EatQOD

Caloric restriction and longevity:

OK, here's one hypothesis. Maybe others have advanced this, I don't know.

We are like camels. Camels store water in a hump on their backs. Humans store energy in glycogen in liver and muscle. The glycogen stores are the first place the body looks when it needs energy. When glycogen store are full, there is no need to engage in lipolysis or gluconeogenesis, since the body can get all of the 3- and 6-carbon chains it wants from glycogen via glucose.

Why full glycogen stores promote obesity and inhibit fat loss:
Because we eat constantly, and overeat, our glycogen stores tend to be always full. Transiently, people often eat more calories than they can promptly dispose of, whether they are lean, malnourished, or obese. When the glycogen storage hump is empty or only partially full, excess caloric intake goes to glycogen. However, if people consume a load of excess calories transiently when their glycogen storage hump is full, the excess has no place to go except fat.

During periods of transient fasting, the opposite occurs. If glycogen stores are always full, we just use up some glycogen, but fat stores are never mobilized. For fat stores to go down, glycogen stores first have to be depleted. So even if we have equal transient periods of caloric excess and caloric deficiency superimposed on a time-averaged caloric intake that meets body needs, in the setting of full glycogen stores, the net result will still be weight gain, even when time-averaged caloric intake is neutral. We can't neglect the phasic nature of caloric intake. This may be part of the mystery of apparently equal caloric intakes resulting in weight gain or no weight gain in people.

What glycogen stores have to do with insulin sensitivity
Someone may have to help me here. We know from basic biochemistry that whenever a series of enzymes are not used, their transcription factors go down. Now think of it - our body has evolved tremendous mechanisms to maintain energy in the absence of glycogen stores, including gluconeogenesis, but with full glycogen stores, these are rarely called upon, except, perhaps, after an overnight fast. So enzymes involved in depleting and building glycogen should be increased in abundance, as would enzymes involved in lipogenesis. Lipolytic enzymes, and enzymes involved in gluconeogenesis should all be reduced, since they are rarely called upon. Why this should give rise to insulin resistance.

- one explanation is by Johan Koeslag from South Africa:
http://academic.sun.ac.za/medphys/insulinresistance.htm
"A muscle cell that is full of glycogen or an adipose tissue cell that is full of fat will also down regulate its insulin receptors, thus becoming resistant or unresponsive to insulin's presence in the blood. Conversely cells whose glycogen or fat stores have been depleted by starvation or exercise return the insulin receptors to their surfaces. This makes them hypersensitive to the presence of insulin in the blood. "

How glycogen storage status might impact on longevity factors
But Sirtuin is intimately involved with gluconeogenesis.

Yeast Sir2p is upregulated by changes in metabolic activity due to calorie restriction (Lin et al., 2000). In particular, reducing glucose levels in the media shifts the metabolic strategy of yeast cells for energy production from fermentation to respiration, and this shift is required for long life (Lin et al., 2002). This metabolic shift upregulates the Sir2p deacetylase by increasing the NAD/NADH ratio (Guarente, 2000; Lin et al., 2004).

this is from:
http://scholar.google.com/scholar?hl=en ... neogenesis

But I suspect that moving from glycogenolysis to gluconeogenesis, both from proteins and fats, is what may upregulate sirtuin, probably via NAD/NADH ratio? Here I'm stretching :-).

Implications for would-be CR dieters:
To get CR effects, is it necessary to lower your caloric intake by a substantial amount over time, in congruence with experiments in rodents? You have the "dose-response" curve everyone looks at - with effects at 40-50% being greater than 20%. In such cases your lean muscle mass HAS TO DROP SUBSTANTIALLY, since this is the prime determinant of metabolic rate.

Or is it sufficient just to periodically (frequently) deplete glycogen stores, and keep lean body mass at a "normal" level.

I think that reduction of lean body mass may be unnecessary and may be unhealthy, although I concede the point that this is debatable.

Perhaps all we need to do is to avoid a constant state of glycogen overload - to deplete our glycogen batteries frequently, to allow induction of gluconeogenetic and other (lipolytic) enzymes.

By the way, a low-carb diet per se may not do this - you need to have periods of caloric restriction. I thought at first that Atkins dieters would have depleted glycogen stores. This has not been well studied. For example:
See Kochan et al:
http://ajpgi.physiology.org/cgi/content ... 236/6/G660
"Dietary alterations alone did not affect glycogen, whereas exercise depleted glycogen stores."

Because one can, after all, go from protein or fat to glucose via gluconeogenesis, and then replete glycogen stores. But I could find not too much good evidence about the state of glycogen stores in Atkins dieters. I would assume that a low-carb, HYPOCALORIC diet would deplete glycogen stores, and taking into account the phasic nature of food intake, perhaps glycogen stores would never top up as much for Atkins dieters as for low-fat high-carb dieters. But the Kochan data (I didn't have access to the whole paper - I was too cheap to pay for it!), seem to show otherwise.

