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

[Vjha]

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

[RapAdmin]

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

[RapAdmin]

UCLA study links fasting to mitochondrial splitting and mTORC2 Activation (UCLA)

Other studies have suggested that increasing mTORC2 can help improve lifespan… and this suggests perhaps why we don’t want to take high regular (daily) dosing of rapamycin, which eventually starts to suppress mTORC2. Perhaps this new research is also a rationale for periodic fasting for those taking rapamycin - it boosts mTORC2… UCLA researchers found that fasting increases the splitting of mitochondria, which may have implications for metabolic and aging-related diseases. In the study published in June, scientists examined the livers of mice that had been starved and identified the activated proteins, said Nuria Martinez-Lopez, the paper’s first author. They found that proteins in the mTORC2 cellular signaling pathway – known to be related to cell growth and metabolism – were activated by fasting, she added. These proteins increased the splitting of the mitochondria during fasting, which might allow cells to more efficiently burn fatty acids to cope with starvation, said Rajat S…

[RapAdmin]

Acarbose, An mTORC2 Promoter We Should All Take?

I have it in my cupboard and I keep it in my wallet for when I may be eating more starch and I have not taken an SGLT2 inhibitor, but generally don’t like, acarbose. Its gotten good results in terms of lifespan improvement from the NIA ITP studies, but the side effects of excessive gas, and sometimes diarrhea are so common as to make this medication less than desirable for me (your results may differ). But I saw these recent comments to renew my interest in acarbose. Perhaps it might be optimal to take lower doses of acarbose, even if you are already taking SGLT2 inhibitors… Research has shown that higher mTORC2 activation seems to increase lifespan and healthspan: Additionally, it was noted that Acarbose can increase mTORC2 activity: So, perhaps acarbose is something that should be added to our protocols even if we are already taking an SGLT2 inhibitor like canagliflozin or empagliflozin and blood sugar spikes are not an issue at all? Your thoughts?

[EnrQay]

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.

[Neo]

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.

[Neo]

@Neo

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

https://onlinelibrary.wiley.com/doi/10.1111/acel.12786

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

https://onlinelibrary.wiley.com/doi/10.1111/acel.12656

[Neo]

• 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?

[RapAdmin]

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

[Neo]

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).

[Neo]

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.