.pdf

Decrease of mitochondrial mass in the NAM-treated human fibroblasts.jpg

The following data points and facts are known.

• 
  Keeping NAD+ elevated by 50% for 5 to 7 days significantly decreases mtDNA mass by 50% (in vitro) "Nicotinamide enhances mitochondria quality through autophagy activation in human cells" (2009) http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2009.00487.x/full
• 
  1000 mg/day (15 mg/kg) in a 52 year old (n=1) increased (peak, after 8 hours) plasma concentrations of
  • 
    NAD+ by 317%
  • 
    NAM by 75% (from 0.8 to 1.4 µM)
• 
  Dose responses of NR chloride (in vivo, n=12) increased
  • 
    NAM by ≈ 62% for 300 mg NR
  • 
    NAM by ≈ 140% for 1000 mg NR
• 
  Predose plasma concentration of NAM in the n=12 experiments ranged from 0.2 to 0.55 µM, and from 0.7 to 0.8 µM in the 52 year old, indicating a wide range.
• 
  NAM levels rose to a range of 0.6 to 0.85 µM for 1000 mg NR in the n=12 experiment.
• 
  NR increases NAD+ in a dose-dependent manner.
• 
  NR has a serum half life of about 4 hours.

From these data points and other facts I can surmise that

• 
  My normal dose of NR at 250 mg twice per day with 50 mg pterostilbene should be sufficient to maintain a generally healthy population of mitochondria.
• 
  While NR induces mitophagy, it has not shown in vivo results as impressive as Urolithin-A, which implies that additional mitophagy might be possible beyond those shown with 300 to 1000 mg doses of NR.
• 
  500 mg every 6 hours for 5 days (2 gm/day) might further increase mitophagy and cause a substantial clearance of defective mitochondria.

Experiment #1
Hypothesis: 500 mg (about 7.5 mg/kg) every 6 hours (2 gm/day) for 6 days might induce mitophagy and cause substantial clearance of defective mitochondria.

Test: NR is well tolerated at 1 gm/day (clinical trial), and at 2.5 gm/day (anecdotal) and showed no adverse conditions in mice at 400 mg/kg/day (≈32 gm/day HED, FDA submission). Since it appears safe, and since there are no in vivo experiments on inducing mitophagy with NR, taking about 4 gm/day should give clear results if this treatment works.

NR is packaged in 125 mg capsules. Taking 10 capsules (1250 mg) three times per day is a total daily dose of 3750 mg. This amount is nearly twice the 2000 mg/day does I estimate from in vitro data that is needed to induce mitophagy. In the absence of in vivo data, along with general safety of NR, this higher dose appears warranted, particularly since treatment with Urolithin A showed a significant 42% increase in running endurance in aged rats, which is a better performance increase than I have seen reported for NR and suggests that greater levels of mitophagy are possible.