With regard to IF, even though protein ingestion increases insulin secretion, I don't believe, as long as a hypocaloric state is achieved, that this will prevent depletion of glycogen stores during the OFF day. In fact, this can be monitored by simply following weight. Whatever IF diet you are following, if you get a marked weight loss (usually overnight after a day of complete or partial fasting) you are probably cycling your glycogen stores.

Contrary evidence
This may, of course, all be "baloney". For example, a review by Ravussin summarized data in fruit flies:

From Ravussin:
"From Fruit Flies to Rodents

In the study by Mair et al., the authors examined life span in fruit flies (Drosophila melanogaster) fed one of four different diets: (1) a combination of yeast and sugar (control), (2) restricted in yeast only, (3) restricted in sugar only, and (4) restricted in yeast and sugar. The authors observed that in the restricted sugar group, as compared to the controls, maximal life span was unchanged and median life span was increased by only 12%. On the other hand, both maximal and median life spans were increased substantially in the restricted yeast group and in the restricted yeast and sugar group (Figure 1). Importantly, the authors claim that total calorie contents of the restricted sugar and restricted yeast diets were similar. Thus, from this study it can be implied that restricting carbohydrate is less advantageous than restricting protein/lipid for mediating the effects of dietary restriction (DR) on life span."

cited from:
http://medicine.plosjournals.org/perlse ... ed.0020231

But, of course, fruit flies fed yeast vs. sugar are not people. Plus, this sort of agrees with what happens in ketogenic diets that are not calorically restricted - glycogen stores may NOT be reduced, unless there is caloric restriction in addition to carb restriction.

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Specific points about the QOD diet:

OK, say I'm 6'4" and by EEE (estimated energy expenditure) is 3000 cal/day. To put me on a diet, you might put me on say, 1600 cal/day. This, however, would lower my metabolic rate acutely, and would make me fairly miserable.

But if as an alternative, I ate say, 2500 calories one day, and 500 the next, my average is unchanged. Yet my body "sees" 2500 calories every other day, so short-term at least, there should be no loss of metabolic rate. In fact, Ravussin (Am J Clin Nutr Jan 2005) found just that. (This does not preclude long-term lowering of the metabolic rate on diets - this is usually due to loss of lean body mass - we want to avoid this as much as possible - see below.)

There's another issue; intake of food is not constant, it's phasic. Our long-term energy storage bank is fat, and short-term debit account is glycogen. If you eat constantly, your glycogen stores are full up. So you are always then vulnerable to weight gain, even if your caloric intake is not very high. Any transient excess of food now can no longer go to glycogen - so it goes to fat. This is NOT balanced off by short term periods of fasting, since your body simply draws down on your glycogen stores, and has no need to go to your fat stores. So even while eating a "normal calorie" intake on average, with full glycogen stores, can lead to obesity over time.

The QOD diet causes glycogen stores to drop during the alternate day fast. You can see this by the marked drops in weight that occur overnight between the evening of the fasting day and the morning of the eating day. So on the subsequent day, even if you eat too much at one sitting, the extra food just goes to glycogen, and not to fat. Plus you can "eat like you were 16 years old again". So you have some fun. (Not overdoing it, of course - binge eating can be dangerous and can defeat any diet), whereas on a regular diet you're basically "miserable" much of the time (may be an exaggeration).

Now there is a risk of lean body mass depletion (on any diet). This is because, after you deplete glycogen on a diet, you start chewing up muscle. In the QOD diet this is minimized- once your glycogen stores are depleted, you are on your ON day. Plus, we do recommend that you take a substantial amount of protein (as egg white or soy or whey powder) during your OFF day. We are now recommending 60 g of high-biologic value protein powder during the OFF day (about 240 calories). Plus 300-400 calories of non-protein food. All of this is still sufficient to deplete glycogen stores, but the protein intake limits any effect on depleting muscle mass. Having said this, the QOD diet is a short-term weight loss diet, and not a long-term lifestyle diet (although it may be - it just hasn't been optimized for that).

Avoiding food QOD also is good training for automatic, compulsive, mechanic eaters, and helps you identify "specific food hungers" - often for the first time. I asked my son about hunger (before trying the diet) - he said - "Dad, I really don't know what hunger is. I've never been hungry". I think constant eating has led to a detachment of food intake from hunger, and such diets can help get it back.


Money market vs. CD approach:

I like analogies, so here is an analogy which sometimes helps people understand.

Each of us has our money in both a money-market account (glycogen) and in CDs (fat-stores).

So you keep getting handfuls of money, and you give them to your money manager to deposit. But the money market has a fixed ceiling or maximum amount.

So, if you keep you money-market account full, any extra money winds up going to CDs. When you need to draw down, though, as long as there's some money in the money-market account, that's where you take the extra from.

So the long-term effect is to build up the CDs. To draw down the CDs, you need to deplete your money-market,

etc. etc. :-)

John

interesting! thank you!