All:
--
On Wed, 20 Sep 2000 16:03:32
Dean Pomerleau wrote:
>Is my "gut feeling" justified - that 35% fat may be too high (even if it
>is "good" fat, mostly monounsaturated with some polyunsaturated)? Michael
>Rae, I know you eat at least 35% fat, and I suspect your Zone Megapost will
>address this very issue. PLEASE send out at least part of it soon...

Your wish is my command!!

Well, sort of ...

Folks, I started this off with much fire & bluster, & tho its been a good
learning experience, its also become a bit of an albatross. I started off
thinking that I could whip up a decent Apologia Pro Zona in a couple of weeks,
just from data I had kicking around the house & a few ideas in my head. Not so!
One thing was always leading to another ... one more paper to review, one more
fact to confirm, one more argument whose logic seemed to have a gap. Plus, I
foud I had a LOT less time on my hands than Id expected, for many reasons,
including what I believe t have been record-high posting volume this summer. I
simply do not have the time to follow up on all the data, all the arguments, all
the loose ends.

The below is incompletely referenced, somewhat jumbled in structure, and
includes places where arguments just trail off midway thru. this was not
intended, but its going to have to do.

OTOH, I accepted from the beginning that much of what would follow is
make-the-case argumentation. Theres no need to point this out: Im fully
aware of it. But the cases are made with real, live science. Read such arguments
w/an appropriate quantity of NaCl -- but also look at the extensive controlled
trials favoring a Zone diet. These, alone, IMHO establish that a Zonish diet is
in every way superior to a high-CHO one.

Im posting this in 2 halves, for easy reding: this half is the text, the other
is the references. If you open them up seperately, ou can then jump from one
window to the other to check references, rather than constantly scrolling &
losing your place.

How this all began:

On Mon, 5 Jun 2000 09:31:33
Phil Harris wrote:
>Apart from making CR more comfortable (not an insignificant matter!) I
>have not seen any justification for the ZONE diet.

When I first read the above, I thought memory was playing tricks on me, but I
went back to the archives of my very first month on the list (sniff!) lookin for
something else, and in the process confirmed my recollection. Phil, youve been
on this list for longer than I have; unless you put a kill file on my posts
almost from day one of my list presence, you should have seen DOZENS of posts
including experimental and clinical data providing scientific justification
for the Zone, both as a whole and in its various aspects, from a health
perspective!

Well, here we go for a massive, hopefully once-and-for-all, discourse. Dont
take this as a personal attack, please! Whom the LORD loveth, He chasteneth.


Lets start at the very beginning.

The Zone is a calorie-restricted diet. CR is the only intervention which can be
shown to consistently and repeatedly extend the mean and maximum LS of mammals.
I take It I neednt belabor this point further.

The Zone is a nutritional program which is, as compared to Walfords
reccomendations:

A) similar in absolute protein for most folks (but really, it should be set much
HIGHER -- see below),

B) with a controlled protein-to-carb ratio

C) achieved by cutting down on empty carbs such as grains, potatoes, and sugar.
It also reccomends

D) a much higher fat intake,

i. sufficient to maintain EFAs, but also
ii. high in monounsaturated fat.

What justification is there for these reccomendations -- again, leaving aside
the proven facts taht they result in more successful weight loss (a serious
health issue for the N American population, if not for most CRONies), and better
satisfaction, which is likely to lead to more comford and better lifelong
commitment to CR (again, itself a far from trivial issue)?

I take Sherm's word
>that Sear's theory is pretty much quackery. There seems to be no experimental
or epidemiological justification.

There is plenty of both. Direct experiments on the full Zone program, including
both CR and the proper macronutrient ratios, which address known disease risk
factors as opposed to issues of diet adherence or weight loss (the inclusion of
which would extend the set considerably) include:

BARRY SEARS, PAUL KAHL, GEORGE RAPIER. A Nutrition Intervention Program to
Improve Glycemia, Lipid Profiles, and Hyperinsulinemia in Patients with Type 2
Diabetes. Diabetes 1998; 47(S1): A312.

The data can be accesed at Sears site, with a free login ID:

http://www.drsears.com/site/Tools/Research/ResearchHome.nsf/9f945249296945278525\
66cc0076418f/e9f61411c0db8654852566f80060201f?OpenDocument
---------------------
Title: Effects of Two Energy Restricted Diets on Fuel Utilization,
Blood Chemistry, and Body Composition.

Researchers: M. Kern, V. Schuab, and D. Harris, from the Department of
Kinesiology, San Francisco State University, SF, CA.

Source: Med Sci Sport Exer. 1998 May;30(5) Supplement; S1-S1339

This study reported the typical lipid changes were used to seeing in Zoners;
however, it was small and rather flawed, as Curt Adams pointed out at the time.
---------------------------

An independent study was also unwittingly performed by Markovik et al (1, 2).

It will be objected that these are not the results of the Zone qua Zone, but of
CR. Indubitably, this plays a major role in these results. But compare these
results to Walfords (3, 4, 5) and a picture emerges which suggests the Zones
superiority.

Let me first state that I think I am exaggerating the performance of the Walford
group by accepting their pre-closure data points as their baseline and their 6
mo data points (5) as the effect of CR alone. CR did not begin until closure,
but very vigorous exercise began well before this, and their baseline was taken
2 mo before closure, so that the first data point is the result of short-term CR
and medium-term increases in exercise. Otherwise, we must accept that just two
weeks of CR produced some very dramatic changes in body composition and lipid
levlels indeed -- in fact, little improvement was seen on most measure s
thereafter, and some got worse.

Second, it is important to use Markoviks normoglycemic subject data as a Zone
comparison. Markovik used both diabetic and normal subjects, and his results
clearly show that the Zone program worked much better on normals: NIDDM started
off worse, and did not improve by as great an amount. In the section on protein,
Below, I present what I believe to be pretty clearly the reason for this fact.
Since Walfords biospherans were all normals, and Sears study was in NIDDM
only, Markoviks normal subjects data is to be a fairer comparison to
Walfords. Let me state up front that this results in more favorable results fo
the zone program than does using Sears NIDDM data. However -- fro reasons to be
discussed in the P:C review below -- it is fully to be expected that healthy
folks will respond better to the Zone than will NIDDM patients.

Also, Walfords group had 6 months to achieve their improvement, where Ms grop
had but 4 weeks; OTOH, Walfords group seems to have achieved most of their
changes almost immediately (with the caveat above).

On the other hand, Markoviks group was more severelly restricted (1100 Cal vs.
1800) -- but note that we would expect some very different sorts of differences
from an increased CR degree in otherwise similar diets than the ones observed
(ie. quantitiative rather than qualitative). Indeed, I will suggest below that
the disadvantages of a low-fat CR diet (noting that ANY CR diet is superior to
ANY AL diet in extending longevity) ACCELERATE with lower caloric intake.

It will also be objected that Markovic did not do the full Zone program, because
his macronutrient profile held across the day, rather than being constant at
each meal. I will provide the justification for the importance of holding the
P:C ratio AT EACH MEAL below. For now, (a) see Sears, and (b) remember that the
overall daily profile still held, as compared to Walfords.

Finally, all of Ms day 28 data is on charts rather than tables or detailed text
summaries, so I have to eyeball the results.

Total cholesterol fell by 17.9% (4.86 to 4 mmol/L) on the Zone (z). amd by 35%
on Walfords program (w). LDL fell 29% (2.47 to 1.75) in z, and 53%
(calculated: 79.7 vs. 37.27 mg/dL) in w.

But while these measures improved more significantly in Walfords group, HDL
simultaneously declined 37%, so that the TC:HDL (CVD risk ratio) was in fact not
significantly changed (3.45 vs. 3.49) by the program. In contrast, Markovic says
that Zoning subjects saw no significant changes in HDL (no data given in the
paper as to the final figures, but they started at 1.32), improving their risk
profile (3.68 vs. 3.03).

Similarly, TG declined in w men by 21%, but they INCREASED in the w women by
53%! Averaging the data out, we get a mean decline of TG of 3.2% (108.5 to
105). By contrast, TG went down 21.6% (1.02 to 0.8 mmolL) in z.

Now: the TG:HDL ratio, whether or not it is an insulin surrogate (see below), is
an extremely powerful predictor of MI (the ratio of triglycerides to HDL was a
strong predictor of myocardial infarction (RR in the highest compared with the
lowest quartile=16.0; 95% CI=7.7 to 33.1; P for trend <.001) -- go ahead, read
that again: RR=16!! ). Ws ratio got 36.6% worse (1.75 vs. 2.76). Granted how
extremely predictive this ratio is, it would seem that WALFORDS PLAN MAY
ACTUALLY HAVE CONSIDERABLY INCREASED RISK OF DEATH FROM MI . By contrast, Zoners
saw their ratio decline by 21.3% (0.77 to .61) -- and again, the highly
predictive nature of the ratio makes this a mch more profound decline than it
sounds.

