15 replies to this topic

[QuestforLife]

I few months ago this study was kicking around the Forum. I was asked for my take and never came up with anything to my own satisfaction. I now have a decent explanation, which may or may not turn out to be correct. It seems to shed some light on the benefits of C60. Turns out there is precedent for an antioxidant to have effects long beyond its last dose.

Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span

https://www.scienced...000961?via=ihub

 

 

Dietary restriction feeding extends survival in a range of species but a detailed understanding of the underlying mechanism is lacking. There is interest therefore in identifying a more targeted approach to replicate this effect on survival. We report that in rats dietary supplementation with alpha-lipoic acid, has markedly differing effects on lifetime survival depending upon the dietary history of the animal. When animals are switched from DR feeding to ad libitum feeding with a diet supplemented with alpha-lipoic acid, the extended survival characteristic of DR feeding is maintained, even though the animals show accelerated growth. Conversely, switching from ad libitum feeding a diet supplemented with alpha-lipoic acid to DR feeding of the non-supplemented diet, blocks the normal effect of DR to extend survival, even after cessation of lipoic acid supplementation. Unlike the dynamic effect of switching between DR and ad libitum feeding with a non-supplemented diet where the subsequent survival trajectory is determined by the new feeding regime, lipoic acid fixes the survival trajectory to that established by the initial feeding regime. Ad libitum feeding a diet supplemented with lipoic acid can therefore act as mimetic of DR to extend survival.

Could ALA be affecting stem cell proliferation? Check this out:

Influence of alpha-lipoic acid on survival and proliferation of mesenchymal stem cells

http://feyz.kaums.ac...d=1&slc_lang=en

 

 

 

Background: Mesenchymal stem cells (MSCs) contribute to tissue repair in vivo and form an attractive cell source for tissue engineering. The regenerative potential of MSCs is impaired by oxidative stress-induced cellular senescence. Alpha-lipoic acid (ALA) is well-known for its antioxidant properties. The Ki-67 antigen is expressed during all phases of cell cycle (G1, S, G2 and M phase) except for G0 phase and is commonly used as a proliferation marker. Herein, the aim of the present study was to investigate the impact of ALA on rat MSCs survival and proliferative potential in vitro.
Materials and Methods: Isolated rat bone marrow and derived mesenchymal stem cells were synchronized by serum starvation for 24h and the addition of hydroxyurea (2µM). Afterwards, the cells were cultured in the presence of ALA (1µM) for 48h. An MTT assay was used to investigate cell survival and proliferation. The expression of Ki-67, a proliferation marker, was also evaluated.
Results: The MMT assay showed a statistically significant increase in proliferation of MSCs in ALA-treated groups for 48 hours. Immunoctytochemistry of Ki-67 revealed significant differences between ALA- treated and Control groups.
Conclusion: In conclusion, ALA is effective in increasing the survival and cell proliferation of isolated rat bone marrow and derived mesenchymal stem cells.

Here is a finger-in-the-air hypothesis. Ad lib feeding results in greater use of stem cells; DR preserves stem cells. ALA increases stem cell use even more when combined with ad lib feeding to the extent that subsequent DR could not extend life.
But it appears that late in life increasing proliferation of stem cells can trump their preservation if they have been saved for the occasion; ALA added to an ad lib diet preserves the lifespan benefits of a prior DR diet.

 

ALA added to Ad lib alone does not increase lifespan; perhaps increased stem cell proliferation, which is beneficial to failing health in old age, is offset by their profligate use in early life.

 

Effect of Alpha-Lipoic Acid on Memory, Oxidation, and Lifespan in SAMP8 Mice

 

This study used old SAMP8 (senescence-accelerated) mice and ALA and showed an improvement on learning and memory but a reduction in remaining lifespan, which supports the using up of stem cells as beneficial to health in the short term, but detrimental to long term survival. 

