The following study shows that NK cells “significantly limit reprogramming”:
That made me think of rapamycin and its immunosuppression function. And indeed, this other study shows that “Rapamycin … Alters Natural Killer Cell Function”:
Or am I just way over my head?
When I do my monthly 5-day fast-mimicking diets, one goal is to help regenerate the pancreas a bit. During the fast, insulin-producing beta cells start to de-differentiate, and then they re-differentiate and proliferate after the fast (see Longo’s work). Can rapamycin help this partial reprogramming along during the fast? If so, I want its mTOR-inhibiting effects to be gone at the fasts’ end so that regeneration and growth can take place.
Browsing Longo’s work I find no mention of an adverse effect of NK cells on this kind of reprogramming, and thus I see no potential benefit of using Rapamycin (in immunosuppressive doses) for this purpose.
EnrQay, do you buy the Prolon boxes or do you have your own protocol? I originally did several cycles with Prolon but found the foods less than palatable (BUT I also had really good results). The more I tried replacing the Prolon with my own “do-it-yourself Prolon” with much better tasting food (Amy’s Organic soups, for instance), it seemed like the worse results I got (lost more muscle mass than fat, felt terrible, didn’t seem to get into ketosis, etc).
I did try Prolon once, but it was too processed and too high carb for me. The point of the diet is to restrict calories and protein while getting you into ketosis; at the same time, they wanted to make the food palatable to most people by having the carbs higher than I am used to. The exact macronutrient ratios used are not as important as these goals. So I always make my own meals, reducing the carbs and replacing them with fat. I get the calories and protein very close to the prescribed amounts.
I’ve had no problems with muscle loss over the years of doing this. I lose a couple of pounds of fat and 3-4 pounds of water/intestinal-content weight during the fast, but that is quickly regained. I think some days are difficult on any fast, and it can affect my energy level and sleep on some days, usually days 2 or 3 of the five days.
@ EnrQay
Re ketones, have you actually tracked your ketone levels during an extended fasting session, Prolon or other? Curious how high a level you typically get to?
Ketone production is a metabolic byproduct of fasting, but is it the ketone “signalling” per se, or the other pathways Longo is suggesting (autophagy, AMPK, IGF-1, mTOR), ergo, the classic pathways of full on CR, that are the root benefits?
There is a large database of ketones being signalling/anti-aging metabolites on their own (outside this forum).
With my ketogenic diet/single meal per day, I’m in mild ketosis all day until my single meal, getting to 1.5-2 mmol/L at 23 hr mark. I’m sure I’m triggering some of these pathways, but to what degree.
Btw, I know you’re trying to improve your pancreatic beta-cell function with these extended fasts/hormetic stressors, any progress?
During my normal diet, my ketones are between 0.5-1.5 mmol, while toward the end of the fasts they are 1.5-3.0 mmol. I have no idea which of the pathways are most influential on tissue and immune regeneration, but I’m guess it is not ketones since I’m almost always in ketosis. Ketones can modulate the immune system for the good, but I don’t think they are involved in the autophagic and apoptoic pruning of the immune system that you have in fasting.
Yes, I think the fasts have been good for my beta cells. First, there is no progression of my diabetes over its 5.5 years, and I am using slightly less insulin with more stable blood sugars than I was a couple of years ago. I’ve always maintained a good A1c=5.3 after getting down from my initial terrible 10.5. I’m hopeful of further improvements with continued fasts and rapamycin.
Fresh off the press: Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1 (Science Signaling, 2025). Further evidence that rapamycin negatively impacts NK cell function. The good news is that ex vivo NK cell expansion+reinfusion is already an active clinical program. I spot an opportunity for Brian Johnson to restart rapamycin in combination with NK therapy. C’mon Brian, do it for the plot.
The multiprotein complex mTORC1 is essential for the increase in protein synthesis and bioenergetic metabolism that supports the proliferation of many cell types, including natural killer (NK) cells, which are important innate effectors of the antitumoral response. Here, we investigated the mechanisms of mTORC1 activation in NK cells by interleukin-15 (IL-15) and IL-18, which promote NK cell function and are components of a cytokine cocktail used to preactivate NK cells for cancer immunotherapy. Through genetic and pharmacological approaches, we showed that IL-15 activated mTORC1 through the PI3K/Akt/ERK pathway, whereas IL-18 signaled through the p38 effectors MK2 and MK3 in both murine and human primary NK cells. Both pathways synergized to promote NK cell proliferation and effector functions in an mTORC1-dependent manner. Moreover, both pathways operated independently of the inhibitor TSC and the activator Rheb, revealing a noncanonical mode of mTORC1 activation by cytokines. Treating mice with IL-15 and IL-18 in combination led to increased NK cell numbers and improved antitumoral activity, suggesting that this cytokine combination could be exploited to enhance NK cell potential in therapeutic settings.
Treatment with the mTORC1 inhibitor rapamycin prevented the increase in NK cell frequency in mice treated with IL-15cplx and IL-18, indicating that NK cell accumulation in response to these cytokines is mTORC1 dependent (fig. S4, A and B). However, rapamycin did not affect IFN-γ production in these mice, thus confirming our in vitro results (fig. S4C).