3 ms·

If this is correct then the converse should also be true; by sticking to glucose metabolism and avoiding ketosis you should prevent cellular ageing?

derefr 3y ago
Maybe in theory, but that doesn't seem to be true in practice. There are two related but distinct kinds of glucose metabolism: 1. a buffered glucose metabolism, where the cell stores glucose as glycogen and then can burn the glycogen at will later on; and 2. an unbuffered glucose metabolism, where the cell passes (phosphorylated) glucose molecules directly into the nucleus to catalyze the one of the rate-limiting steps of the Krebs cycle. Note how this actually forms three (or maybe four) distinct sub-modes that a cell still has to switch between — buffering glucose into glycogen; consuming buffered glycogen; consuming glucose directly; and rejecting glucose altogether (if it has both too much ATP and too much glycogen.) For a cell to not need to switch between these glucose-metabolic modes, the intercellular matrix would have to contain a perfect level of glucose at all times — and every cell would have to always need exactly the same amount of energy at all times (which would make things like mitosis impossible.) Even animals that subsist entirely on glucose, and don't really convert glucose into fat (e.g. hummingbirds) go "long" (in intracellular terms) periods between eating, such that muscle cells still need to keep glycogen buffers to do their jobs as the blood depletes in glucose. Also, specifically re: unbuffered glucose metabolism, note that "unbuffered" here really is "unbuffered" — the cell only has a boolean "open/close the direct path for phosphorylated glucose to enter the nucleus" mode-switch it can flip. Not a knob it can turn to vary the speed at which the phosphorylated glucose is passed into the cell; nor a knob to control the phosphorylization rate; nor a knob to control the number of open glucose pores. As long as the full "unbuffered" path is open, the nuclear Krebs-cycle reaction cranks as fast as glucose can enter (and be phosphorylated by) the cell. So if — or rather, when — a cell gets too much ATP from this process, it's going to respond by doing a mode-switch out of direct glucose metabolism; either over to glycogen-buffering metabolism, or to the "transition mode" that shunts around ions to cause all the cell-membrane glucose pores to squeeze shut. Interestingly, we have invented substances you can put in your body that prevent this mode-switch out of direct glucose metabolism, e.g. 2,4-Dinitrophenol. Some people consider these substances to be "diet drugs." But I hope you can see why they're very bad for you — without the cell able to say "I have enough ATP, I don't need any more glucose, let's buffer it / stop phosphorylating it / stop letting it in", you just get an indefinite runaway Krebs cycle loop spitting out all the ATP it can make, flooding the cell with it; where most cellular organelles in turn perform their function every time they get enough ATP to be able to do so, so suddenly the whole cell is just Sorceror's Apprentice-ing along — overheating itself, depleting itself of other stored chemicals, building up wastes too fast to excrete them, and doing other minor mode-switches as fast as they can happen, such that the nuclear DNA will burn away its telomeres (and introduce copying errors) at record speed.
- elevaet 3y ago
  Thank you for the picture there, that was very interesting. My one doubt about all this is if mode-switching really does burn telomeres. Is there any actual evidence of this? I find it hard to imagine that somewhere along the course of evolution we didn't adapt a less destructive way to manage switching metabolic modes. > 2,4-Dinitrophenol Wow that stuff sounds extremely dangerous.

derefr 3y ago

Maybe in theory, but that doesn't seem to be true in practice. There are two related but distinct kinds of glucose metabolism: 1. a buffered glucose metabolism, where the cell stores glucose as glycogen and then can burn the glycogen at will later on; and 2. an unbuffered glucose metabolism, where the cell passes (phosphorylated) glucose molecules directly into the nucleus to catalyze the one of the rate-limiting steps of the Krebs cycle. Note how this actually forms three (or maybe four) distinct sub-modes that a cell still has to switch between — buffering glucose into glycogen; consuming buffered glycogen; consuming glucose directly; and rejecting glucose altogether (if it has both too much ATP and too much glycogen.) For a cell to not need to switch between these glucose-metabolic modes, the intercellular matrix would have to contain a perfect level of glucose at all times — and every cell would have to always need exactly the same amount of energy at all times (which would make things like mitosis impossible.) Even animals that subsist entirely on glucose, and don't really convert glucose into fat (e.g. hummingbirds) go "long" (in intracellular terms) periods between eating, such that muscle cells still need to keep glycogen buffers to do their jobs as the blood depletes in glucose. Also, specifically re: unbuffered glucose metabolism, note that "unbuffered" here really is "unbuffered" — the cell only has a boolean "open/close the direct path for phosphorylated glucose to enter the nucleus" mode-switch it can flip. Not a knob it can turn to vary the speed at which the phosphorylated glucose is passed into the cell; nor a knob to control the phosphorylization rate; nor a knob to control the number of open glucose pores. As long as the full "unbuffered" path is open, the nuclear Krebs-cycle reaction cranks as fast as glucose can enter (and be phosphorylated by) the cell. So if — or rather, when — a cell gets too much ATP from this process, it's going to respond by doing a mode-switch out of direct glucose metabolism; either over to glycogen-buffering metabolism, or to the "transition mode" that shunts around ions to cause all the cell-membrane glucose pores to squeeze shut. Interestingly, we have invented substances you can put in your body that prevent this mode-switch out of direct glucose metabolism, e.g. 2,4-Dinitrophenol. Some people consider these substances to be "diet drugs." But I hope you can see why they're very bad for you — without the cell able to say "I have enough ATP, I don't need any more glucose, let's buffer it / stop phosphorylating it / stop letting it in", you just get an indefinite runaway Krebs cycle loop spitting out all the ATP it can make, flooding the cell with it; where most cellular organelles in turn perform their function every time they get enough ATP to be able to do so, so suddenly the whole cell is just Sorceror's Apprentice-ing along — overheating itself, depleting itself of other stored chemicals, building up wastes too fast to excrete them, and doing other minor mode-switches as fast as they can happen, such that the nuclear DNA will burn away its telomeres (and introduce copying errors) at record speed.

elevaet 3y ago
Thank you for the picture there, that was very interesting. My one doubt about all this is if mode-switching really does burn telomeres. Is there any actual evidence of this? I find it hard to imagine that somewhere along the course of evolution we didn't adapt a less destructive way to manage switching metabolic modes. > 2,4-Dinitrophenol Wow that stuff sounds extremely dangerous.