Longer-term exposure to rapamycin or rapologs (1 week to 1 month) can lead to consequences of mTORC2 inhibition, such as hyperglycemia and hypertriglyceridemia.

“what we've learned about rapamycin since that time is it inhibits two complexes of tor complex one and complex two now today we believe most of the longevity benefits of rapamycin come from the inhibition of complex one not complex ii and furthermore we believe that some of the negative consequences of constitutive use of rapamycin come from its uh inhibition of complex two”

“when you look at some of the more recent human data using wrapalogs such as everolimus they seem to favor an intermittent strategy so dosing rapamycin say weakly which is enough to inhibit if you give a big enough dose it's enough to inhibit complex one but not enough to inhibit complex two”

“it's kind of confusing because there's actually some data both directions that chronic inhibition of mtor complex 1 can lead to activation of mtor complex 2 in some context mostly i think the data supports the idea that chronic inhibition of mtar complex 1 with rapamycin can lead to inhibition of mtor complex 2 in the long term”

“mostly i think the data supports the idea that chronic inhibition of mtar complex 1 with rapamycin can lead to inhibition of mtor complex 2 in the long term um and that's definitely true in mice at higher doses of rapamycin at lower doses of rapamycin it's it's not completely clear to me how how much uh effect on mtor complex 2 there is”

“biochemically rapamycin is an extremely clean drug and that as far as i know and i haven't really seen any good data otherwise there's no direct inhibitory effect of rapamycin on anything other than mtor complex one what people have observed is that chronic long-term inhibition of mtor complex 1 can have feedback effects on mtor complex 2”

“if you took it all the time you're suppressing mtor complex 2 and mtor complex one”

“if you took it all the time you're suppressing mtor complex 2 and mtor complex 1.”

“they're kind of like you can think of them as knobs right and so what David said about you need a lot of M torque 1 activity to survive and and the same thing is probably true for M torque 1 but rapy is kind of turning down M torque one immediately a lot and that's going to depend on the dose of rapamycin that we give and then over time turning down the M torque 2 knot but it's not going to zero.”

“sure so so you know I think you know Matt answered your question perfectly well and I think it shows you the complexity of the issue right it's not only M torque 1 versus mtor 2 which which cell type right is it is it muscle fibers is it inflammatory cells immune cells at what dose is it which process autophagy is it protein synthesis so these are very complicated questions Now on to your question Peter certainly if you dose it high enough in our experience you will inhibit MTR 1 in all tissues that we've looked at it takes a little bit of time if you're talking about classic Romy to get in the brain you typically need to do a little bit of a loading dose but you'll get it into the brain”

“rapy partially inhibits mtor 1 and over time can also partially inhibit mtor 2 so they're very dramatically different how they act”

“the way that we're preventing mtor to formation and therefore mtor to inhibition is dramat is completely different how that impacts mtor 1 it's basically preventing the biogenesis the formation of mtor 2”