http://www.sciencedaily.com/release...50528124202.htm



Real leap from mice to humans. Bit of an assumption here about carbohydrate/protein ratio as well--no mention of the fat content of the diet, presumably that's kept constant. All that can really be said is that if you keep the fat and non-protein and digestible carbohydrate nutrients constant, swapping protein for carbohydrate in these animals has this effect.

When I've gone looking for calorie restriction studies, methionine restriction studies etc., I've found that usually the diet includes fair amounts of sugar. I went looking for this a few years back when two monkey studies were done. One resulted in extended lifespan (with some complications, there was an increase in mortality related to infection, this wasn't included as age-related mortality), and the other didn't, the study with the extended lifespan with restriction included sugar in the diet, the other did not.


If you want to improve the metabolic profile of an animal by reducing calories, it's good to load the deck by designing a diet that will cause a poor metabolic profile if eaten to appetite. This observation is made from another angle by defenders of fructose--people will say that sugar and high fructose are only dangerous if people are consuming too many calories. Why not eat a diet that you won't want to overconsume in the first place? And one where the damage will be minimal if you do overeat? Alcohol is also not damaging unless you overconsume it. But there are sure as heck lots of people who ought to avoid it entirely.

Although this is a pro-high carb article, I think it also illustrates the point--calorie restriction is beneficial because it limits a diet that's harmful when fed ad-lib.



And this is not true. It's only true that with a certain nutrient profile, in a homogenous chow-style diet, reducing food intake does these things.

Hmmmm. Were these mice metabolically impaired to begin with? Seems to me that weight management for obesity pertains entirely to people who have a tendency to grow obese, many of whom have a problem with insulin-related fat storage. This certainly isn't everyone.

Cutting calories is a fine weight-loss strategy for many. Problem is, it's very hard to sustain. Mice (and other experimental mammals) never have a chance to voice their opinions about these dietary strategies that they try out for us humans. Bet they'd complain plenty if they could!

Probably. When researchers do nutrient self-selection studies, letting animals choose their own macronutrient ratios, it never matches the standard crap-in-a-bag that's sometimes mistaken for a mouse's "natural" diet--that diet is very low in fat, most animals like fat.

There's so much to consider. This study says, raise the carbs, lower the protein. It depends where you start. Say you feed these animals 8 percent protein vs 15, and they do better. Blood glucose and insulin are lower. But take the same animals, cut carbs to 15 percent, protein 40, fill in with fat--and maybe that's an improvement again. There's also the question of omega 6. At 8 percent omega 6, a high-fat, high sugar diet is fattening and diabetes-promoting for mice. At 1 percent, it's not. Saturated fat is disease promoting, at least in the breeds of mice used in the studies, but only if the omega 6 pulls the trigger.

Dr. Seyfried talks about mice overeating ketogenic diets to the point of being hyperglycemic, I wonder how much omega 6 the diets contained? That diet was 5 percent protein, so it's possible the animals overate simply because that's what they had to do to meet their protein requirement, though.

From the study:

Regardless what I think about rodent studies, the common macro that keeps reappearing in other, similar studies is the question about the role protein plays. While protein is essential, I'm curious to learn more about optimizing my protein intake, as there have been some conclusions that IF is effective due to the restriction of protein during the fasting period. As IF purportedly results in longer life span, is it the protein restriction that is influencing this outcome? I'm wondering how much of a role carb or calorie restriction plays in this dynamic. Carbs seem to be always included in studies due to the major role they play in today's diet, but they are not an essential macro for people. And for those with metabolic syndrome/ insulin resistance, carbs tend to wreak metabolic havoc. We know, and it's mentioned in the study summary, that calorie restriction does not favor long-term adherence. So, regardless of the results of a LPHC study, what is the governing factor related to the outcome? This is the question that I'd like to see addressed.

I sort of doubt that there's "an" optimal protein intake, it all depends. There's so much play between the different nutrients.

Campbell would probably point at Seyfried's mice and say that the reason they didn't get cancer wasn't the glucose necessarily so much as the protein restriction. There have been studies where exogenous ketones had a similar effect to the ketogenic diet on cancer, though.

I've seen at least one study where rodents were given diets with protein pretty high, where cancer was inhibited.