2016-09-28 Day 1. Begin taking 10 capsules (1250 mg) three times per day. I have not taken C60-OO for a month or, for 10 days, any supplements or medications .
2016-09-29 Day 2 AM: My skin is definitely smoother and I have more energy, the kind of energy and sense of health and well being one feels in youth. Otherwise there are no apparent side effects. Smoother skin is not something I anticipated, but it is consistent with research showing cells returning to normal shape when (aged or dysfunctional) mitochondria is removed.
“Mitochondria shown to trigger cell ageing” (2016) http://www.ncl.ac.uk/press/news/2016/02/mitochondriashowntotriggercellageing/, http://emboj.embopress.org/content/35/7/724
Late afternoon - my face has the feeling of being slightly flushed, as if I were taking a niacin.
2016-09-30 Day 3. Woke up with a headache, otherwise OK. The headache could have been caused by dehydration. It went away after drinking water and a cup of coffee. My muscles feel firmer and stronger: I am slouching less when sitting. This sensation is probably related to increased ATP production and other benefits of NR, and not related to mitophagy.
2016-10-01 Day 4. The ambient temperature is 76° and I feel slightly cold. Less body heat generation is consistent with reduced mitochondrial mass. I feel no other symptoms.
2016-10-02 Day 5. Today is the fifth of this treatment. I am unusually clear minded. As for other symptoms, there is a slight feeling of niacin-like flushing when I take NR, otherwise nothing. Since in vitro experiments should additional decrease in mitochondrial mass through 7 days of treatment, I plan to continue taking NR for one or two more days.
“Nicotinamide enhances mitochondria quality through autophagy activation in human cells" (2009) http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2009.00487.x/full
2016-10-03 Day 6 and final day of this treatment. My muscles feel small, inadequate and ache, which is consistent with significant decrease in mitochondria. Otherwise I feel OK. General autophagy does not seem to be affected, as lipofuscin deposits on my hands remain the same. Another observation is that my sense of smell has been unusually acute for the last several days. My mitochondrial mass should be reduced by about 30% by the end of today if in vitro measurement results are an accurate indication.
2016-10-04 Day 7. Took 10 mg PQQ about 7 AM, which should stimulate mitogenesis and restore my mass of mitochondria back to normal within hours. Noontime: Other than muscle aches, I feel good, energetic and healthy.
2016-10-04 Day 8. I feel completely normal.
2016-10-05 Day 9. I feel energetic.
2016-10-06 Day 10. I feel even more energetic and my skin is noticeably smoother on my arms and face. This treatment is unequivocally beneficial.


Other thoughts

• 
  mtDNA 4977 bp deletion has been shown to increase at and average rate (in years) t ≈ 0.0002 exp(0.042 t) “Mitochondrial DNA 4977 bp deletion is a common phenomenon in hair and increases with age” (2012) http://www.ncbi.nlm....les/PMC4362429/
• 
  Measurements of averaged accumulation of dysfunctional mitochondria bely much higher concentrations in aged and postmitotic cells.
• 
  If in vitro tests are any indication, the experiment I described above should have reduced my mitochondria mass by an estimated 30%
• 
  Since dysfunctional mitochondria are preferentially recycled, as 30% reduction in mass might correspond to a 60% reduction in the mass of dysfunctional mitochondria (just a guess, assuming twice rate).
• 
  Then 3 treatments should reduced dysfunctional mitochondria by 65%, or by about 20 years average accumulation. 6 treatments would reduce dysfunctional mitochondria by about 89%, equal to about 50 years average accumulation.

I am 61 years old.

In the light of the study below I am wondering whether your NR flooding had another effect, DNA repair:
http://science.scien...t/355/6331/1312
The mice got pretty high doses, 500 mg/kg per day intraperitoneally but I would think the levels you took have some impact too.

[Logic]

Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance
http://connection.eb...yloid-clearance
 
Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan
http://www.pnas.org/...1/8638.abstract
 
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
http://journals.plos...al.pbio.1000298
 
Mitochondrial Quality Control: Decommissioning Power Plants in Neurodegenerative Diseases
http://www.hindawi.c...wj/2013/180759/
http://jcs.biologist...ntent/125/4/795

Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance
http://www.ncbi.nlm....les/PMC3975659/
 
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
https://www.ncbi.nlm...les/PMC2592826/
 

http://jcs.biologist...ntent/125/4/795

 

Nilotinib Group Buy:

http://www.longecity...roup-buy/page-1
 

 

Parkinson's Disease: The Mitochondria-Iron Link.

https://www.ncbi.nlm...ubmed/27293957/

 

Lysosomes in iron metabolism, ageing and apoptosis

http://www.ncbi.nlm....les/PMC2668650/

 

Tiron Group Buy:

http://www.longecity...&topicID=188785

 

 

Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart
Metformin Restores Parkin-Mediated Mitophagy, Suppressed by Cytosolic p53

http://www.longecity...ndpost&p=771997

 

 

the mechanism of melatonin-mediated autophagic activation in prion-mediated mitochondrial damage...related with to autophagy pathway as a result of α7nAchR regulation

http://www.longecity...ndpost&p=782544

 

 

[Rocket]

This thread is too long for my attention span to tonight.... What about good old fashioned niacin? I take a couple grams a day and it has cleared up my skin, keeps my cholesterol low despite a high meat anabolic diet, and is supposed to be good for mitochondria.

