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Feeding stem cells: the strange case of dietary restriction and alpha lipoic acid

alpha lipoic acid c60 stem cells antioxidants healthspan lifespan

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#1 QuestforLife

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Posted 19 February 2020 - 12:50 PM


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.

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#2 kurt9

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Posted 19 February 2020 - 11:12 PM

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


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#3 QuestforLife

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Posted 22 February 2020 - 09:30 AM

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.
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#4 QuestforLife

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Posted 24 February 2020 - 09:28 AM

This is the survival curve:

 

acel13110-fig-0001-m.jpg

 

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

 

acel13110-fig-0005-m.jpg

 

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


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#5 Nate-2004

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Posted 26 February 2020 - 05:40 PM

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.



#6 Blu

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Posted 26 February 2020 - 06:05 PM

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.


#7 QuestforLife

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Posted 26 February 2020 - 06:06 PM

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.


#8 QuestforLife

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Posted 08 August 2020 - 12:13 PM

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.

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#9 QuestforLife

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Posted 29 September 2020 - 07:03 AM

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.


#10 QuestforLife

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Posted 29 September 2020 - 02:32 PM

This is the survival curve:

acel13110-fig-0001-m.jpg



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.






Also tagged with one or more of these keywords: alpha lipoic acid, c60, stem cells, antioxidants, healthspan, lifespan

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