I'm not sure that calorie restriction doesn't just reverse the life-shortening effects of a poor diet eaten ad-libitum, though.

http://www.sciencedaily.com/release...10614115037.htm



So one study says protein bad, another says good, if it's replacing carbohydrate--less glucose.

All that blather about protein foods increasing insulin as much as or worse than carbohydrate, after the insulin index study was done. It's something to consider, but I've never seen a study where carbs were replaced gram for gram with protein and insulin went up. Maybe it would happen, short term, with fructose.

It's possible protein and carbohydrate are both rate-limiting--as long as one or the other is brought low enough, certain cancers could be inhibited.

There are studies where branched chain amino acids are added to high fat chow, and the animals develop fattier livers and higher blood glucose. Amino acids are involved in various ways in recycycling of carbon from the breakdown of glucose back into glucose again, so it's possible that even at an increased carbohydrate intake, if protein intake is below a certain threshhold and the stars are all in alignment, certain aspects of carbohydrate metabolism are still decreased, providing protection from cancer. The more that glycolysis results in glucose carbon being ultimately disposed of through mitochondrial respiration, the less glucose will be available for the fermentative metabolism that feeds some cancer.

http://cancerres.aacrjournals.org/c...71/13/4484.full



Beyond the cancer thing--this study throws into question the idea that lower protein necessarily means longer life span as well.

That's one of my points, that there are variables depending on many things including the relative amounts of macronutrients, the condition of the test subjects, and the quality of the diet. It goes to reason that if periods of fasting rather than calorie reduction favors a longer lifespan, it may also trump diet quality in this case. So, I'm wondering if fasting in healthy individuals, meaning the absence of protein for a period of time, helps regardless of protein quantity consumed during eating periods. Certainly, the cancer conclusions make sense in this case, since severely limiting carbohydrates as a glucose source inhibits the cellular fermentation process on which cancer depends. I am more curious whether there is a way to consume protein to create the optimal metabolic condition in individuals without cancer, if that makes sense. Is protein restriction during a fast a key in this or just one of the variables that needs to be considered in relative context with the others?

I don't doubt it. The A-TO-Z study shows protein intake gradually went up and down across diets to match all diets in the end at around 20% total calories. All species are adapted to their own diet, and each of those diets contain a corresponding fixed protein ratio. Protein intake may be different across species, but not across individuals within the same species, unless manipulated by humans in experiments or by nature in starvation, but not by nature in abundance. If we assume the measures of health are accurate for these mice, then whatever protein intake produces the best measures of health must be optimal for this species. Rather, whatever protein intake we find to be best for these mice must reflect protein intake when they eat a diet of genuine food. Conversely, a diet of genuine food contains X amount of protein, and this in turn should determine the optimal protein intake for any diet for this species, genuine food or not.

Something very pertinent about that constant 20% protein intake across diets in the A-TO-Z study. It means the very idea of testing various protein intakes makes no sense. Diets didn't do better or worse because of protein, but because of the other two macros. Manipulating protein intake is like trying to starve or overfeed, then compensate, not to find out what happens when starving or overfeeding, but when compensating for either. Thus, in this mouse experiment, the extra carbs compensate for the lower protein. Compensation in this case implies sub-optimal. I expect extra fat instead of extra carbs will compensate too, and likely produce even better results. After all, that's exactly what happens in humans.

OK, but with zero protein, tagged glucose lights up tumors, indicating increased glucose metabolism in these tumors. Maybe protein would protect here, not in a lower protein kinda way, but in a more protein kinda way, at least more than zero. Is it because of the protein itself, some amino acid doing stuff somewhere? Doubt it. Protein doesn't protect against cancer specifically, but it does protect (corrected typo) against death, if we consider Campbell's experiment with mice/casein/aflatoxin. Incidentally, this also tells us more protein is better than less protein, regardless of health status. Anyway, I think it's got something to do with the difference in insulin response between carbs and protein. The more protein the less carbs, the lower the insulin response. Tumors don't grow just cuz we feed them glucose, they grow cuz of insulin. With zero insulin, tumors don't grow at all. Less insulin is better than more insulin. If that's how it all works, why go with carbs+protein in the first place when we can just cut out all the carbs and go with fat+protein instead?

But then you have to ask, what is the increase in glucose metabolism driving, in the tumour cell? Maybe an increase in protein synthesis, supporting cell growth?

