#1

The aging process contributes significantly to the onset of chronic diseases, which are the primary causes of global mortality, morbidity, and healthcare costs. Numerous studies have shown that the removal of senescent cells from tissues extends lifespan and reduces the occurrence of age-related diseases. Consequently, there is growing momentum in the development of drugs targeting these cells. Among them, mTOR and SGLT-2 inhibitors have garnered attention due to their diverse effects: mTOR inhibitors regulate cellular growth, metabolism, and immune responses, while SGLT-2 inhibitors regulate glucose reabsorption in the kidneys, resulting in various beneficial metabolic effects. Importantly, these drugs may act synergistically by influencing senescence processes and pathways. Although direct studies on the combined effects of mTOR inhibition and SGLT-2 inhibition on age-related processes are limited, this review aims to highlight the potential synergistic benefits of these drugs in targeting senescence.

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#2

I love this. I am currently taking high dose Rapamycin (17-18 mg equivalent weekly) and 12.5 mg Empagliflozin daily. I feel great, but more dehydrated than usual. So, I need to drink a lot more water. Not sure if it’s the Empagliflozin or the ungodly heat here in Hong Kong. Anyone else on an SGLT2I notice they need to drink more?

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#3

I’m not as yet, but intend to , starting in November - my plan sounds like what you are dosing, I’ll be buying the 25mg empag, and spiltting the pill in two, so 12.5mg/day to begin with; if it doesn’t bring down my sugar enough - so that I’m no longer prediabetic - I’ll consider moving to 25mg/day, although it is my understanding that you get 90% of the sugar out at the 10mg dose, and don’t gain much more at the 25mg dose.

As to being dehydrated, I imagine it makes sense - If you are peeing out sugar, you need fluids to replenish… that’s how diabetes works, you pee a lot, but are constantly thirsty as you are peeing out sugar. I don’t know as yet, I guess I’ll find out soon when I start taking empa myself :sweat_smile:!

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#4

Lifespan IO covers this paper:

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#5

Thanks, RapAdmin, that’s an interesting article. I found this notable:

“SGLT-2 inhibition’s anti-inflammatory properties are also useful in reducing the factors involved in chronic, age-related inflammation (inflammaging). The expression of some of those pro-inflammatory factors is regulated through SGLT-2 inhibitors and proteins in the mTOR network, and lowering mTOR activity can reduce their expression [5, 6]. However, the authors also mention that some research shows that using the mTOR inhibitor rapamycin doesn’t impact chronic inflammation, but it reduces cellular senescence markers [7]. Future work is needed to better reconcile those two observations.”

If rapamycin doesn’t affect chronic inflammation (FWIW, Matt Kaeberlein thinks the opposite, that one of rapamycin’s primary modes of operation is through tamping down of systemic inflammation, a view he expressed many times, among others to Peter Attia on his podcast), then using some other agents to suppress chronic inflammation seems like a good idea, even if you already are on rapamycin. It seems it would be additive - as long as there isn’t some bad interaction between that agent and rapamycin. So if SGLT2i do the job, perhaps indeed there can be synergy along that axis.

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#6

Other big reducers of inflammation are Bempedoic Acid and statins. It seems that we are approaching a synergistic nexus of Rapamycin + SGLT2I + Glucose control + Lipid reduction for longevity.

And that’s great because I’m using all of the above. :wink:

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#7

Yes on statins. In particular it seems pitavastatin lowers hsCRP the most of statins. Whether that is a clear indication of overall lower inflammation I don’t know, but I do hope it works, as I’m switching from atorvastatin 10mg/day to pitavastatin 4mg/day :sweat_smile:. And I didn’t realize bempedoic acid was anti-infammatory, glad to learn something new!

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