And bringing the Biospherans caloric intake down to Markovics levels is only
likely to make this worse. I make this sspeculation on the basis of (40). This
trial found that the problems associated with low-fat eating -- lowered HDL and
elevated TG -- stay stable and get worse (respectively) as caloric intake
decreases. what they actually report is that TG only start to go down on
low-fat, high-CHO when energy is restricted below AL; this, however, contradicts
all the evidence below, which shows increased TG under AL low-fat, high-CHO
conditions. I conclude that it is more likely that Walfords group might have
gotten WORSE STILL relative to z, from a blood lipid raito perspective, had
caloric inake been brought down to z levels, than that they would have caught
up.

These results are paralleled in AL dieters, as will be seen in following
sections. Lets take the Zone program point by point.

PART ONE: You want more fat.

Lets start with high-CHO versus high-mono-fat diets (although NB that cutting
out CHO in favor of fat increases P:C -- a subject to which we will return).


>Apart from that, there has been a
>wealth of studies implicating saturated fats, mostly from animal
>sources, in vascular inflammatory diseases and etc..etc...found almost
>exclusively in modern Western societies.

I firmly agree -- and so does Sears. Phil, its a shibboleth of critics of Sears
who havent read his books that they will suggest that the Zone involves lots
of saturated fat. The Zone involves very consciously choosing the leanest
protein sources one can get (excepting salmon, tuna, et al), and bringing total
fat up to >=30% fat with MUFA and some n3s. Sears repeatedly warns one that SaFA
and n6 are to be avoided. Eg:

When you add those fat blocks, though, you must pay careful attention to the
KIND of fat you eat. Just as there are favorable and unfavorable carbohdrates,
there are also good fats and bad fats.

What are bad fats? The real villain fat is [AA]... Saturated fats should also
be kept to a minimum. [SaFA] are found in animal protein sources and in whle-fat
dairy products. You want t restrict these fats in a Zone-favorable diet because
they tnd to raise ... insulin resistance ... Thats why I reccomend low-fat
animal protein sorces like white meat poultry and fish - theyre low in [SaFA].
-Sears, _The Zone_: 85-6.

The only way to get lower SaFA than Sears standard plans is to go vegan -- and
those wishing to do just that, may see his latest book, _The Soy Zone_ (89)
(gosh, does Sears pay me for this shit?!). So, what are we left with? Cut out
SaFA and n6; increase mono and n3.

Zone gives you way-over the essential oil
>requirement. Why bother when you could be getting calories with more
>goodies (e.g. seriously good phyto factors), as in veg and fruit?
>There is a good case for omega3 oil from plants (see the Lyon study of
>a Mediterranean diet that used an experimental margarine derived from
>plant sources), and some evidence in favour of substances that
>accompany Xtra Virgin Olive Oil.

There is not some evidence, but an overwhelming mountain thereof, that a diet
high in mono fat is superior to one high in CHO. Compared to the high-CHO
AHA/ADA & SSCN, a diet quite dripping with MUFA leads to similar reductions in
TC & LDL (this is likely due at least partly to reducing postprandial insulin,
as insulin increases the activity of HMGCoA reductase (70)) but maintains or
elevates HDL where it usually drops in AHA, and significantly lowers TG, which
are ELEVATED by AHA! This latter is evidently due to increases in liver VLDL TG
secretion in response to carb (20).

And note that it is a  high MONOUNSATURATED FAT diet, NOT specifically an
OLIVE OIL diet, that has these effects: peanut (12), high-oleic sunflower (9
b-d), macadamia nut (11), avocado (19, 19b, 23), pecan (12a), hazelnut (12b),
canola (37, 37a, 37b), pistachio (12c), and almond (10a-c), MUFA sources have
been tried, and they all yield essentially the same results. While there may
be confounding factors in the effect -- phytochemicals in this oil or amino acid
balance in that nut -- the overall effect is quite powerfully consistent.
Indeed, far from being an effect unique to olive oil, one review (9a) claims
that olive oil yields INFERIOR results to 2 other MUFA sources (canola and
high-oleic sunflower). It might be argued that the canola results are due to the
n3 content added to the MUFA (and this is almost surely a factor: see below),
but this certainly cannot apply to HOSO.

Note also that it is a HIGH-mono fat diet: ie., ~40% of an *AL* diet in nearly
all these trials! Mild-fat diets which are high % MUFA fail to lower blood
pressure (30), unlike the high-mono diet. And note that a diet which holds to a
high-CHO, moderate-low fat prgram like Step I, or a truly low-fat one like step
II, but replaces standard fat with MUFA from avocado (19a) or canola (35, 37x,
37y), does not cause a significant improvement in lipid profiles. Its not
enough to just switch fat types. FAT MUST REPLACE CHO.

The best trial, imho, was (12), a crossover trial using AHA Step II, SAD, and
high-MUFA diets from two different sources (olive oil and peanuts), all in the
same trial, and clearly proved that high-MUFA, irrespective of source, yields a
better risk profile than low-fat. In fact, after an extensive review of the RR
associated with changes in all the tested lipids (and not including the TG:HDL
ratio, which would REALLY have accelerated the difference), these authors
calculated that, relative to SAD, the MUFA diets cut CVD risk by 25% (olive),
16% (peanutoil), and 21% (peanuts & peanut butter -- NB thislatter, with all the
crap thats in commercial PB!!), while the AHA Step II diet cut risk by just
12%. Now recall that lowering Cal while on high-CHO diets appears to make them
LESS favorable (40) ...

High-MUFA works in normals(10, 10b, 10c, 11, 19, 37a), hypercholesterolemics
(10a, 11, 15, 19, 19b, 41), autoimmune diabetes (9), and NIDDM patients (11a,
13, 14, 17, 20- 27, 32); it works for smokers (16) and nonsmokers (all other
trials) alike. It lowers blood pressure, as one would expect granted the effects
of a higher P:C on eicosanoid metabolism (below)(11a, 21, 25). It even improves
lipids in patients already taking lovastatin (37a)! It improves glycemia in
NIDDM (11a, 17, 21, 22, 24, 25, 26, 27, 32) and diabetes type I (9). (More on
glycemia and the recent Why doesnt the Zone lower FBG? threads below). And
then there is the evidence of protection from cognitive decline (31). Not EVERY
trial yielded EVERY one of these results, but the overall pattern is clear, as
per the meta-analyses and systematic reviews (18, 28, 29).

And even diets which are high in fat and low in cho, yet are NOT specifically
focussed on mono fat, appear to be better for you than a high-CHO one. One trial
(45) found that a diet tht is high in fat (45%) with equal amounts of poly,
mono, & SaFA leads to better risk profiles in healthy postmenopausal women than
does a high-CHO (60%) one with equal protein (15%) content: compared tot he
high-fat diet, high-CHO women had higher TG, insulin, and VLDL, lower HDL,
poorer muscle insulin response, and lousier uptake of fat-soluble vitamin A
(extrapolate to CoQ, E complex, etc). Likewise, another controlled trial
compared hypercholesterolemics put on 4 progressively lower-fat (with relative
amounts of SaFA and unSaFA held constant), higher-CHO diets (41). THE LOWER
THEIR FAT INTAKE GOT, THE WORSE THEIR LIPIDS BECAME: most notably, those who
started out with normal TG saw them climb, dose-dependently, on lower-fat diets.
BAD!

Lower fat intake is also epidemiologically linked to greater risk of ischemic
stroke (42), one of the biggest killers we know. And what PARTICULAR fat was
most correlated with stroke protection? Mono. Likewise, an epidemiological study
(62) found that red blood cell oleic acid, independently of cholesterol levels,
was tied to lower AA levels -- and to reduced risk of CVD death.

Further, we may be able to infer something about the insulin resistance of
individuals even in trials where glycemia were NOT tested, as the clear
improvements in TG:HDL these diets induce (vs. the clearly DELETERIOUS effects
induced by the high-CHO diet) may be a marker for fasting insulin. Low HDL is
strongly correlated with hyperinsulinemia (60, 61), t the point where Gerald
Reaven has flatly declared that Isolated low HDL cholesterol [is] An
insulin-resistant state (60) and Individuals with high total cholesterol/HDL
cholesterol ratios are insulin resistant (61). And not only do high TG
CORRELATE with insulin resistance (59) due to insulins stimulation of hepatic
VLDL synthesis (30), but in fact a case-control study (58) concluded that
isolated low HDL cholesterol [is] an insulin-resistant state only in the
presence of fasting hypertriglyceridemia. Taken together, the Sears surrogate
for insulin claim seems like a reasonable hypothesis -- and, in fact, the lead
!
author of (58) confirmed in PC that he tends to agre with this analysis: with
regards the paper by Gaziano et al. that you mentioned, you are absolutely
right. I would not be surprised if the TG/HDL ratio is a surrogate marker for
insulin resistance. In which case we have even clearer evidence, from these
trials, that high-CHO diets induce hperinsulinemia, and high-MUFA ones reverse
it.