 

https://www.research...lipoic-acid.cfm
https://pubmed.ncbi....-in-samp8-mice/

 

 

Mice tend to spend more time exploring new objects than familiar ones, so the mice in the behavior study were exposed to two similar objects (plastic frogs) for five minutes. Twenty-four hours later, one of the frogs was replaced with a novel object (a plastic bird). The 10 mice that had been given alpha-lipoic acid before the test spent more time exploring the new object than 10 others who had not been given the drug.
These mice also were given a test using a maze, to see if the mice could learn the location of an escape chamber. In this test, the mice that were administered alpha-lipoic acid learned the location of the "target area" more quickly than those who had not received the acid, especially during the first few days of testing. Since all 20 of the mice in the study were extremely old for the species (18 months), the study indicated that even more advanced dementia can be reversed by alpha-lipoic acid…..The lifespan study, however, provided less encouraging results. In this study, 50 11-month old SAMP8 mice were given alpha-lipoic acid every day until the day they died. Their longevity was compared with a control group of 50 SAMP8 mice that were not given the drug. The team found that mice receiving the drug lived for an average of 20 weeks after the drug was first administered, and those who did not receive the drug lived an average of 34 weeks from the beginning of the test—a significant difference.

 

What does this mean for C60 use? C60 fullerene added at 10 months of age for 7 months allowed rats to live to 50 months + (normal max lifespan ~35). This suggests that stem cell stimulation is beneficial if used in youth to middle age. My research above suggests however that the benefits seen in the Baati study will be hard to replicate if the study design is significantly deviated from.

For us self-experimenters it suggests stem cell stimulation should be used with caution, and mitigation for loss of stem cells should be accounted for. See for example, Turnbuckle’s Stem Cell Protocol that uses supplements to encourage self-renewal or my approach using telomerase.

It also begs the question - for any intervention that appears to be healthy in the short run, is it depleting stem cells?

Edited by Mind, 29 September 2020 - 09:26 AM.

[kurt9]

ALA, if used properly , is a chelat0r of heavy metals.

[QuestforLife]

This recent paper demonstrates exactly what I'm talking about

https://onlinelibrar...1111/acel.13110

Mobilization-based transplantation of young-donor
hematopoietic stem cells extends lifespan in mice

In it they mobilised resident stem cells (rather than using chemo) in middle aged/old mice and then injected young stem cells. This enables the young stem cells to take up residency in the bone marrow. Doing this repeatedly enabled an extension in mean and max lifespan. What's really interesting to me is they also used a mobilisation control,where stem cells were mobilised without replacement. There was a sizeable increase in health span with no increase (maybe even a slight decrease) in max lifespan.

See fig 1 of the paper.

https://onlinelibrar...-fig-0001-m.jpg

Excellent evidence that stem cell availability is limiting for health due to being held in reserve by the body.

[QuestforLife]

This is the survival curve:

 

 

And this is an interesting diagram on repopulating of the stem cell niche

 

 

This is encouraging for approaches that use small molecules to free and/or rejuvenate stem cells in vivo.

[Nate-2004]

There's a lot of attempts going on https://www.lifespan...nation-roadmap/ with stem cell mobilization but not a lot going on with replacement or repletion of stem cells. Not like the mouse experiment mentioned above. The wnt pathway experiments have progressed the most but these still don't address replenishment.

 

Turnbuckle's hypothesis with C60 is something I've experimented with but we don't have enough data yet to know if it would be the equivalent of what is being done in these proliferate and replace experiments or not.

 

In between the protocol with C60 I've been taking the base ingredients found in Nuchido's product which includes R-ALA. Perhaps cycling between all these will help. I'm not seeing improvements in my insulin function (fasted blood glucose) or blood pressure though, outside my direct attempts to intervene with beet root, flaxseed and perhaps garlic.

 

After a few rounds though, I'll get my DNAge done again and see what it says. Last time I took it, it said I was a year older than I am. Fingers crossed and following TB's protocol exactly, it'll show I'm younger next time.

[Blu]

I'm not seeing improvements in my insulin function (fasted blood glucose) or blood pressure though, outside my direct attempts to intervene with beet root, flaxseed and perhaps garlic.

 

OT.

Give a look at DatBTrue's Carbless Post-WO protocol. It's very interesting for insulin sensitivity.
 

Edited by Blu, 26 February 2020 - 06:06 PM.