Edited by Rocket, 10 April 2017 - 12:54 AM.

[Fafner55]

Pharmacological agents that induce cellular mitophagy and their mechanisms are listed in this publication.

“The pharmacological regulation of cellular mitophagy” (2017) http://www.nature.co...embio.2287.html

[Fafner55]

More reason to maintain mitochondria quality control.

"Fueling Inflamm-Aging through Mitochondrial Dysfunction: Mechanisms and Molecular Targets" (2017) http://www.mdpi.com/1422-0067/18/5/933/htm

[Turnbuckle]

This thread is too long for my attention span to tonight.... What about good old fashioned niacin? I take a couple grams a day and it has cleared up my skin, keeps my cholesterol low despite a high meat anabolic diet, and is supposed to be good for mitochondria.

 

 

The thread was getting a bit long, so I started a new one with a new protocol that I'm so far very happy with--Manipulating mitochondrial dynamics. In that thread I propose using fission and fusion on alternate days to eliminate dysfunctional mitochondria.

[Ovidus]

 

 

Experiment #5: Inducing Mitophagy with 3750 mg NR per Day

This experiment attempts to induce mitophagy by simply depolarizing mitochondria with large doses of NR without consideration of activating autophagy. 

 

For 6 days on an empty stomach take NR, 1250 mg doses 3 times per day.  No other supplements will be taken during this period.

 

2017-02-17  Day 1. Began taking the above described treatment.  Felt generally energetic and clear minded.

2017-02-18  Day 2. Awoke with a slight headache. It was gone by mid morning after coffee.  I definitely have feelings of more energy.

2017-02-19  Day 3. No headache today and good energy.

2017-02-20  Day 4. I have felt cold off and on today. Exercise capacity has not been impaired.  I have been clear minded and productive at work.

2017-02-21  Day 5. I have felt cold off and on today, shivering at times at the normally comfortable temperatures I keep my home and office. Exercise was more difficult than usual.

2017-02-22  Day 6. This is the last day of the treatment. I felt slightly cold off and on today. Exercise was no more difficult than yesterday.

2017-02-23  Day 7. I am unusually alert and energetic today.

2017-02-24  Day 8. Exercise came easier today than usual.

2017-02-25  Day 9. My energy level continues to be high and my muscles feel much more toned than usual.

2017-02-26  Day 10. My muscles are more toned  and my daily exercise routine continues to get easier.

 

This experience is consistent with inducing mitophagy and upgrading mitochondrial population.

 

 

Followup:

2017-03-01  Day 13. My muscles remained toned and exercise remains about the same as Day 10. I am alert and have energy throughout the day into the evening.

 

Fafner, 

How has your general well being exercise performance and all else been since?

(as an aside it is astounding that someone will undertake such an enormously valuable experiment and not one person will even be curious enough to ask how it went after the latest update)

[Fafner55]

Ovidus,

The activity in this thread has migrated to Manipulating mitochondrial dynamics. You should follow it. Turnbuckle's insight of fissioning mitochondria to the minimum possible size and inducing mitophagy to preferentially remove the defective ones is persuasive. There is a lively, interesting discussion on how to best accomplish this.

 

To your question, improved muscle tone persists despite my sedentary habits and inconsistent exercise. I am personally convinced that this protocol works and plan to take a maintenance treatment once per year going forward. However, I do not believe that my Experiment #5 is optimal for the reason that no experiment with NR has shown the same degree of benefit as urolithin A. 

“Urolithin-A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents” (2016) http://www.nature.co...l/nm.4132.html 

 

Also keep in mind that mine is an n=1 experiment. Hopefully someone else will repeat it and report the result.

 

My updated profile lists this and other interventions I feel are important.

 

 

Edited by Fafner55, 17 July 2017 - 12:02 AM.