In fact, the mechanism posited for the lowering of TG & elevation of HDL by
high-MUFA, and the reverse in high-CHo, assumes exactly this (20; cf. 81).
High-CHO diets result in higher posprandial insulin response, which leads to
increased TG-rich VLDL secretion. By conrast, high-MUFA does not directly
stimulate insulin, & in fact BLUNTS it, because it delays gastric emptying.
Thus, the difference in TG.

What then enters into the equation is the cholesteryl ester transfer protein
(CETP). CETP swipes cholesteryl esters (cholesterol, as stored in lipoproteins)
from HDL (high in CE density) and GIVES them to VLDL (very low in CE). It thus
lowers HDL, and has the potential to elevate LDL, tho from the trials it
doesnt appear that it actually does so.

While both high-MUFA and high-CHO diets, for different reasons, reduce the
ABSOLUTE AMOUNT of CETP (REFERENCE), the ACTIVITY of CETP is lowered by oleic
acid (REF). by contrast, the increased VLDL caused b high-CHO meals actually
INCREASES CETP activity, because of sheer stoichiometry: when theres more VLDL
around, it tends to swipe more from HDL.

So: insulin elevates TG and lowers HDL. Higher insulin = higher TG:HDL.

Now, the Lyon trial (33, 34, 35). The trial saw reductions >75% in CV mortality
rates MORE DETAILS HERE -- a more impressive result than any drug or lifestyle
change yet known to the world. What did they do that controls didnt? Their
protein stayed the same; their intake of fruit & veggies went up marginally
while grains went down marginally; and their mono and n3 fats went up as a
replacement for saturated and n6 fat, without any change in %fat compared to
controls. Conclusion: the fat, not the vegetables or the butler, did it. This
was not a fat-reduced diet compared to the Zone. In fact, it was 30% fat by
calories -- very Zonish. Except that it was, again, AD LIB, so total fat was
much HIGHER.

Aso note that the Lyon trial, at this moderate fat intake, did NOT see the
dramatic lipid changes noted above. Why? Presumably, because they didnt eat
enough fat! See 19a, 35, 37x, 37y again. This includes their Lp(a) -- see (36).
Now, imagine what could have been accomplished with an improved lipid profile
resulting from higher fat intake, and resulting lower TG, higher HDL, lower
insulin levels, and lower Lp(a).

Note that other work shows that a similar modification in fat pattern --
starting with a truly HIGH-mono fat diet and replacing some of the mono with ALA
-- yields mildly better standard lipids than even a pure high-MUFA program
(36, 37), and also lowers the highly atherogenic (almost exclusively in men, it
would seem: 38, 39) and very difficult to lower lipoprotein(a). The trial which
reported this latter fact (36) showed additional reductions in Lp(a) of 6.2% --
which sounds like tiddleywinks, until one realizes just how difficult it is to
lower Lp(a) AT ALL (niacin does it; little else does). The Framingham study
found (39a) that The odds ratio for CHD risk in men with Lp(a)-C >/=0. 259
mmol/L (>/=10 mg/dL), after adjusting for age, HDL-cholesterol, LDL-cholesterol,
smoking, diabetes, blood pressure, and body mass index, was 2.293. A recent
meta-analysis (103) puts the risk much lower than this & many previous studies
(1.6 RR top to bottom tertile), but includes st!
udies involving women -- who evidently arent at significant risk from Lp(a),
somehoow, so its a bit artificial. Also, they went by tertiles, which will tend
to blunt any progressive risk, as compared to quartiles or quintiles.

So, as per the most cardioprotective diet known to science, we want to get >30%
fat from mono and n3 while restricting saturates and n6. Hmmm. this sounds
familiar, somehow...

Here are the conclusions of a recent analysis of the Nurses Health Study (104):

Each increase of 5 percent of energy intake from saturated fat, as compared
with equivalent energy intake from CARBOHYDRATES, was associated with a 17
percent increase in the risk of coronary disease ... As compared with equivalent
energy from CARBOHYDRATES, the relative risk for a 2 percent increment in energy
intake from trans unsaturated fat was 1.93 ...; that for a 5 percent increment
in energy from monounsaturated fat was *0.81* ...; and that for a 5 percent
increment in energy from polyunsaturated fat was *0.62* ... Total fat intake was
NOT signficantly related to the risk of coronary
disease...

 We estimated that the replacement of 5 percent of energy from saturated fat
with energy from unsaturated fats would reduce risk by 42 percent ... and that
the replacement of 2 percent of energy from trans fat with energy from
unhydrogenated, unsaturated fats would reduce risk by 53 percent ...

Then theres cancer. I wont bother documenting the protective effect of n3 vs.
cancer, but I WILL note that the only (case-control) studies I can find on the
subject (43, 44, 46) show that higher mono fat intake is associated with lower
risk of cancer (and, BTW, that higher starch intake is associated with higher
risk (46)). And the Lyon study (34) gives prospective evidence that a diet that
is Zonsily high in mono and ALA can cut your risk of cancer death by 61%
(p<.05).

Now: if almost all of the Lyon results are attributable to getting more mono and
ALA (no other changes were terribly large), in moderate, Zonish %s of an AL
diet, does it really make sense to cut down on these fats dramatically on CR? I
put it to you that it does not. I might cut back on my saturates and n6 intake
to keep a similar % fat, however. This conclusion is reinforced both by the
comparison of the Biospheran and Markovic-Zone experiences, and by the following
rodent CR material, which Ive previously referenced, from Weindruch & Walford,
in _The Retardation..._:

> p.108ff: Data showing that a high-percentage fat diet does not increase
> tumors on CRON, even tho the form of fat used -- corn oil -- is
> acknowledged by W&W to be a particularily carcinogenic one when fed ad
> lib [because its high n6]. If they used a balanced EFA mix [I would add
today, and lots of mono fat too], I wonder if it would show [a DECREASE]...?

"Kubo ... found that LSs were most strikingly prolonged by DR when
moderate intakes (38% of energy as fat) and not very high fat intakes (69%...)
were used." p. 59. [From the descriptor moderate, I take it that it worked
better than low-fat diet as well, tho this isnt specified and I dont have the
original].

"High fat diets are used more efficiently than are low fat ones... Quite
probably the severity of the [CR] tolerable by animals could be increased
by feeding high fat diets... whether this would further increase
lifespan is worthy of study [see above quote: evidently, it DOES]
...*what* (not just how much) is eaten affects metabolism." -255

On this last, efficiency point: a monkey study (47) found that higher-fat diets
lowered mitochondrial metabolic rate, WITHOUT altering the state 3:state4 rato.
I had been meaning to ask Aubrey da man de Grey about this, and a related
question, for MONTHS, so preparing this opus put the coal to my ass. Here is our
discussion:

------------------
>Me
A de G:

> In comparison to animals fed low fat diets, mitochondrial respiration
> in the marmoset was reduced by high fat diets irrespective of the
> dietary level of lipid saturation.
> Though it's not mentioned in the abstract, the paper also asserts that
> the state 3: state 4 ratio was not altered by the different diets. So
> there was lower metabolic rate (depending on substrate, state 3
> absolute levels went down between ~ 1/9 nd ~ 1/3) with no increase in
> e- fumbling.

That doesn't absolutely follow. "Mitochondrial respiration" means the rate of
respiration of isolated mitochondria (extracted from cells) in defined states
(states 3 and 4), and it doesn't necessarily tell us about the metabolic rate
(per unit mass, i.e. the specific metabolic rate) of the intact organism. In
particular, if the state 3:state 4 ratio (normally termed the respiratory
control ratio) was unaltered then state 3 respiration and state 4 respiration
were both lower in isolated mitochondria, but if the fat-supplemented organism
was running closer to state 3 (i.e. keeping its ADP supply higher) then the
organism's specific metabolic rate (which wasn't measured) could have been
unaltered.


> I also note from your book (p.17) that "ubisemiquinone exists only
> fleetingly withie CoQ is interacting with Complexes I of III. However,
> its existence is ... the weak link in the chain, because it can
> spontaneously revert to ubiquinone" and thus fumble e-. I take this to
> imply that this fumbling does NOT occur (or is at least much less
> likely to occur) in the transfer of e- from FADH2 via fatty acyl CoA
> dehydrogenase to CoQ. IIRC, you actually say this explicitly somewhere
> in your corpus, tho' I can't find t just this minute.

You have it right; the explicit statement is in a footnote on p140.