[QuestforLife]

Well done for doing a test Nate. The more of us that do,the faster we'll zero in on things that work. I did DNA methylation age tests 1 per year for 2017,18,19 and I'm about to do one for 2020. It's takes considerable data to get anywhere and 2019 was the first time I got improved results. Here's hoping 2020 will be even better.

Oh and agreed, there's plenty of ways to make the bone marrow release more stem cells. Rejuvenating and re-populating the bone marrow is the part I'm less sure about.

Edited by QuestforLife, 26 February 2020 - 06:08 PM.

[QuestforLife]

ALA upregulates fatty acid oxidation via AMPK and SIRT1 (https://link.springe...0125-012-2530-4)

ALA increased the NAD+/NADH ratio to enhance SIRT1 activity and production in C2C12 myotubes. ALA subsequently increased AMPK and ACC phosphorylation, leading to increased palmitate β-oxidation and decreased intracellular triacylglycerol accumulation in C2C12 myotubes

Fat burning is very important for many stem cells (https://journals.lww...role_of.12.aspx)

The findings discussed in this editorial com-
ment are in line with the emerging role of FAO as
a conserved metabolic pathway for stem cell main-
tenance and quiescence

Therefore we can consider the strange case of dietary restriction and AlA to be solved.

Based on this understanding the optimal lifestyle for lifespan is periods of fasting interspaced with (saturated) fat heavy meals.

Edited by QuestforLife, 08 August 2020 - 12:16 PM.

[QuestforLife]

I'm moving this discussion over from my telomeres thread, as I think it fits better here. I'd like to discuss in more detail an ideal way to feed stem cells, a stem cell diet if you will - based on fats. 

 

 

 

28th July 2020:  I've been thinking for some time about the importance of fatty acid oxidation and wanted to devote a whole post or series of posts to it.

It's only tangentially related to telomeres, but I believe it is extremely important for health and longevity.

 

We know AKG results in a reduction of triglycerides, LDL cholesterol, presumably because of increased demand on the Krebs cycle resulting in a requirement for beta oxidation (https://www.longevit...sults-in-humans).

Other supplements like resveratrol that activate SIRT1 also increase beta oxidation. AMPK activation increases fat burning. So does carnitine, which increases import of fats into the mitochondria (https://pubmed.ncbi.nlm.nih.gov/12404185/)
Alpha lipoic acid also seems to have some benefit as it's also important in the Krebs pathway and in AKG oxidation. Forskolin increases cAMP, which increases fat burning (https://www.ncbi.nlm...one.0029735.pdf) and incidentally also leads to symmetrical division at least in egg cells.

 

Stearic acid is a trigger fat that signals the body to burn fat (https://www.nature.c...467-018-05614-6). This might be the best way of all - eating highly saturated fat and not relying on any over stimulated supplement pathways.

 

It turns out that children do more beta oxidation than adults (https://nutritionj.b.../1475-2891-6-19). Elderly patients were able to increase beta oxidation by supplementing glutathione precursors (https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12073).

 

Cells burning fats produce more ROS and use fused rather than fissioned mitochondria. Note this is also a signal for cells to become insulin resistant, which helps with weight loss.

 

I'm not posting all references here - there are many other interesting avenues for research and self experimentation (another time i'll post about using AKG, berberine and ALA). But I want to focus this post in a specific direction - stem cells.

 

Beta oxidation is very important in maintaining stemness. I found it easy to find supporting evidence in pluripotent stem cells (https://stemcellres....-018-0792-6#

:text=Recent%20reports%20suggest%20that%20the,cells%20%5B9%2C%2032%5D.&text=Our%20study%20showed%20that%20Cpt1,for%20promoting%20the%20reprogramming%20process.)

 

Also check out this excellent paper on self renewal in intestinal stem cells (https://www.scienced...934590918301632)

 

Neural stem cells (https://www.ncbi.nlm...les/PMC5583518/)

 

and hematopoietic stem cells (https://pubmed.ncbi....h.gov/22902876/)

As a result I've decided to change my diet to incorporate much more saturated fat with an emphasis on stearic acid.