[ceridwen]

My 1st attempt at taking 3000mg niacin today. I have been sick. Head still feels as if it is burning and throbbing. Tinnitus still hissing and throbbing. Front panel of face nose,upper lip still feels as if it is burning with what I suspect is neuropathy.I only had a flush with the 1st tablet I took that was extensive went down to my knees. Felt like sunburn. Difficult to tell the difference between the burning feeling caused by the neuropathy and the Niacin flush. The other tablets did not make me flush. Any ideas as to why that could be? Also should I continue the protocol? Perhaps the sickness was caused by something else?
I have ordered ribose but was impatient to start
I have ordered ribose but was impatient to start

[Turnbuckle]

My 1st attempt at taking 3000mg niacin today. I have been sick. Head still feels as if it is burning and throbbing. Tinnitus still hissing and throbbing. Front panel of face nose,upper lip still feels as if it is burning with what I suspect is neuropathy.I only had a flush with the 1st tablet I took that was extensive went down to my knees. Felt like sunburn. Difficult to tell the difference between the burning feeling caused by the neuropathy and the Niacin flush. The other tablets did not make me flush. Any ideas as to why that could be? Also should I continue the protocol? Perhaps the sickness was caused by something else?
I have ordered ribose but was impatient to start
I have ordered ribose but was impatient to start

 

Niacin is not going to be as good as niacinamide as a NAD+ precursor as it is chemically further away and has only a fraction of the biological half-life. It is also rather acidic and causes a flush while niacinamide does not. People who've taken that much without building up to it have ended up in the hospital thinking they were having an allergic reaction. But it is harmless except for being scary for the uninitiated. If you try this again I suggest you use nicotinamide and ribose and leave off the niacin.

[albedo]

In case you have missed Josh Mitteldorf's lastest blog on "Mitochondria in Aging, II: Remedies"

https://joshmitteldo...ng-ii-remedies/

 

"Commercial interests can make some messages louder than others, and the health news we hear is affected by what is profitable as much as by what is healthy.  Exercise is primary, but has no sales value.  Of the supplements reviewed here, NAC is the best-established for mitochondrial health and a possible effect on lifespan.  It is cheap and available.  Liposomal glutathione is certainly more expensive and possibly more effective.  Melatonin is even cheaper, and has been found to increase lifespan in multiple rodent studies, with broad benefits apart from modification of mitochondrial function.  Humanin and MOTS-c, not yet close to commercial availability, seem to be promising substances to explore for health, though not for profits."

[brosci]

I wonder if tomatidine would make sense for this protocol:

 

https://www.ncbi.nlm...pubmed/28397803

 

"Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy."

 

1.  Nicotinamide riboside (250mg x 2?)

2.  Fasted HIIT / Aerobic exercise

3.  Tomatidine  (250mg?)

4.  Low-protein hypocaloric ketogenic diet

5.  Micro-dose lithium

 

1.  Na-R-ALA

2.  PQQ

3.  CoQ10

4.  ALCAR

5.  BCAAs + High protein hyper-caloric diet

6.  Resistance Exercise

 

Rinse, repeat?

Edited by brosci, 21 October 2017 - 08:52 PM.

[Nate-2004]

Brosci I'd swap the resistance and HIIT, resistance should probably go with the NR, see the other thread on manipulating mitochondrial dynamics. HIIT builds up lactic acid pretty sufficiently and that's good for biogenesis.

 

I'd go with straight 100% whey or hydrolyzed collagen, they also both contain high amounts of leucine which may help with biogenesis plus with the latter you get hydroxyproline and hydroxylysine. The rest is up to you. Maybe add some berberine to the top one. This thread has migrated to the other one I think, so it's a bit outdated.

Edited by Nate-2004, 22 October 2017 - 01:23 PM.

[mitomutant]

I just stumbled upon this fantastic topic. It is quite interesting to treat my condition.