> If a higher-fat diet slows metabolism without making mt any sloppier, and
> if some of the e- from fat are transferred into ETS via a less fumble-
> prone route, then shouldn't a higher-fat diet (with constant caloric
> intake) to some extent reduce mt oxidative stress and thus slow aging?

Possibly, but the effect would be slight: for each two-carbon slice of a fatty
acid, only two electrons enter the electron transport chain via the fatty acyl
CoA dehydrogenase, whereas eight enter via Complex I and two via Complex II. In
the case of carbohydrate metabolism, if we presume that the glycerophosphate
dehydrogenase pathway is not used we get a bigger ratio through Complex I, five
out of six rather than four, but that's a pretty small difference.

"respiration rate declined [so much] so e- flow through Complexes I and III
declined by that same amount, so the rate of e- fumbling declined by about that
same amount" seems more persuasive.

> Is it at least fair to say that a higher fat diet would
> slow aging by at least 1%? Any better estimate? Or am I missing something
> colossal?

I think that in view of the small differences in how much each enzyme is used
and the quite substantial differences in metabolic rate, it is certainly
justified to explore whether highly fat-biased diets might lower metabolic rate
in other primates, as well as other variations on the study you mention. I
found an interesting related study in Medline: Yerboeket-van de Venne and
Westerterp, Appetite 1996 Jun;26(3):287-300 found a reduction in energy
expenditure from medium or high fat diet relative to low, but only in people
described as
"restrained eaters". This may suggest that the reduction in metabolic rate is
associated with retention of the fat, i.e. weight gain, which curiously was not
measured in the McMurchie study.

MR: I actually would conclude the OPPOSITE re: the fat accumulation: if the
reduction in energy expenditure only happened in restrained eaters, then
presumably it happens in people who are NOT gorging and getting fat, no? In any
case, we CR folks are certainly restrained eaters!

Aubrey de Grey: Absolutely right - I totally zoned out there. Moreover I
didn't know about the results you quote from W&W [ie. the data which MR posted
above in the PRESENT post to the CR ng]. I agree with your interpretation.
----------------------------------------------------

From Da Man hisself. NB that the same conclusion holds if one accepts the
Hagen/Ames MiFRA theory -- or ANY theory that accepts that mt ROS are somehow
central to aging -- instead of Aubreys.

Conclusion on fat: low-fat diets, eaten AL or CR, will increase your odds of
CVD, cancer, maybe even accekerate aging, and ultimately kill you. Why put up
with that shit? Yes, CR can make up for the risk entailed by slowing down
aging, but youre still better off on a higher-fat CR diet.

PART II: You want more protein.

Lets start with basic, physiological need: you need protein in your diet, or
you die. The same cannot, evidently, be said of CHO. But how much protein?

Well, if your goal is to maintain LBM as much as possible (which is not just an
ego thing, or even a quality of life issue (old folks who cant open the jam jar
or get into shopping malls), but is a real survival issue, affecting your odds
of faling & breaking a hip, saving yourself from a fall, and dying because you
didnt CLOSE the jam jar & got some evil thing in the stuff), it would appear
tat the answer is, quite a bit. I suspect weve all seen the fruits of Sherms
ingenuity by now, but just in case, and for posterity :) :


-------------------------------------------------------------------
This data comes
from Modern Nutrition in Health and Disease, 8th ed.,
1994, Ch. 1, pp. 24-29. The faulty reasoning below is
my own.[Fortunately, there isnt any :) -MR].

....

the book says
Nitrogen balance is also affected by energy
intake. ... N balance becomes progressively more
negative as energy intake is reduced below the
needs of the body. ... A direct relationship
exists between energy intake and N balance from
negative at low-energy levels to positive at
excessive intakes of energy.
A table then shows measured requirements varying by
a factor of two over a calorie intake range from
57 cal/kg (RDA would be 0.5g/kg) to 40 cal/kg
(RDA would be 1.02g/kg).

Now I personally weigh about 57 kg and eat about 1750 cal/day. This is not
particularly low for a CR diet, yet at 31 cal/kg is way off the chart.
Fortunately the data were fairly linear at that end, so I extended the table
with a ruler and came up with a requirement of 1.5g/kg! That is near double the
US RDA of 0.8g/kg and would put my daily requirement for protein at 87g, which
is about what I eat.

For your own use, try this formula:

RDA protein (g/day) = 3.22 BWInKg - .055 totalCalsPerDay

So if you weigh 70 kg and eat 1800 cal/day, your protein RDA
is 3.22 * 70 - 0.055 * 1800 = 126 g/day. The above formula
is a linear fit to the low end of the data in Table 1-6, pg 24...

However, I still think this is an underestimate, because:
(1) Protein requirements are higher for lean body mass
than for fat, and
(2) these experiments would have been done on people of
normal body fat content, and
(3) CR people have lower-than-normal body fat.
If we assume that normal people have 20% body fat, the above formula can be
rewritten in terms of lean body weight (LBW):

RDA protein (g/day) = 4.03 LBWInKg - .055 totalCalsPerDay

Now if a CR person has 10% body fat, then a 70kg 1800 cal/day person requires
4.03 * (0.9*70) - (0.055 * 1800) = 155 g/day. That would be 34% of calories from
protein, which seems very high. My own requirement by this formula would then
be 108g/day,
meaning that 25% of my calories should come from protein.

[Paul Wakefer added]:

In animals on CR, protein turnover it more rapid. During protein turnover
(catabolism followed by anabolism) not all amino acids (nitrogen) is reclaimed.
Some catabolic products are not reclaimable and are excreted in one form or
another, thus increasing nitrogen (protein) loss.

[Walford points out the limitations of these data, which are relevant, but not
IMHO of very little likely significance]:

none of the material in Modern Nutrition in Health and Disease was
>derived from long-term CR studies in either rodents or humans, and may not
>be directly applicable since CR is (probably) a different metabolic state
>than either controls, short-term fasting, or starvation.

-------------------------------------

So it would appear that, simply because youre eating less FOOD, youre gonna
need a surprisingly large amount of protein. In the face of such estimates,
Sears reccomendations for AVERAGE people(which NEVER exceed 1.0 g/POUND of LBM,
even for elite athletes) seem really quite tame. Indeed, for a person of avg
weight, body fat, and activity level, his suggestions come out rather close to
the RDA. High protein, my ass: Sears reccomends an excessively LOW protein
diet for CR!

But lets move on to the Zone issue per se. The most controversial, and most
definitive, Zone hypothesis is that optimal health is to be achieved within the
context of a CR diet in which the protein:carb ratio is held constant at a
figure between 0.6 and 1.0, with 0.75 optimal for most. The reason for this lies
in the effects of such a ratio of macronutrients on hormonal response to a meal
(most notably the ratio glucagon: insulin), and resulting effects on a variety
of biochemical parameters, most notably eicosanoid synthesis. Lets start with
the hormonal effects of macronutrients, individually and in mixed meals, and
work our way to eicosanoids.

Now, it is the Zone line that protein has a much lower insulin-stimulating
effect than does CHO. Immediately, numerous folks with reasonable memories will
recall fairly recent posts from Doug Yonkin and Sherm, which seem to have been
interpreted as showing that protein had at least equal, and sometimes greater,
insulin-stimulative powers as does CHO. Actually, the data cited by DY and MS
have been partly misread, and partly overextrapolated (this latter being in part
the fault of the abstract, as distinct from the full-text, of DYs studies).
They, along with other, related studies, actually help prove Sears point, FOR
HEALTHY INDIVIDUALS, tho perhaps not for NIDDM folks. Lets dig into em.

First, the insulin index paper (63). Theis paper did NOT show that protein has a
high insulin response, but the reverse. Total carbohydrate (r =0.39, P < 0.05,
n = 36) and sugar (r = 0.36, P < 0.05, n = 36) contents were POSITIVELY related
to the mean insulin scores, whereas fat (r = -0.27, NS, n =36) and protein (r =
-0.24, NS, n = 38) contents were NEGATIVELY related [my emphasis]. What caused
the confusion was the statement that protein-rich foods ... elicited insulin
responses that were disproportionately higher than their glycemic responses. 
This, however, is what one would expect: as noted abve, protein does cause SOME
insulin response, whereas the higher the protein content of a food, the lower
its glycemic response will be -- the extreme case being a slab of lean beef,
which has essentially zero carb (although it still elicits a small glycemic
response), but a nonzero insulin response. This doesnt mean the insulin
response PER CALORIE -- ie. the insulin index!
s absoute value -- is high, however. In fact, the II of the protein foods, on
average, tested lower than the averages for most other food categories tested
(fruit, bakery products, confectionar) except (counterint;uitively) breakfast
cereals, and CHO-rich foods, whichwere a little lower in II -- but this is
reversed by the removal of baked beans, which were mysteriousy put in the
high-protein category despite obviously not belonging there, having but 12.17
g protein for 52 g CHO (including 12.7 g fiber), as per DWIDP, NOT INCLUDING the
tomato sauce which the paper says they were in! The beans thus, not surprisingly
had by far the highest II of all the foods in the protein category: 20106, over
TWICE its nearest food in the category (fish, at 9350!) and nearly THREEFOLD the
category avg excluding it (7453). This latter figure makes protein foods tied
for lowest II as acategory.