It will be interesting to see if it has any effect on my epigenetic age. I have already experienced a loss of fat and gain in muscle whilst eating as many carbs as I want. There are also some potential downsides to this diet, which I will cover in a future post.

Edited by QuestforLife, 29 September 2020 - 07:05 AM.

[QuestforLife]

This is the survival curve:

I wonder what would have happened if the mobilisation of residence stem cells (red curve) had continued indefinitely (or atleast beyond HSCT end)? Obviously there are some limiting factors like the extra requirement to feed all the new cells (and possible side effects of long term stem cell stimulation).

But in principle is the difference in lifespan between 'mobilisation control' (red) and the animals that received younger stem cells (blue) only the extra telomere length of the younger stem cells - which would equate to a greater number of replacements overall? Is this evidence that maximum lifespan is just a function of stem cell availability?

Edited by QuestforLife, 29 September 2020 - 02:33 PM.

[QuestforLife]

This post is the culmination of the research of this thread.

It pulls together elements of antioxidant research and ROS, the insulin receptor, calorie restriction and stem cells.
People have been commenting on another thread about the ‘paradox of Q10’, i.e. why it is an important molecule for heath, but reducing it appears to greatly increase LS in model organisms. It is easy to be confused by talk of antioxidants, mitophagy, etc. But it is my view that almost all lifespan extension in animals is as a result of the insulin receptor, or closely related pathways.

 

I had to get this post out all in one go, with minimal references, to express the essence of my understanding – I couldn’t jump the crevasse in small hops. It is no doubt woefully inadequate, but I will try and fill in all the necessary references and gaps in my reasoning later. In the meantime, I hope people find it useful. 

 

Why limiting Q10 is the same as reducing energy supply and may have the benefits of calorie restriction

 

First, a quick refresher on the Electron Transport Chain (ETC):
Q10 is the electron acceptor that passes electrons along the ETC.
This action also allows H+ ions to be transferred out and across the inner mitochondrial membrane.
These H+ ions are later sucked back in causing the rotation of Complex V, which produces ATP (Adenosine triphosphate = stored energy).
A reduction of ATP supply due to a limitation of Q10 will obviously give the organism less energy.
Even if Q10 supply is not limited per se, but electron flow is too great into the ETC, the effect will be the same -  there will be increased ROS as more electrons are leaked from the ETC, and this likely downregulates the Insulin Receptor. Hence the benefits appear like CR. 

 

Is this actionable, without CR, and without reducing Q10?

 

Yes. It can be accomplished by taking advantage of the Q10 bottleneck.
What is this bottleneck, I hear you ask?
The bottleneck occurs when there is competition between Complex I and Complex II for Q10, when oxidising both NADH and FADH2. Instead of most the electrons coming from Complex I via NADH oxidation, if electrons are simultaneously coming from Complex II due to the oxidation of FADH2 then not enough Q10 will be available at any given moment to accept all the resultant electrons. This results in leakage of electrons and the creation of more Superoxide.

 

Isn’t this a bad thing?

 

Not necessarily. The Q10 bottleneck has existed for evolutionary time; it must serve a purpose. Complex II doesn’t release sufficient energy to allow any H+ ions to cross the inner mitochondrial membrane, so less ATP will be generated when it is being used. More importantly, the increased ROS due to the bottleneck will also cause various adaptations due to the Antioxidant Response Element (ARE, to turn the extra superoxide into hydrogen peroxide) and the hydrogen peroxide will downregulate the Insulin Receptor. Basically, if the Insulin Receptor is downregulated due to ROS you will become mildly insulin resistant and your cells will be reticent to uptake glucose. 

 

Note H2O2 can both stimulate and abrogate Insulin signalling, depending on concentration. Hence too low ROS can be harmful. But here we are intentionally increasing ROS to downregulate Insulin. 

There are various benefits of stem cell proliferation downstream of reduced insulin signalling. This is likely what causes the extension of lifespan in model organisms. 

 

So how can we do this? And do we want to do it?

 

Eating long chain saturated fats means that more FADH2 will be made by Beta Oxidation than would otherwise be the case. Beta Oxidation is what the body does to release energy from fats. If we were only feeding the Krebs cycle with carbs, for example, you’d get a ratio of 3:1 NADH to FADH2; beta oxidation produces a 1:1 ratio before the acetyl-CoA is fed into the Krebs cycle. 