 

I just wanted to add that there is an additional, supplement-free way to induce mitophagy of damaged mitochondria. It has been tested in humans, although there is a catch. Those humans were, like me, mutant. We all have a large scale deletion in our mtDNA. So, we really do have some very-faulty mitochondria.

 

Progressive external ophthalmoplegia (PEO) is a common manifestation of adult‐onset mitochondrial myopathy (MM), often caused by sporadic heteroplasmic single deletions, point mutations of mtDNA, or multiple mtDNA deletions caused secondarily by mutation of nuclear genes involved in mtDNA maintenance (Ylikallio & Suomalainen, 2012). MM manifests typically in the early adulthood, with progressive ptosis, ophthalmoplegia, and exercise intolerance (Zeviani et al, 1989)

 

How did they induced mitophagy of defective mitochondria ? with diet

 

Encouraged by the beneficial effects in mice, we performed a pilot study in PEO/MM patients, as well as for age‐ and gender‐matched voluntary controls with ketogenic “modified Atkins diet” (mAD). We demonstrate that mAD can dramatically modify the disease course of adult‐onset MM by inducing muscle damage, especially targeting respiratory chain‐deficient fibers. The patients recovered well and showed a moderate long‐term increase in muscle strength.

 

 

The study took 2 weeks, but the beneficial effects were still measurable after 2.5 years !

 

We asked whether the mAD‐induced RRF lysis in our patients would affect long‐term muscle function, hypothesizing that the damage might induce satellite cell fusion and regeneration. In 2.5 years of follow‐up, three out of four patients showed slight improvement in muscle strength of leg and back muscles and in six‐minute walking distance (Figs 3A–C and EV2A–C). All of the patients had improved lower extremity extension strength, and three out of four had improved static back muscle strength

 

 

Note, however, that the control patients did not seem to get any benefit (emphasis mine)

 

These results indicate that mAD causes subacute muscle damage in MM patients, independent of the underlying genetic defect, but has no such effects for healthy muscle.

 

 

After reading this paper last year, I have been doing cyclic ketogenic diet (3 weeks every 8 weeks) and I can tell you that it is definitely working as expected. I am now able to workout  5 days per week, including 2 very high intensity boxing classes. Before this, I could barely do 2-3 workouts per week and I was very tired most of the days. Note also that adding melatonin + gluthatione at bed time has helped a lot as well, so we may have some confounding variables here.

 

You can read the whole paper here

Edited by mitomutant, 14 November 2017 - 07:32 PM.

[Turnbuckle]

I just stumbled upon this fantastic topic. It is quite interesting to treat my condition.

 

 

 

 

You might want to see the later thread--Manipulating mitochondrial dynamics. Whether this would help would be dependent on what aspect of mito quality control has failed. 

Edited by Turnbuckle, 14 November 2017 - 07:48 PM.

[mitomutant]

 

I just stumbled upon this fantastic topic. It is quite interesting to treat my condition.

 

 

 

 

You might want to see the later thread--Manipulating mitochondrial dynamics. Whether this would help would be dependent on what aspect of mito quality control has failed. 

 

 

 

Thanks. Posting there in a couple of minutes

[brosci]

Very interesting -- "How did they induced mitophagy of defective mitochondria ? with diet"  And a modified Atkin's Diet at that (which I tend to think of as a high-protein diet?)

 

Right now, I'm in ketosis, but it's a sort of intermittent ketosis.  Dr Mercola put out a book on his "feast famine" cycling approach dubbed the MMT program (metabolic mitochondrial therapy.)  His stuff always comes across as a little woo-wooy, but it's the same idea: https://articles.mer...troduction.aspx Protein here for 150lb at 15% body fat calculates out to a mere ~60g/d (which is nearly vegan if you're eating nuts + vegetables.)

 

His take on the importance of pulsing in carbs is sort of unique (although, maybe not applicable to some disease states.)

Edited by brosci, 20 November 2017 - 07:38 AM.

[bladedmind]

I’ve done the Turnbuckle Alzheimer’s protocol 32 times, the stem cell renewal seven times (which in 2018 ended exercise intolerance I’d suffered since 2013), the senescence protocol once, and the mitochondrial twice.

