Calorie Restriction, Okinawa and lifespan conclusions?

Is it possible to draw any conclusions on increase in median and max lifespan regarding calorie restriction and centenarians in Okinawa? “A study on the dietary intake of adults living in Okinawa, a Japanese island having nearly five times higher number of centenarians than any other part of the world, revealed that Okinawan’s consumed 17% fewer calories than the average adult in Japan and 40% less than the average adult in the United States [69, 70].” Emerging Anti-Aging Strategies - Scientific Basis and Efficacy - PubMed

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Yes, being over weight increases your risk of death.

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FWIW…

It is not only calorie restriction, they have a totally different diet than the West. Large amount of sea food, fermented products, etc.
Search and you should locate published papers on Okinawan’s diet.

History and characteristics of Okinawan longevity food

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I’ve read quite a few papers on Okinawans, and other Longevity Blue Zones.

It’s hard to tease out the specific “lifestyle” confounders, but one thing these zones have in common is very low genetic heterogeneity. That is, there has been much less genetic intermixing, and longevity genes are enriched. I think they call it “narrow haplotypes”.

Isn’t it curious how many of these longevity zones are historically remote islands: Okinawa, Sardinia, Crete?? Thus, lending credence to the low intermixing genes theory.

They all do eat a relatively low protein diet, thus reducing IGF-1, mTOR, leucine/methionine (said to be the key longevity amino acids…see L. Fontana work)

There are some towns in Sardinia where almost everyone is a descendant from just a handful of families.

https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.545.7339&rep=rep1&type=pdf

But back to CR, yes, it is one of the most powerful lifespan enhancers in mice. Is it the CR itself, or the protein restriction within CR?

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The limitations of drawing conclusions based on calorie restriction or several other dietary interventions was dealt with in a November 2021 paper by Matt Kaeberlein et al, " Antiaging diets: Separating fact from fiction". Antiaging diets: Separating fact from fiction - PubMed unfortunately only a synopsis is available from NCBI, but if you search the net a bit, you can find most of the important information from the paper.
The factors of genetics, life style, and no out and out dietary blunders (obesity, processed foods, high glycemic carbs, etc.) probably account for a large majority of the experienced longevity. It is difficult to say how much of the longevity experienced is due to caloric restriction by itself.
My own gut feeling is that caloric restriction, by inhibiting mtor, does have a positive effect on longevity (for humans). We don’t know how much effect it has.

Lamming adds another wrinkle into the CR debate.

Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice

“demonstrate that daily prolonged fasting, and not solely reduced caloric intake, is likely responsible for the metabolic and geroprotective benefits of a CR diet”

Does this still leave a residual effect of lower protein AUC signal??

So maybe fasting AND reduced protein as hedge, without full on CR?

Do the bluezone longevity centenarians of TODAY, express the famine (fasting, food intermittency) and low animal protein (rich in leucine/methionine/valine) availability of their earlier livelihood?

Been 5 years on strict ketogenic, OMAD (one meal a day) regiment. So daily 24 hr fasting.

Was considering extended fasts intermixed, but now that I’m only weekly Rapamycin, I “may” be getting some immune/anti-cancer/autophagy/other benefits that are conferred with long fasts, without the possibility of weight/lean muscle loss?

My best guess is primarily enriched longevity genes, combined with some level of CR/fasting/protein restriction explains these blue zone longevity cohorts. You can throw in avoidance of western man made food/processing aids, low pollution living in generally remote islands as well.

I was in Nuoro, Sardinia years ago, and was amazed at the number of very old people “out and about” going on with their daily activities. You just don’t see that as much in the western world.

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I like the conclusion of this paper (emphasis mine):

https://onlinelibrary.wiley.com/doi/10.1111/acel.13626

12 CONCLUSIONS

There are still questions surrounding dietary AAs, metabolism, and longevity that remain unanswered by the current literature, especially in humans. The work discussed above raises new questions about how the amount and quality of protein intake influences health, and suggests that perhaps these dietary recommendations will need to be personalized. For example, as detailed earlier, the elderly may need to consume more BCAAs to prevent muscle loss and stave off frailty, while athletes may need to consume more BCAAs to build and maintain muscle. These protein or BCAA recommendations may be personalized based on one’s circulating amino acid levels and genes, allowing us to find the best diet for each person. Further research into the molecular mechanisms which underlie the benefits of BCAA and protein restriction may allow the development of pharmaceuticals to mimic these dietary interventions.