 

The extra FADH2 from Beta Oxidation will cause the Q10 bottleneck to become relevant. It is important to use a long chain Fatty Acid, because each time around the beta oxidation loop cycle generates 1 FADH2 and 1 NADH and cuts 1 Acetyl-CoA off the chain to go into the Krebs cycle; so the longer the chain the more is FADH2 made. 

Stearic acid seems to have big effects on mitochondria and has been reported to have health benefits, so it is my choice to use. 

 

Is activating beta oxidation really the same as CR?

Think about it. When you’re starving your body burns fats. Increasing the burning of fats through eating more saturated fatty acids will certainly activate the same pathways, albeit to a lesser degree. 

Isn’t this crazy?

Yes, it is quite crazy downregulating the Insulin Receptor and voluntarily becoming LESS insulin sensitive. Effectively, this is becoming slightly diabetic.  But it is consistent with a lot of animal studies on rapamycin.   The downsides of having higher glucose in the blood are far outweighed by reducing the activation of the insulin pathway.

Have you tried this?

Yes. I was encouraged to try this when I found this guy. He has lots more information on how to put saturated fat into your diet. I found the amount of saturated fats he was introducing into his diet to be excessive. But he started off pretty seriously overweight. He also combines this idea with intermittent fasting. This kind of happens anyway after a fatty meal, as you’re not hungry for ages. He also drinks a lot of red wine (also a favourite of mine). Alcohol is another way of increasing ROS in mitochondria and deactivating the insulin pathway.
Look at the people you know who drink a lot of alcohol. They are generally thin. Look at Aubrey de Grey! Is this is secret? Obviously, lots of beer might not have this effect, as it’s high in carbs - think of the alcohol you can drink on a keto diet.

When I tried increasing stearic acid in my diet, I lost significant weight almost straight away. This is MORE effective for weight loss than a keto diet. Also, on the Keto diet I started losing hair thickness after a while, probably due to biotin deficiency because of all the protein my body was having to metabolise. If anything my hair got thicker on the high saturated fat diet.

But after 3 months or so my energy levels and my weight lifting sessions were suffering, so I took a break from the diet. This was similar to how I felt on keto, but the loss of strength took longer than from keto. This might be a diet best done intermittently. I also found that after a couple of months I needed to add Silymarin to help me digest all the fats. I also recommend monitoring BP during this diet. I didn’t experience any significant rise, but others might. Again I stress if you want to try this, too much of anything is not good for the body, even CR is beneficial only up to a point.

Do you have to restrict carbs?

No. This isn’t a Keto diet. Carbs, particularly starchy carbs like bread or potatoes help you to absorb the fat. One might think too many carbs would make beta oxidation irrelevant. But no, the fats might be initially stored, but they start to get burned for energy a few hours after you’ve eaten. I got to know the feeling of what burning fats for energy feels like. And I kept going back into it during the day. Those that have done Keto will know what I am talking about. You also tend to wake up having lost weight on this diet even if you ate a load of popcorn or bread before bed.

Edited by QuestforLife, 19 January 2021 - 11:36 AM.

[capob]

"The bottleneck occurs when there is competition between Complex I and Complex II for Q10"

Do you have any papers that detail this bottleneck?

 

 

"More importantly, the increased ROS due to the bottleneck"

Where do you get the idea ROS would occur because of the supposed bottleneck?  What I read is, radicals result from the unfinished Q cycle (ubisemiquinone), which would not be a result of too many electrons.

 

[QuestforLife]

 

"The bottleneck occurs when there is competition between Complex I and Complex II for Q10"

Do you have any papers that detail this bottleneck?

 

 

"More importantly, the increased ROS due to the bottleneck"

Where do you get the idea ROS would occur because of the supposed bottleneck?  What I read is, radicals result from the unfinished Q cycle (ubisemiquinone), which would not be a result of too many electrons.

