Is there a way to selectively upregulate Mtor2 while on Rapamycin?

Has anyone explored the idea of getting an “insurance policy” against overdosing of Rapamycin; by upregulating Mtor2 through medication or supplements?


The two things I am aware of are fasting and acarbose. There may be others…


I take acarbose 25mg once per day even if it is with a low-carb meal, just for its other effects: I didn’t know about the mTORC2 effect but knew if it positive effects on the gut biota and lifespan.


And 17α estradiol

Joan Mannick & Dudley Lamming recent paper says:

the lifespan of male mice is extended by acarbose and 17α estradiol, and these compounds increased hepatic mTORC2 activity[118]. mTORC2 activity is also elevated in long-lived Snell dwarf mice and Ghr−/− mice119. Inhibition of mTORC2 also results in negative effects on metabolism and immunity

Targeting the biology of aging with mTOR inhibitors | Nature Aging.


But then that paper says

We have previously observed that male-specific increases in glucose tolerance and hepatic mTORC2 signaling with 17aE2 treatment are inhibited in males that are castrated in adulthood, prior to treatment onset (Garratt et al., 2017)

And it seems like it is the Garratt / Miller paper above that actually looked at that:

Sex differences in lifespan extension with acarbose and 17-α estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling

  • That fasting lowers mTorc1 makes sense, but does anyone have a sense whether acarbose and 17aE2 are neutral on (or decrease) mTorc1?
    (So it’s not that they help us with mTorc2 but offsets rapa’s mTorc1 lowering benefits…)

  • Btw, do we know the direction of SGLT2i on mTorc2 - does that go in the same direction as rapa, making a strategy to increase mTorc2 even more important for someone on Rapa and Cana or other SGLT2i?


This paper may have some information Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation

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Nice, thx, haven’t looked at it deeply by they say:

mTOR forms two complexes, mTORC1 and mTORC2. Data from our lab have suggested that mTORC1 is diminished by each of these three drugs, whether treatment is started at 6 or at 22 months of age).


Although the same section continues

Our lab has also found that Rapa, ACA and 17aE2 treatments can enhance mTORC2 signaling in liver [11], but the implication of this mTORC2 effect for the aging process is not understood.

Which seems to go against the experience of rapa decreasing mTORC2 while the other two increase it?

The below is also interesting

The data showing similar effects of Rapa, ACA and 17aE2 on mTORC1 and its downstream targets - including stimulation of CIT- [8], suggested other common pathways, such as pathways mediated by AMPK[[24(Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation | Immunity & Ageing | Full Text)] or MAPK pathways [25], might be affected by these agents.