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Rapamycin, OXPHOS, Glycolysis, and CR

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This all started when I found an article about a method that increased the viability of sperm stem cells by culture them in a low oxygen, high glucose medium. This promoted the stem cells to use glycolysis as their energy source instead of mitochondrial oxidative phosphorylation (OXPHOS) for their energy needs.

The article went on to explain that glycolysis produces a lot less ROS than OXYPHO and it prevents a lot of DNA damage.

 

 

“If you’re a stem cell that is going to give rise to sperm essentially through the whole lifetime of an individual, you want to have a pristine genome,” said Oatley. “You don’t want it damaged by reactive oxygen species. That’s why we think glycolysis is important for the stem cell. So we tried to change the culture environment to favor glycolysis.”

"The researchers found they could dramatically improve the percentage of stem cells capable of making normal sperm when put back into the testes. Where before only 5 percent of the cells remained viable after six months, now 40 percent were viable." [link]

So i went on to look if this was just a specific case but it appears that Haematopoietic SCs, Embryonic SCs, pluripotent SCs, and most adult stem-cells, use glycolysis as their main way to create energy. I couldn't figure out if its because of a predominant hypoxic environment or if this is a trait of stem-cells.

When stem-cells go on to differentiate, they go through a metabolic reprogramming and start using the mitonchondrion (OXPHOS).
nihms591572f5.jpg

 

[2]

 

CR is known to cause a shift away from Glycolysis to OXPHOS, so its not clear how this would be beneficial. Could be part of a hormesis response. Its likely that stem-cells do not go through this metabolic shift, only differentiated cells.

I tried look for rapamycin and mTOR inihibition and how it effects stem-cells, and it appears some mTOR activation is beneficial in ESCs:

In ESCs, mTOR is important for self-renewal; (...) inhibition of mTOR impairs the self-renewal of ESCs in vitro.
(...)

In contrast to ESCs, in which mTOR activity is necessary for self-renewal, adult stem cell self-renewal might actually benefit from reduced levels of mTOR signaling, perhaps because adult stem cells are relatively quiescent
(...)
Although maintaining lower TOR activity is beneficial for adult stem cells, a complete loss of mTOR activity is detrimental. Indeed, deletion of Raptor, a key component of the mTORC1 complex, leads to defects in HSC function upon transplantation [1]

But lower mTOR activation is better on the long-run as it prevents stem-cell exhaustion.

The observation that maintaining lower mTOR activity prevents adult stem cell exhaustion is not limited to HSCs. In the mouse epidermis, mTOR activation by chronic Wnt signaling leads to a premature depletion of epidermal stem cells, which manifests itself as premature loss of hair [1]

 

I was thinking of doing a 1-month intake of rapamycin while on CR to further suppress mTOR activity. I don't know now if this is a good idea.
We know that whatever happens here and the shift in metabolism to OXPHOS in cells during starvation will lead to a healthier life, but i can't reconcile this stuff as it appears glycolysis is a lot better to avoid DNA damage as you can see from the sperm cells that reached 40% viability from 5% when using OXPHOS.

 

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575699/

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095859/

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