 

 

Try this:

https://www.ncbi.nlm...les/PMC5103874/

 

Being right on Q: shaping eukaryotic evolution

 

 I proposed a kinetic model in which the ratio between electrons entering the respiratory chain via FADH2 or NADH (the F/N ratio) is a crucial determinant of ROS formation. During glucose breakdown, the ratio is low, while during fatty acid breakdown, the ratio is high (the longer the fatty acid, the higher is the ratio), leading to higher ROS levels.

 

The idea is that there is a fixed number of Q molecules available per unit time, and feeding in electrons via both complex I and complex II will exceed Q's ability to accept them, increasing ROS, whereas if they are mainly coming just from complex I this capacity is not exceeded. 

 

Based on my n=1 experience, this is clearly right, as eating enough stearic acid in your diet results in weight loss, tiredness and higher body temperature, the latter probably based on mitochondrial uncoupling. 

[capob]

Try this:

https://www.ncbi.nlm...les/PMC5103874/

 

Being right on Q: shaping eukaryotic evolution

 

 

 

 

The idea is that there is a fixed number of Q molecules available per unit time, and feeding in electrons via both complex I and complex II will exceed Q's ability to accept them, increasing ROS, whereas if they are mainly coming just from complex I this capacity is not exceeded. 

 

Based on my n=1 experience, this is clearly right, as eating enough stearic acid in your diet results in weight loss, tiredness and higher body temperature, the latter probably based on mitochondrial uncoupling. 

 

 

Interesting article.

Speijer's model doesn't make sense.  If the issue were the unavailability of Q because Q and QH2 were in transit elsewhere, then a high concentration of NADH would also produce this problem (rapid NADH oxidation at complex I would exhaust Q availability), and the blame would not be solely on FADH2 or even inherently related to FADH2.  

 

Instead, the issue is complex I runs in reverse, creating ROS, when QH2 is high.  

https://www.ncbi.nlm...les/PMC6016480/

 

IE, the issue is high QH2, not the lack of availability of Q.

 

I suspect that QH2 would be a problem more along the lines of 

(QH2 * (QH2 / (QH2+Q) )) / (# Complex I's)

or

(QH2 * %QH2) / (# Complex I's)

 

(given a major source of ROS is said to be ubisemiquinone) I also suspect ROS is in part a result of total Complex I runs (both forward and backward), wherein each Q transformation at Complex I presents a potential for ubisemiquinone to react and create ROS.

 

 

It's presented that beta oxidation raises QH/Q.  I have a model for this, but I'm not certain whether current science has a model for this.  They should, but I've detected recent scientists aren't great at models.

 

Since beta oxidation raises QH/Q, it makes sense beta oxidation would result in more ROS at Complex I.

 

"The idea is that there is a fixed number of Q molecules available per unit time, and feeding in electrons via both complex I and complex II will exceed Q's ability to accept them, increasing ROS, whereas if they are mainly coming just from complex I this capacity is not exceeded. "

 

I think you are misunderstanding the ETC based on what I think is a false diagram/model presented of ETC

https://en.wikipedia...Respiration.svg

 

I think Complex II incorporates FAD as a link in using succinate, it does not grab electrons from FADH2 produced by beta oxidation.  The incorrect diagram seems to show unincorporated FADH2 being used and then disposed of as FAD outside of complex II.

 

Instead, what almost all presentations of beta oxidation fail to show is that FADH2 from the first step of beta oxidation is immediately oxidized with ETF, and then ETF uses ETF-O to transport the electrons to Q.  Odd that this should be so universally left out.  I expect it is because most people are just copying original models which don't show this.

https://en.wikipedia...n_dehydrogenase

https://www.scienced...005272810007152

 

"Based on my n=1 experience, this is clearly right, as eating enough stearic acid in your diet results in weight loss, tiredness and higher body temperature, the latter probably based on mitochondrial uncoupling. "

 

I don't follow the logic of "this is clearly right",  I could predict tiredness, weight loss, and high temperature independent of the model regarding ROS.

 

[QuestforLife]

 

Interesting article.

Speijer's model doesn't make sense.  If the issue were the unavailability of Q because Q and QH2 were in transit elsewhere, then a high concentration of NADH would also produce this problem (rapid NADH oxidation at complex I would exhaust Q availability), and the blame would not be solely on FADH2 or even inherently related to FADH2.  