And, indeed, previous research found that a 50g portion of protein from beef,
tested in normals, yields an insulin AUC that is only 21% (64) to 28%(65) of
that of 50g of carb as glucose . (At a guess, the difference here might be due
to the use of lean beef by (65) vs. (64)s standard beef: fat slows gastric
emptying).

Now, some of you are remembering Doug Ys posts of abstracts (66, 67) reporting
that many protein sources, incl beef, had insulin responses nearly identical to
that of glucose, and created a heady synergistic insulin response when combined
with the latter. True, but there are two reasons why these reports do not
contradict the Zone in healthy folks. First, these latter reports were on NIDDM
patients. No, I am not just waving my hands: (66 & 67) were reports from the
SAME group that issued (65), above (and several similar reports), usign the same
methods. And (65), which did test CHO combined with pro, did NOT report a
synergistic effect in NORMALS, but rather a summed effect which was
nonsignificantly LOWER than the sum of the insulin responses of the beef & the
glucose alone. Likewise, (64) actually compared healthy folk and NIDDM and
reported a dramatically higher insulin resonponse to protein in the latter.So,
from these papers, it would appear that, in normals, replacing !
CHO with protein will lower insulin response to a meal, while simultaneously
increasing glucagon.

But it goes further. (68) reported that, if CHO is held constant at 58 g,
increasing the protein dose beyond an initial 10 g all the way up to 49.9 g does
not increase the insulin response! This finding is highly counterintuitive: one
might expect continuous additive increases; but it is replicated in (69), an
experiment done by the same authors as (65, 67, 68) with a very similar
experimental design as (68) (constant CHO, increasing PRO), precisely because
it was designed to test another of (68)s findings (to which we shall return).
(69) found that there were ONLY further increases in insulin response when (wait
for it!) the P:C was elevated to 1:1 -- thats right, the extreme end of the
Zone-favored P:C ratio (0.6-1.0, with 0.75 considered optimal for most folks).
(68) never got up this high (its highest P:C was 0.86), so the two are
consistent in this regard.

Thus, on the one hand, if CHO is held constant, then as protein is added into
the meal, P:C climbs, glucagon levels go up (69), but insulin levels stay
steady, WITHIN THE CONFINES OF THE ZONE. And, on the other hand, REPLACING CHO
with protein will actively LOWER insulin, as the summed effect, in normals, is
less than additive -- within the Zone -- and the insulin response of protein is
lower than that of carb to begin with. So, in an isocaloric diet, you get both a
significant increase in glucagon, and a significant reduction in insulin,
resulting in a VERY significant elevation in glucagon:insulin, when you raise
P:C by replacign CHO with protein -- within the Zone. Beyond 1.0 P:C, you
plateau (glucagon and insulin are both elevated) or perhaps begin slowly losing
ground.

Now lets go back to fat: since fat slows the release of carb into the blood,
and thus blunts insulin response t a meal (as per the insulin index, above, and
as expected from fats effects on the GI), replacing some carb with fat (or
lowering carb while holding fat steady) FURTHER lowers insulin response, further
elevates the glucagon:insulin ratio. See how this all fits together?

Now, Im sure we all agree that lowering insulin levels is a good thing, to
avoid the known consequences of constantly high insulin levels: slow development
of insulin resistance, and thus hyperinsulinemia, high blood pressure,
dyslipidemia (due in large part to insulins stimulatory effects on HMGCoA
reductase (70)), and serious risk of CHD. But why do we care about this
glucagon: insulin ratio so damned much? Well, for one thing, insulin isnt the
ONLY hormone with effects on HMGCoA Red: while insulin stimulates it, glucagon
inhibits it (70). So the higher g:i gets, the more powerfully cholesterol
synthesis is inhibited. But beyond this -- and here is Sears real focus -- the
glucagon:insulin ratio is one of the most important diet-dependent modulators of
eicosanoid synthesis.

But first, a little background. All eicosanoids are produced from long-chain
PUFA, which come either direct from the diet, or are synthesized endogenously.
This latter is done by taking short-chain PUFA (ALA and LA) and adding more
double bonds in, using desaturase enzymes (and elongation enzymes, but its the
desaturases which are rate-limiting). The desaturation of LA goes LA [delta-6
desaturase]--> GLA ---> DGLA, which is then either used to make series 1
eicosanoids, like PGE1, or is acted on by delta-5 desaturase, forming AA and
thence series 2 eicosanoids. ALA also uses these same enzymes, using d6d to turn
ALA into SDA, and d5d to make EPA from ETAn3; from EPA, series 3 eicosanoids are
made. Broadly speaking, series 1 eicosanoids are good for one in the long
term, and series 2 are bad: series 1 are anti-inflammatory, hypotensive,
immunostimulative, antithrombotic, etc, while series 2 eicosanoids are the
reverse. ( The exception is PGI2, prostacyclin, which is anti!
thrombotic -- but as well see below, its not a real exception in terms of the
practical implications). Series 3 LEAN toward the good: they are certainly
dramatically less inflammatory etc than series 2. Accessible details on the role
of eicosanoids in heart disease, cancer, and the whole mishmash can be found in
_The Zone_ and Simopoulos _The Omega Diet_, but the former ignores the role of
series 3, and the latter, that of series 2.

Bottom line: if you can lower the d5d:d6d ratio, you will produce more series 1
and less series 2 eicosanoids, thus improving your odds of long-term health.

Now, how do macronutrients -- and their effects on the glucacon:insulin ratio --
affect these enzymes? Hard human studies have not been done on this issue
DIRECTLY (but see below). However, extensive rodent data are available (reviewed
in 50-52). What these data show is that insulin (which is stimulated by both
CHO and protein, tho much more by CHO) stimulates, while glucagon (released by
protein exclusively) inhibits, the desaturation enzymes, so that higher P:C (&
thus an more-than-linearly higher glucagon:insulin, as discussed above) results
in lower EFA desaturation by delta-5 desaturase. This effect is reinforcedby the
fact that glucagon inhibits insulin release.

If the hormonal effects were the only factor involved, then the same would hold
for delta-6 desaturase. HOWEVER, the presence of protein ITSELF, sans
mediator, potently *activates* d6d, sufficiently (in combination, presumably,
with its effects on insulin) to overcome the inhibitory effects of glucagon, an
effect not seen with d5d. This fact is offhandedly explained as being due to
stimulation of protein synthesis, as if this self-evidently explained the
discrepancy. It does not, at least not to my educated laypersons eears. But the
end result is clear: the higher ones P:C, the more d6d is activated, and the
more d5d is inhibited. In other words, higher P:C means more series 1 good
eicos and less series 2 bad ones. It also means less-peroxidizable PUFA (DGLA
vs. AA) will be available for mt membrane incorporation.

But as you increase protein, you also increase glucagon relative to insulin,
which inhibits both d6d and d5d. So beyond a certain point, we expect that we
will see diminishing/negative/plateau returns on increasing P:C. And where is
theGoldilocks point for this effect? Glad you asked. A rodent study (53) found
tht the protein activatoin of d6d increases with isocaloric P:C, with the peak
activity reached at a ratio of 0.64,after which it levelled off. Unfortunately,
th next data point is P:C of ~1.0, so we dont know if an intermediate ratio
(say, 0.75 :) ) might have produced a higher peak, from which subsequent values
slowly fell. But clearly, a zonish P:C is the best range; at the very least, no
additional gains are to be made after P:C 1.0, and gains ARE to be made up to at
least 0.64.

But, you say, this is rodent data. Our hormonal metabolisms are different.
How do we know that the ratio will be at all similar in humans?

