Another point, what exactly triggers mTOR mediated autophagy? Could the primary mTOR induction be a decrease of intracellular calcium?
Verapamil and lithium seem to be some of the most effective agents currently known. They both affect calcium homeostasis (verapamil decreases intracellular calcium, with lithium it seems more complicated, but it could ultimately release calcium from the cell too).
And indeed, I just found a confirmation: Testosterone Activates mTOR/S6K1 Pathway Through Intracellular Calcium and ERK in Cardiomyocytes
So, might one of the primary reason why autophagy is reduced in age be an increase in intracellular calcium? Might be interesting to find out, an obvious experiment could consist of inducing a reduction in accumulated intracellular calcium in aged animals and seeing whether autophagy activation is stronger after that.
Apparently
calcium actually activates macroautophagy. Also, calpain, calcium-dependent cysteine protease, is one of the controllers that modulate if a signal causes autophagy or apoptosis. In this case,
calpain stops apoptosis and activates autophagy (what we want). So, calcium is very important for activating autophagy and preventing apoptosis through this effector.
Now, the interesting thing about calcium is that the signal it confers to the cell is dependent on its concentration. Low levels, medium levels, and high levels of calcium all mean different things to a cell.
Very high levels of calcium influx to the mitochondria (as activated by certain signals) activates the mitochondrial transition pore, loss of mitochondrial coupling of proton motive force to ATP production, and massive increases in ROS production, which then signal and start apoptosis. Too low levels of calcium lead to cellular and mitochondrial metabolism dysfunction (seen in fasting mice by knocking out UCP3; which has been recently discovered to be
the ruthenium red sensitive mitochondrial calcium uniporter, and not likely a direct uncoupler like UCP1). Medium levels of calcium (gained by a high calcium diet ironically) on the other hand stimulate ATP production and dehydrogenase activity,
leading to obesity resistance and such, possibly through UCP3.
Add to this that old age is also marked by decreasing calcium content in the bones, and it seems the opposite is more likely: that the reason autophagy is reduced in old age is because of decreasing intracellular/intramitochondrial calcium levels.
The experiment you propose though should be easy and immediately answer this issue. Let's hope someone decides to do it just to see (if there isn't research I'm just not finding on it already).
Edited by geddarkstorm, 06 March 2009 - 02:22 AM.