 

Instead, the issue is complex I runs in reverse, creating ROS, when QH2 is high.  

https://www.ncbi.nlm...les/PMC6016480/

 

...

I think Complex II incorporates FAD as a link in using succinate, it does not grab electrons from FADH2 produced by beta oxidation.  The incorrect diagram seems to show unincorporated FADH2 being used and then disposed of as FAD outside of complex II.

 

 

That is interesting, I was not aware that the electrons from FADH2 were taken straight from beta oxidation into the ETC.

 

So are you saying these join at Complex I and not Complex II? What then does Complex II do in the ETC?

 

If there is another mechanism by which mitochondria produce more ROS when Beta Oxidation is utilised, please share it.

 

There must be some difference between an increased FADH2: NADH ratio, and just increasing NADH.  Having more NADH might make more ROS via electrons being stolen by passing Oxygen, but it is hard to imagine how this would reverse electron flow in the ETC. Reversed flow is easier to imagine if there is a bottleneck further up, such as at Complex II.   

 

Perhaps my choice of language, saying my explanation was 'clearly right' is unjustified. But it is partly based on years of my own practical experience with keto and later with eating long chain saturated fats. It does feel different to a normal 'balanced' diet and has the effects I described. There is evidence the the metabolism is altered significantly in rats eating keto (https://journals.phy...endo.00717.2006). We also have evidence mitochondria change their morphology in response to stearic acid in the diet (https://www.nature.com/articles/s41467-018-05614-6).  None of this is decisive, but it certainly hints that this area is worthy of further investigation. 

Edited by QuestforLife, 10 February 2021 - 10:09 AM.

[capob]

That is interesting, I was not aware that the electrons from FADH2 were taken straight from beta oxidation into the ETC.

 

So are you saying these join at Complex I and not Complex II? What then does Complex II do in the ETC?

 

If there is another mechanism by which mitochondria produce more ROS when Beta Oxidation is utilised, please share it.

 

There must be some difference between an increased FADH2: NADH ratio, and just increasing NADH.  Having more NADH might make more ROS via electrons being stolen by passing Oxygen, but it is hard to imagine how this would reverse electron flow in the ETC. Reversed flow is easier to imagine if there is a bottleneck further up, such as at Complex II.   

 

Perhaps my choice of language, saying my explanation was 'clearly right' is unjustified. But it is partly based on years of my own practical experience with keto and later with eating long chain saturated fats. It does feel different to a normal 'balanced' diet and has the effects I described. There is evidence the the metabolism is altered significantly in rats eating keto (https://journals.phy...endo.00717.2006). We also have evidence mitochondria change their morphology in response to stearic acid in the diet (https://www.nature.com/articles/s41467-018-05614-6).  None of this is decisive, but it certainly hints that this area is worthy of further investigation. 

 

 

The FADH2 -> ETF -> ETF-QO -> quinone.  This is not considered a complex, and QH2, after this process, goes to Complex III.

 

"If there is another mechanism by which mitochondria produce more ROS when Beta Oxidation is utilised, please share it."  Perhaps eventually.

 

I don't recall whether QH2 forward path to Complex III is at all directed.  Without knowing this, I would expect Q and QH2 to act sort of like randomly moving gas particles.  As such, you can imagine Q and QH2 would randomly encounter Complex I-III at random, potentially dependent on collision with nearby particles, and would port variably based on affinity to the port.  I suppose you need to remove the paradigm you might get from models that the ETC complex chain is in some nice linear formation and think of them more like a grid of Complexes.  I suspect that QH2 is ejected from Complex I at initial Q->QH2 transformation, and that this ejection serves to move QH2 away from Complex I and more likely to encounter a different complex.  If you have a lot of QH2 particles around, they may collide and redirect QH2 back to a Complex I.  Just my guess without knowing the details.

 

"clearly right" I thought you were referring to Spiejers model, not to your protocol/efforts.  I didn't contend against your efforts or results, just the model.

 

 

Edited by capob, 10 February 2021 - 02:49 PM.