As noted above, the direct dietary effects on desaturases have not been
characterized, AFAIK. However, there is a fair amount of research comparing the
desaturase activity in healthy humans, insulin resistant persons/type II
diabetics, (who have unusually HIGH insulin levels) and type I diabetics (who
produce NO insuin themselves & have to shoot up). All of this ends up giving us
a consistent picture of the rle of insulin (but not glucagon, as yet, AFAIK) on
desaturases in humans. Here are the data:

(1) Type I diabetics fed DGLA show the same rise in TG and phospholipid DGLA as
do normals -- but their AA levels stay at baseline until they shoot up,
whereupon their AA levels climb to the normal range.  The effect of insulin and
the data from the literature of animal studies suggest insulin dependence of
delta 5 desaturase in humans. (71)

(2) Obese children have the same LA levels as normals, but higher levels of
fasting immunoreactive insulin, and of all downstream metabolites, & in
particular higher AA. We conclude that the significantly higher values of n-6
long-chain polyunsaturated fatty acids (LCP) in plasma lipids of obese children
than in age-matched controls may be caused by an enhanced activity of delta
6-desaturation, and we speculate that elevated fasting immunoreactive insulin
seen in obese children...may stimulate synthesis of n-6
LCP fatty acids. (72)

(3) Insulin action ... correlated with composite measures of membrane
unsaturation (% C20-22 polyunsaturated fatty acids ... ), unsaturation index ...
, a number of individual fatty acids and with delta5 desaturase activity ... The
results demonstrate that delta5 desaturase
activity is independently related to both insulin resistance (73).

(4)  Insulin positively correlated with increased C20:4n6/C18:3n6 (index of
delta
5-desaturase) (p < 0.05) and C20:4n6/C18:2n6 (index of overall n6 pathway
activity) (p < 0.01) in serum, and the n5 pathway in platelets (p < 0.01), but
there was no correlation for insulin with platelet C18:3n6/C18:2n6 (index of
delta 6-desaturase activity).  (74).

What about direct measurements of the results of P:C on eicosanoid synthesis in
humans? Well, we dont have them, although granted what has been covered to
date, itd be pretty damned surprising if things didnt work out similarly to
whats seen in rodents. However, early on in his work with atheletes & others,
Sears (54) developed a qualitative battery of tests with which to test out
different P:C for effects on eicosanoids. These are mocked, without explaining
their interdependence & underlying logic, in _Beyond_. Most of tests are based
on the known effects of eicos themselves (eg. vsodilation, keratin synthesis,
peristalsis); others are based on the known effects of insulin and glucgon
themselves on balancing blood sugar etc (see below), from which we can partially
extrapolate to eicosanoid synthesis as per the above; yet others appear to be
purely Sears intuition that you should feel good in the Zone. And what he
found (apparently in utter ignorance of (53), to which!
he never refers or includes in his bibliographies) was that the Goldilocks
point -- the P:C where people entered the Zone -- was between 0.6 and 1.0, and
for most folks, at 0.75. It was on the basis of THESE data tjt Sears set the
Zone goldilocks point here; again, he seems ignorant of the op cit rodent
data.

This may be a coinkidink, but its pretty damned striking if so.

And, strangely, the synthesis of the only good series 2 eico -- PGI2 -- is
actually inhibited by insulin (56). So youre not losing out on even THIS by
Zoning.

High-protein diets are widely believed to increase risk of heart disease. This,
I believe, is entirely due to the confounding variable that those who get the
most protein (especially in the US, which has unusually fatty meat) tend to also
get the most saturated fat and long-chain n6. When we isolate out this factor,
we find that women who eat more protein have a LOWER risk of ischemic heart
disease (48). Likewise, I find that, just as replacing CHO with MUFA improves
CVD risk factors, so it is with protein (49). This is to be expected, at least
from a cholesterol POV, because of the known effects of insulin and glucagon on
VLDL synthesis, CETP, and HMGCoA reductase (30, 70); also, the P:Cs effects on
vasodilation, thrombosis, hpertension, etc; and perhaps because more protein may
lower Hcy, counterintuitively REFERENCE. Hence the much greater risk of CVD
mortality in Syndrome X and diabetes, in which insulin is elevated, and the
benefits of the P:C largely nullified.

Now, Walfords third objection on the Zone is as follows:

>Third: the Biospherians were on 10-14% cals from protein, 10% fat, the
>rest carbohydrates, including lots of bananas (high GI index) and sweet
>potatoes; had BMI's averaging around 20 (i.e., good but higher than a
>lot of persons on the Internet CR list) -- but had health risk
>factors (blood sugar, lipids, etc) somewhat better than what seems
>the averages in the Internet group.

Ive already addressed everything here except glucose. Phil raises the same
objection:

>What I find curious is blood sugar levels being reported on this list
>(Zoners and some non-Zoners alike) that are not nearly as 'good' as
>those uniformly found in Walford's half-dozen Biospherians despite the
>latter's high banana intake.

And, curiously, they ALSO arent as good as Markoviks data, which (again) used
Zone macronutrients, but (crucially) did NOT balance P:C at every meal. This has
caused much angst amongst we Zone types, myself included. But in the course of
looking at the data on the impact on insulin secretion from adding protein to
carb, above (68, 69), as well as reading a paper on GI (80), I came across the
answer to this conundrum -- and it FURTHER emphasizes the superiority of the
Zone.

Lets start at the beginning. (68) reported that, as more protein was added to a
fixed amt of CHO, the initial glucose peak was blunted. This makes sense,
because (as noted in the discussion of this paper & related stuff, above) adding
protein does cause a mild increase in the insulin response to a meal -- a
less-than-fully additive one. Yet it does NOT, itself, significantly increase
glucose levels. So the extra insulin will drive a bit more sugar into the
muscles, blunting the blood glucose response.

Then, as the initial postprandial glucose & insulin surge wanes and the
proteins glucagon-stimulating effect comes into play, glucose levels would be
expected to rise again -- and so they do, whereas in the CHO-only meal they
continue to fall, more & more slowly.

So the picture is that, DOSE-DEPENDENTLY, higher & higher P:C (at least up to
0.86) result in smoother & smoother glucose responses: less extreme peaks AND
nadirs. Likewise, the glucose AUC was dose-dependently reduced by added
protein .

In short, the blood glucose response to adding increasing protein to a meal
looks pretty darned close to lowering its GI.

Now, this would seem to offer a prety attractive explanation for why we Zoners
have higher FBG than the Biospherans (although their intense physical labor is
clearly also a factor, this had begun before closure, & so doesnt explain the
DROP, tho it may explain a significant amount of the ABSOLUTE NUMBERS). This
may seem an unreasonable speculation from the similarity of their 2h glucose
curves, but work by Wolever (83) has shown that eating a low-GI supper leads to
greater insulin sensitivity at breakfast. And another trial (80) reported that
the increase in insulin sensitivity at lunch after a low-GI breakfast was
accompanied by increased plasma glucose just before the second meal, and that
meals which had just slightly higher GIs, and did not result in higher 4h
glucose levels, did not improve insulin sensitivity. So the finding or higher
FBG in Zoners is quite consistent with whats been found in low-GI meals -- and,
indeed suggests a benefit in sustained insulin sensi!
tivity.

IIRC, those Zoners who have both FBG and F insulin have seen no decrease in the
former but significant decreases in the latter, consistent with the above.

But what folks are worried about is AGE. So take pyridoxamine! No, no, htats a
joke. Seriously: the conventional wisdom in the group is that FBG is the key
number, since we dont spend much time in the immediate postprandial state, and
since it gives us a baseline level onto which the postprandial spike is added.
But glycation happens dose-dependently. According to Brand-Miller, in her
popular book GET REFERENCE, lowr GI foods do reduce, not just the 2h curve, but
the TOTAL GLUCOSE EXPOSURE from the meal, ever, in spite of the slight elevation
in the late period. And, in addition, it SEEMS TO ME that glycatoin must
proceed more than linearly with glucose concentration, so that doubling blood
glucose must more than double glycation -- just because of sheer kinetics. If
so, It seems to me that one is in much more danger from the massive postprandial
glucose spike than one is from slightly elevated FBG, even if the latter lasts
longer. And blood glucose over the 2h pospran!
dial period is both lowered in total amount (AUC), and made smoother and less
spiky. As in, 50 g glucose alone yields an AUC of 1700 mg*min/dL abpve
baseline, vs. 0.35 for the protein-added group. It therefore seems to me that a
higher P:C would significantly reduce glycation.

The best evidence for this would be to test glycation on high- and low-protein,
isocaloric diets in which P:C is held constant at every meal; I dont know that
this has been done. The NEXT best thing, however, would be to look at the
effects on glycation from high-and low- GI meals, due t o the similar effects on
postprandial glucose curves. Several studies have shownthat low GI meals do
reduce glycation in rodents; however, they were relatively short-term studies.
The only lifetime study comiparing different CHO sources for effects on AGE(82)
found (surprisingly) that, whereas CR inhibited glycation, different CHO sources
(from high-GI glucose down to low-GI fructose) does not. This at first might
seem a point against my hypothesis.

However, remember that (68) used a CONSTANT amount of glucose, with increasing
protein dosage, to achieve their results. As per the Zone, one isnt doing that,
but LOWERING CHO while holding protein constant (Sears purists) or actually
elevating protein (per Sherms extrapolation). And further remember that youre
actually to use low-GI CHO on the Zone in ADDITION to the higher protein intake,
and getting the GI-lowering addition of a relatively high %fat. So youre
looking at both lower total POSSIBLE glycemic exposure, and considerable
blunting of the postprandial glucose spike due to (a) higher P:C, (b) lower CHO
GI, and (c) GI-lowering mono fat, relative to a Walfordian mode.