And, before going into an aside--we're not really talking restricted protein there. There's a difference between zero protein as in "I've just fasted overnight, and then taken some tagged glucose," and the various changes in gene expression, up and down regulation of protein breakdown and synthesis enzymes, competition from healthy tissue for amino acids, etc. that would occur with an ongoing relative scarcity of dietary protein. The question there is--take two subjects, one at this ongoing level of protein intake, one with that ongoing level of protein intake--what will this difference in habitual intake do to the uptake of glucose by the cancer cells (indeed if it has an effect at all), what will it do to ongoing glucose metabolism?

At any rate, a high protein diet can increase tumour growth, decrease it, and everywhere inbetween, depending on the conditions going in. We might be starting to know what those conditions are for mice and rats, but not for humans.

Bit of a crap shoot. And you're right, it's not worth risking possible dangers of protein deficiency, unless you know for sure that it has a high probability of fighting the cancer.

I have an idea about optimal protein intake. Let's say we don't know how much protein is optimal. The A-TO-Z study says all diets matched protein intake by the end at 20% total calories. We could argue that's indication of optimal intake by some internal demand for it or some such. But then we have to explain this internal mechanism, it gets complicated real quick. Instead, we call this protein intake sub-optimal, cuz we don't know, and there's many more numbers which are just as good and could be seen as optimal too. So now we call the other two macros compensators for this sub-optimal protein intake. We fool around with them up and down, keep total kcals and protein constant, then find out which of the other two macros compensates best for this sub-optimal protein intake. In that mouse study, they didn't do that, they only fooled around with protein and carbs. It could not tell us the complete picture about any macro.

True. If there were only two macros, it would be a little easier. Throw in fat, and there's all sorts of interactions that might be going on.

I was looking at a study that sort of approaches the idea of finding the optimum ratios in mice yesterday. Peter at Hyperlipid posted on it a few years back.


http://www.cell.com/cell-metabolism...Fshowall%3Dtrue



This one's kind of involved. 25 diets fed, different ratios of protein, fat and carbohydrate.




And this. Suppose you give a rodent a high-fat diet--but don't want it to overeat due to protein leverage. So, you raise the protein level of the diet--by definition, you're decreasing the carbohydrate content. If protein and carbohydrate are separately limiting factors for food consumption in these animals--that is, if protein is above a certain level, or carbohydrate is above a certain level--and in the original diet, carbohydrate rather than protein was what was limiting consumption (protein was below the level that it would have triggered satiety--the animal might then eat more, until one of the appetite controlling nutrients finally satisfied.

The idea that fat is neutral to satiety is of course hogwash. Something about how the animals are exposed to the fat--the pelleted rat chow form--or the type of fat, maybe linoleic acid being driven up beyond a certain level, has to be at work. Perhaps the animals were weaned on to a low fat chow, and simply never learned during development to be satiated by fat. I mean learned here in both a literal, neural sense and in a more figurative metabolic systems sense.

Human lifespan is nowhere near so malleable as that of a mouse. A mouse can slow its metabolism down to ten percent... they just have more metabolic flexibility than we do.

Supplement S2 is worth checking out. The highest median lifespan is in the group of mice that ate the most protein. (Strike that, make that the second highest protein). Also the fifth highest maximum lifespan. Sure, a mouse eating some of the diets with a lower protein to carbohydrate might have lived longer--but it's a lottery ticket. You have to ask yourself--do I feel lucky? Most mice would have lived

The second longest living mouse was in the 75 percent fat group. Again, it was a lottery ticket. Eventually, as mice die off one by one, you end up with the George Burns type mice, telling the others that the secret to their longevity is that when they started, smoking was good for you.

The kicker here for me is the fiber. Calorie density of the diets was altered by adding insoluble fiber. Pretty much without exception, the lowest maximum and median lifespans were in the animals fed the most fiber.

Which of course suggests that whether a particular blend of protein, carbohydrate and fat is deadly or helpful to a mouse depends on something as silly as fiber. We have to assume then that less silly things, like choline, various vitamins, minerals, etc. affect it as well.

This is the problem with chow. It's a very specific food stuff. Maybe you'd get better information feeding animals a more varied diet--but at a specific macronutrient ratio, all the same. Real food even.

Let's invent an ideal Human Chow. We could call it, um, I know! Soylent Green! Yeah. Catchy.