That conclusion seems to conflict with this new paper

From this new paper (emphasis mine):

High protein diets are indeed indicated for certain clinical conditions or life stages, such as pregnancy and old age, but epidemiological evidence suggests that overconsumption of protein outside of these conditions could be deleterious (Delimaris, 2013).

I would guess it always depends on your worst problem and your best remedy at any given moment. For overweight people, nothing beats the weight loss from CR or some sort of mimicking CR. But for pro athlets, lean and strong, and for older, frail people, nothing beats proteins.

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Caloric restriction does have mtor inhibiting effects but are in fact very different from only mtor inhibition and rapamycin.

Caloric restriction is a state of low overall energy intake, that does multiple things. It boosts repair and maintenance, while lowering expenditure. The effect is very broad.

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I agree. I also think that the mtor inhibition from rapamycin is significantly different from the overall effects of calorie restriction. Much of the world has had diets similar to the longevity diet (low calorie, mostly carb, low protein, and very little to no animal flesh) and one does not observe a slowing of the aging clock in these populations, not the type of slowing that experiments indicate rapamycin may cause…

Its almost impossible to gauge aging in world populations though theres so many factors, but in controlled research environments rapamycin when started early has extended mice total lifespan around 26% at the maximum (kaeberleins study the % extension was the remainder not the total)…

CR has actually extended in mice the total lifespan up to 65% the maximum , so its very hard to rate rapamycin as higher than CR. In truth rapamycin creates a subset of the effects of CR rather than the reverse.

What sticks to me about the people living in the blue zone areas is that they are very concerned about their gut microbe. I think if you look at what they eat of protein/carbs/fat etc. You’re looking at it the wrong way. The more I have read about these places the more puzzled I was, because I could not get the connection, other that they all have high spermidine content in their body. Other people also noticed this and pointed at high amount of mushrooms or cheese consumed etc, and that contributed to their longevity. But if you look at spermidine it is very hard if not impossible to get that high levels in your body by just starting to consume food stuff with high spermidine content or supplements. However if you have a very healthy guy microbe system then they will produce spermidine that comes from synthesizing this food. So my guess is that blue zone areas has a population with an extremely healthy gut system. It is not necessary what they eat or when or how much. It is probably more important to eat food that fuels and keep the gut microbe on steroids. Just my 2 cents

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Microbiome is getting a lot more attention these days - but (and I may have missed it) I have yet to see any mice studies where they manipulate the microbiome and get a longer lifespan. Has anyone seen anything like that?

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I think they did have a study on microbiome transplant in mice, I can not remember where is was. But the result was amazing if I remember correctly. Like really amazing.
ITP did a study on inulin (prebiotic fiber), that was a dud. Maybe they needed probiotic with it, to get a better result?

Yes - it was sad news about the inulin study in the ITP.,

I can find this study - but I’m not sold on “progeria” mice being a great model for normal aging.

This seems relevant, but no lifespan study:

This is looking more interesting:

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Fiber rich foods high in prebiotic such as beans, pumpkin. Its the unrefined fiber that sustains microbiome long term.

The blue zones are only hints of whats important , with the right knowledge 110+ years is the goal way beyond the average of the blue zones.

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Related, in terms of health-promoting activities people can take from “middle age” (prior to rapamycin):

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And an interesting new paper the covers the overlapping area of diet and mTOR (as it relates to cancer):

In this review, we discuss the current status of first-, second-, and third-generation mTOR inhibitors as a cancer therapy in both preclinical and clinical settings, with a particular emphasis on the mechanisms of drug resistance. We focus especially on the emerging role of diet as an important environmental determinant of therapy response, and posit a conceptual framework that links nutrient availability and whole-body metabolic states such as obesity with many of the previously defined processes that drive resistance to mTOR-targeted therapies. Given the role of mTOR as a central integrator of cell metabolism and function, we propose that modulating nutrient inputs through dietary interventions may influence the signaling dynamics of this pathway and compensatory nodes. In doing so, new opportunities for exploiting diet/drug synergies are highlighted that may unlock the therapeutic potential of mTOR inhibitors as a cancer treatment.

Are there any studies that shows what Rapamycin does to the microbiome? it is technically an antibiotic so it should do something. I don’t take Rapamycin yet, but do you feel you have looser or firmer stool after you take your weekly dose? or is there no difference

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