And remember that theremay be tradeoffs, glycation-wise, in the lower-GI carbs
vs. higher ones: galactose and fructose, IF they circulate as such systemically,
are more potent glycators, unit er unit, than is glucose. This may explain the
lack of long-term effect on AGE of lower GI sugars: they lead to significantly
lower glucose, but somewhat higher levels of a more glycating sugar. Combining
the GI effect with the lower absolute CHO exposure from all sources, AND the
effects of higher P:C and fat:CHO ratios on the Zone, might be expected to tip
the balance.

PLUS, remember the insulin-sensitizing effect mentioned above. this wouldnt
play into the results of (68), as CR animals tend to gorge all at once, so they
have a 24h wait for their next meal; theres no guarantee that insulin
sensitivity is still significantly higher THAT much time after a low-GI meal,
whereas timing meals at 4h intervals (as I do) clearly does improve glucose
tolerance, per (80).

All that said: many Zoners have failed to see reduced HbA1C. So maybe Im full
of shit :). OTOH, many classical Walfordians arent seeing much progress here,
either.

Now, what about the really interesting issue: aging per se? Again, the evidence
appears to be that higher-protein diets decelerate aging. (Some of you just
thought, But wasnt that recently disproved? Read on!).

As part of his eat more protein post, op cit, Sherm provided these

>quotes from The Retardation of Aging and Disease by Dietary
>Restriction, by Weindruch and Walford:
> The average LS [lifespan] of rats on DR increased as the amount
> of protein in the diet increased suggesting that the
> effects of DR on LS may be enhanced by diets high in protein
> content. (pg 54) ... epithelial ... adrenal and thyroid
> tumor morbidity were ... inversely related to dietary protein
> ... In short, both LS and tumor data suggest that high
> protein diets accentuated the benefits of DR in Ross' colony.
> (pg 81) [the extremely restricted rats that did best were on
> a 51% calories-from-protein diet!]


Walford replied:

>First: looking at Table 2.4 in the Weindruch/Walford book, study 7, one
>observes that the shortest LSs were at 8% casein; but there wasn't much
>difference between 21% casein and 51%. In fact, 21% gave the longest
>MLS, better than both 30% and 51%.
>Looking also at Study 9, 10% casein was shortest, and 51% better than --
>but not much better --than 20%. With regard to tumor incidence, the stated
>comparison is between the 51% casein and the 8% casein. So the higher
>protein seems better but only when compared with a very low protein
>intake. The intermediate ranges might be even better.

At the time, I was not in posession of a copy of _The Retardation_, but WAS in
posession of the only paper of Ross which I could find in which various
%proteins were tested for effects on LS, tumor incidence, and malignancy (77). I
responded:

--------------------------------------------------------------------------

But that isn't what Ross' data shows. In fact, to my surprise, it
shows what we are constantly told that the data DONT show: that
MACRONUTRIENT COMPOSITION CAN INFLUENCE MAX LS, and that the higher
the protein, the longer the LS.

Turning to their [77] table 2, we find that there is improved max LS in
BOTH the Cr AND the ad lib groups, correlated postiively with
protein intake.

> >>>DAYS
> >>>
> >>>SURVIVAL AD-LIB % PROTEIN CR % PROTEIN
> >>>
> >>> 10% 22% 51% 10% 22% 51%
> >>>
> >>>900 8 2 6 145 116 149
> >>>1000 0 0 1 93 85 122
> >>>1200 0 0 0 48 61 91
> >>>1300 0 0 0 5 31 59
> >>>1400 0 0 0 0 11 24
> >>>1500 0 0 0 0 1 10
> >>>1600 0 0 0 0 0 3


Lest anyone object that what we're really seeing in the high-pro
CRONies is just adequaate-protein diet, note that the same results
were observed in the ALers.

Further, Ross' table 10, summarizing all tumor data, shows taht,
again for boht ALers and CRONies, the highest-protein groups had the
lowest ratios of malignant to benign tumors, and the lowest
AGE-SPECIFIC tumor rates of all isocaloric groups: that is, the
low-protein group had fewer cancers only because they died sooner --
thir rate of tumor formation was higher.

This is only one study, but they used a lot of animals (1600), and I
know of no contradictory evidence. Even [78] tends broadly to support these
conclusions.
------------------------------------------------------------

[After posting the above, but BEFORE Walfords recent proxy post to the list on
protein, I wrote the following]:
****************************************************
Again, at the time, I was not in posession of a copy of _The Retardation_, and
thought there must simply be a mistake of some kind in same. I just got a copy
out on interlibrary loan, however, and what I actually find is that Walford is
referring to ANOTHER study, also by Rosss group (79). I havent seen this
study, but will assume that the book accurately summarizes the data. And, yes,
in this study *a* group of 21% casein rats did outlive *a* group of 51% rats,
albeit not by much: 49 mo vs. 46. Now, right off the bat, theres a question of
the power of this result, since there were more than half again as many rats in
teh 21% group as in the 51%, which can result in more absolute numbers of
animals reaching a higher max LS just by default; a similar problem exists with
the lower TOTAL population of this colony compared to (77)s, which makes the
latter a more important study to look at. But sheer population numbers are the
LEAST of the problems with this study.

It would appear taht the Grand Old Man wasnt reading the tables as carefully
as he might when he wrote his reply above, for two reasons. First, from the
table itself, I note that the 21% casein CR group in THIS study (79) were only
fed 16 Cal/day -- vs. 25 Cal for the 51% casein CR rats! The average AL rodent
in this study ate 75.2 Cal/day, so the 51% casein group were 66% restricted --
but the 21% casein animals were *78%* restricted! By contrast, (77)s diets
were isocaloric.

And then, I see that the tables notes indicate, Groups 7g & 7h [the 21% casein
CR and AL groups in (79), respectively] ate diets enriched in vitamins and
minerals relative to the other groups in the study. Now, whether this means
the 21%-protein animals diets were enriched just enough to make the 21%
casein CR diet isonutient with less severely restricted 30% and 51% casein CR
animals, or were higher nutrition in an absolute sense, is unclear from the
table, as BOTH the AL & CR med-pro groups diets were so enriched. Having
looked at the paper, Im still unclear what the story is.

But whatever the case, we see that the 21%-protein animals were 12% more
restricted, but they only lived 6% longer. Further, the AVG LS of the two
groups in question were the same! When you extend max LS but DONT extend avg,
it means that more critters are dying off early (relatively speaking) under
the influence of the regime.This is hardly a ringing endorsement of the
21%-protein regime, esp if they were more (micronutrient) ON as well as more
CR.
***************************************
By strange coincidence, Walfords second analysis of (79) etc , which confirms
its obscurity and the difficulty in using it to make meaningful comparisons,
came just DAYS after I wrote the above. Importantly, W notes that, in the more
easily-interpreted, better-controlled (77), while max LS was greater in the
high-protein group, mortality-rate doubling time (a more accurate measure of
aging per se, many agree -- see Austad) was better in the 21% casein group, as
per data from Finch, _Longevity, Senescence and the Genome_, Table 10.1 on page
508 (thanks to Sherm for providing this reference: I dont have Finch to hand).

For graphic illustration of the relationship between a survival curve and the
slope of a line of age-specific mortality, and thus MRDT, see:

http://brittanica.com/bcom/eb/article/single_image/0,5716,4555+asmbly%5Fid,00.ht\
ml


Well, that SOUNDS bad, I agree. However, aside from the inherent
counterintuitiveness of a discepancy between max LS and MRDT -- between the
longevity of th longest-lived, and the rate of aging, which is the very factor
which determines same -- there is actually some reason to question Finchs math
in calculating MRDT. Again, I am not just hand-waving. Here is Aubrey de Grey on
the subject:


The main quarrel that I have with the usual way of calculating MRDT (as set
out by Finch) is that it considers
the whole life table from puberty to the death of the oldest member of the
population. This has problems at both
ends. At the young end there are many known examples of early mortality of a
substantial minority of a
population, resulting from environmental factors which may be altered by an
intervention such as CR but do not
intuitively have much to do with the rate of aging. At the old end there is
the well-known deviation from the
Gompertz curve, the deceleration of mortality, whose magnitude is -- according
to some models -- highly
dependent on the population's degree of heterogeneity (either genetic or due to
environmental influences during
development) for characteristics that affect the rate of aging.

http://x70.deja.com/[ST_rn=ps]/getdoc.xp?AN=593787913&CONTEXT=965958005.97681411\
7&hitnum=0

To eliminate the prejudice of the excessive early mortality (seen, NB, in the
22% casein group (which, of course, is not exactly a big score in favor of this
regimen)) and the effects of genetic heterogenity, Aubreys calculation methods
(personal communication), after much math, boils down to a formula which ought
to be surprisingly simple:

But the slope is (as above) 0.5 divided by the difference bwtween the age at
which 1/4
are dead and the age at which 3/4 are dead. So, that difference is [2.27*] the
MRDT itself, not even any scaling factor needed.