 

I’ll stay on topic, and raise an item of interest relevant to the mitochondrial protocol.  I’ve had chronic paresthesia in the extremities for three years and have tried various remedies (it’s about 50% better than peak worst).  I just checked and there are multiple recent references about a possible relationship between peripheral neuropathy and mitochondrial damage.   For example:

 

https://www.sciencedaily.com/releases/2011/03/110303184111.htm

Neuropathies tend to hit the feet first, then travel up the legs. As they reach the knees, they often start affecting the hands. This painful condition tends to affect people who are older or taller more often than younger, shorter people. Though these patterns are typical of almost all cases of neuropathy, scientists have been stumped to explain why…. the reason might lie within mitochondria, the parts of cells that generate energy. While mitochondria for most cells in the body have a relatively quick turnover -- replacing themselves every month or so -- those in nerve cells often live much longer to accommodate the sometimes long journey from where a cell starts growing to where it ends. The nerve cells that supply the feet are about 3 to 4 feet long in a person of average height, Hoke explains. Consequently, the mitochondria in these nerve cells take about two to three years to travel from where the nerve originates near the spine to where it ends in the foot….

The researchers report in the January Annals of Neurology that in patients with neuropathy, DNA from mitochondria in the nerve endings at the ankle had about a 30-fold increase in a type of mutation that deleted a piece of this DNA compared to mitochondrial DNA from near the spine. The difference in the same deletion mutation between the matched samples in people without neuropathy was about threefold…..as mitochondria make the trek from near the spine to the feet, their DNA accumulates mutations with age. These older mitochondria might be more vulnerable to the assaults that come with disease than younger mitochondria near the spine, leading older mitochondria to become dysfunctional first. The finding also explains why people who are older or taller are more susceptible to neuropathies….if this discovery is confirmed for other types of neuropathy, it could lead to mitochondria-specific ways to treat this condition. For example, he says, doctors may eventually be able to give patients drugs that improve the function of older mitochondria, in turn improving the function of nerve cells and relieving pain.

 

https://medicine.uiowa.edu/diabetes/targeting-mitochondrial-fission-neuroprotection-diabetic-neuropathy

August 2018

​…grant from the National Institutes of Health and the National Institutes of Diabetes Digestive and Kidney Disease (NIDDK) entitled “Targeting mitochondrial fission for neuroprotection in diabetic neuropathy” for a total award of $1,702,888 over four years. The grant will support studies that will examine a new approach for treating Diabetic Nerve damage, also known as diabetic neuropathy. Presenting with chronic pain or loss of sensation, peripheral diabetic neuropathy (PDN) is a debilitating comorbidity of diabetes that affects at least half the diabetic patient population. Since only palliative treatments are available, there is an urgent need for therapies that prevent or reverse the “dying back” degeneration of sensory fibers innervating the skin. Recent evidence suggests that diabetes compromises mitochondria, the cellular powerhouse, in sensory neurons. However, the underlying mechanisms are unknown….Mitochondrial shape is controlled by opposing fission and fusion events….

The research team further proposes to investigate how diabetes causes mitochondrial fragmentation in sensory neurons and how inhibiting mitochondrial fragmentation protects peripheral axons in diabetes. Using new mouse models and innovative in vivo imaging approaches, they will test the hypothesis that dysregulation of the mitochondrial fission/fusion equilibrium contributes to the pathogenesis of diabetic neuropathy…

 

I raise this this issue for two reasons.  First, there may be readers who suffer from peripheral neuropathy and are looking for things to try.   Second, although educated, I am not trained in biochemistry, and would be glad to hear comments from more informed people about the proposed relationship between mitochondria and neuropathy. 

 

It’s interesting that it takes 2-3 years for mitochondria to migrate to the feet from nerve origin at the spine.  Implications for protocol? 

 

 

 

 

 

 

 

 

Edited by bladedmind, 27 July 2019 - 02:37 AM.