Now, this is actually made a bit more complicated, because Ross only reports his
data every 100 days. Thus, I made the assumption that animals died at an exactly
even rate in these 100 day periods, so that (eg.) if there are 197 animals alive
on day 700, and 176 on day 800, and I want to know when 187.5 animals are still
alive (the 3/4 point), then I calculate that this point is reached at day 700 +
{100 * ([197-187.5]/[197-176]) } = 745.2. And so forth.

Quoth Da Man:

I bet that this way of calculating MRDT gives numbers that correlate exactly
with max LS in the Ross+Bras study.

He wins his bet!

I pumped the data for (77) thru, with the above assumption, and found an MRDT
for the 51% protein group of 403.7 days, versus 398.4 for the 21% protein
group. So by THIS method, the Gompertz slope -- the rate of acceleration of
mortality -- is ever-so-slightly HIGHER in the 21% casein group -- or, IOW, it
takes just a little bit LONGER for the 51% casein groups age-specific mortality
rate to double.

Or, to simplify further: the high-protein group was aging more slowly. But
because the 22% casein group experienced greater early mortality, the illusion
was cast that they had a slower rate of aging later on.

And, in fact, (77) actually PROVIDED the age-specific mortality rate for each
100 day period -- and its consistently lower, after the early period before 400
days, in the 51% protein group.

And how could this happen? Heres ANOTHER of my little theories at work.
Remember what has come before: higher P:C, up to a point, somewhat increases
the activity of d6d, and inhibits the activity of d5d. The result to be
expected of this, in terms of PUFA available for MIM incorporaation, would be
that higher P:C leads to somewhat more medium-chain PUFA, but considerably less
long-chain PUFA: eg. somewhat more SDA (18:4n3) but much less EPA (20:5n3) and
(I ASSUME) even less DHA (because of the extra desaturase step required, which
(at the very least) is rate-limiting, and (I expect) should also be inhibited by
glucagon and stimulated by insulin). As has been discussed on a recent thread,
it is my hypothesis taht aging is accelerated by the incorporation of more
long-chain PUFA in the mt inner membrane. So the above scenario suggests that a
higher P:C, within the Zone, will actually slow aging. and if, as I do, one
restricts ones PUFA intake to the ACTUAL EFAs (LA and ALA!
), the total long-chain PUFA produced will be reduced further, due to
competition at BOTH rate-limiting steps for the desaturase enzmes, without
keeping DHA out of brain cell membranes. These rodent data thus happen to tend
to reinforce my pet hypothesis: although the P:C was too high to be optimal in
the longevous 51% casein group, it was also too low in the shorter-lived 22%
casein group -- and the rodent data suggest that the declining slope, above the
goldilocks point, must be much lower than the slope leading up to it from a
desaturase POV.

Note that this is, in fact, observed in CR animals (84): aging is associated
with greater accumulation of long-chain PUFA in MIM, which is retarded by CR.
Higher P:C is thus reinforcing a known action (and perhaps a causal one) of CR.

And then theres the human evidence. IF Sears review of the evidence is
accurate -- and my experience has been that it generally is, and abstracts to be
cited tend to suggest that he is here too [although I positively BEG EVERY
PERSON ON THIS LIST to see if their local Universities carry any of these
journals, and to dig up the papers he cites (85-88) which my U doesnt carry (I
beg you! Id pay you for copies! Youd be a hero f the Revolution!)] -- then
THE OKINAWANS ARE IN THE ZONE.

In Sears latest book (89) , I find the following statements, evidently derived
from the above papers:

-Chart showing that the Okinawans eat 100 g of soy protein per day (p. 12). Same
statement made on pp. 25 and 231. I believe that Sears is wrong, here: I think
he has confused intake of soy PROTEIN SOURCES with soy protein itself. An
article I read (90) suggests that the average Japanese person eats ~34 g of
soyfoods (IIRC) which provide 7.7g pf pprotein (Im quite sure of this datum).
Sears suggests that the average is 40 g.

-Statement that they eat twice as much fish as mainland Japan (p. 12).

-Statement that they eat 2-3 times more vegetables than mainland Japan (ibid).

-Statement that their diet is ~30% fat (p. 235).

State,emt that the most imprtant factor for teh Okinawan longevity is that
they consume 20 to 40 percent fewer calories than the Japanese. (p. 12)

In the abstracts to (85-88), I find statements which are certainly consistent
with the above, although they dont give numbers (PLEASE get the papers,
folks!!); more importantly, however, what they DO say is that the incidence of
longevity within the Japanese population is correlated with more protein and fat
in the diet -- ie the more Zonish the diet, the higher the incidence of
centenarianism:

They took rice or potato as carbohydrate with abundant vegetables and vegetable
protein or fish protein. (87)

Nutrient intakes in 94 Japanese centenarians investigated between 1972 and 1973
showed a higher proportion of animal protein to total proteins than in
contemporary average Japanese. 2. High intakes of milk and fats and oils had
favorable effects on 10-year (1976-1986) survivorship in 422 urban residents
aged 69-71. The survivors revealed a longitudinal increase in intakes of animal
foods such as eggs, milk, fish and meat over the 10 years. 3. Nutrient intakes
were compared ... between a sample from Okinawa Prefecture where life
expectancies at birth and 65 were the longest in Japan, and a sample from Akita
Prefecture where the life expectancies were much shorter. .. the proportion of
energy from proteins and fats were significantly higher in the former than in
the latter. (86)

we studied geographic distribution of centenarians in Japan, ...By prefecture,
the highest
proportion lived in Okinawa (133.8), whereas the fewest were found in Akita
(8.9) [see above on diet comparisons between the 2] .... correlation
coefficients
between proportion of centenarians and protein (% of energy) was positively
significant, while intake of total energy was negatively significant. (85)

The energy intake of the Okinawan centenarians living at home was about 1,100
kcal/day for both sexes, which was similar to that of centenarians throughout
Japan. (88)

This reinforces my belief above: 100 g of soy protein would barely leave any
room for anything else in an 1100 Cal diet -- let alone double the large
Japanese national average in fish!

Now, if, indeed, the Okinawan centennarians eat an 1100 Cal diet; if it contains
a great deal of protein, from fish and soy, and greater protein intake is
associated with greater longevity; if it is 30% fat; if the carbs are fairly
low-GI, high-nutrient ones, at least compared to the average Japanese person
(who certainly eats a lot of rice & not enough veggies) -- Indeed, there really
isnt much room for rice or potatoes; then then their macronutrient ratios are
must be pretty damned Zonish. If we really can take Sears 100 g soy protein
figure seriously, then the numbers work out to be P:C:F of > 36: <34: 30. But
even if not, it would seem that the Okinawans are in the Zone -- and Zonishness
of diet correlates with % of centenarians in the Japanese population.

MISCELLANEOUS OBSERVATIONS, THROWN IN TO FINALLY FINISH AND POST THIS MONSTER:

Lower than average protein intake (ie. 100g +, far more than is NEEDED for the
sedentary AL) is not protective against kidney disease in longitudinal studies
in humans (91). Nor does it evidently improve the clinical outcomes in persons
wh already HAVE kidney disease (92). The protection against nephropathy in CR
animals may perhaps explain why some studies have reported such benefits: cut
protein out of SAD, and you cut out a lot of excess Cal (from saturated fat --
esp in fatty US meat). Some (93-95), but not all, studies suggest that protein
restriction has little or nothing to do with this protection, and is not
protective without CR. (96) sounds interesting in this regard, tho I have not
seen it.


High CHO intake, irrespective of GI, increases odds of diabetes in men (97) and
women (98), and heart disease in women (99) -- all the worse if high-GI, but
total CHO is the major factor; total available CHO intake, ignoring fiber, also
increases ones odds of cancer (100), a finding supported by other studies on
foods high in glycemic load (101, 102).

Enough!! To press!

So, folks, here is my closing threat. I am, for once, going to show the
foresight to save this sucker in my sent-mail archive. And the next time
someone says

Sear's theory is pretty much quackery. There seems to be no
>experimental or epidemiological justification.

... I serve notice to all involved that I will post the whole, unGodly,
Gargantuan mess all over again.

Possibly with ADDITIONS, if any striking research comes my way.

Remember, O children of high-carb darkness: you were warned.

-Michael




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