Monday, December 28, 2009

Intermittent fasting prolongs life in mammals

Although experiments have demonstrated that caloric restriction (CR) can extend lifespan in yeasts, worms, mice, and possibly primates, few people would want to pay the price of caloric restriction to extend life. The Caloric Restriction Society has a page listing the risks of CR, which include

-chronic hunger, cravings, or food obsession
-large loss of body mass, up to 25% below normal
-loss of strength
-low body temperature
-decreased testosterone
-menstrual irregularities
-slower wound healing
-loss of emergency energy reserves

When Ancel Keys did the Minnesota Starvation Study, he restricted young men to 1800 calories daily, 20-40% below average needs -- similar to recommendations for caloric restriction for longevity. His goal was to get the men down to 25% below normal weight -- the CR society also suggests reaching 10-25% below normal weight.

As reported in the Journal of Nutrition, one of the participants in this experiment, Harold Blickenstaff, "recalled the frustration of constantly thinking about food:

I don’t know many other things in my life that I looked forward to being over with any more than this experiment. And it wasn’t so much ... because of the physical discomfort, but because it made food the most important thing in one’s life ... food became the one central and only thing really in one’s life. And life is pretty dull if that’s the only thing. I mean, if you went to a movie, you weren’t particularly interested in the love scenes, but you noticed every time they ate and what they ate. found men depression, and other effects making for many a long life not worth living.

Energy restriction had numerous adverse effects in the Minnesota Study:

"They experienced dizziness, extreme tiredness, muscle soreness, hair loss, reduced coordination, and ringing in their ears. Several were forced to withdraw from their university classes because they simply didn’t have the energy or motivation to attend and concentrate."

The subjects of the Minnesota Starvation Experiment developed all the visible signs of starvation: "sunken faces and bellies, protruding ribs, and edema-swollen legs, ankles, and faces. Other problems such as anemia, neurological deficits, and skin changes became apparent." The men lost interest in sex, and had no functional energy.

Again from the Journal of Nutrition: "The St. Paul Dispatch reported: '... the ... men on the starvation diet have lost so much physically and mentally that their ambition is gone, their will to go forward is gone, and they cannot do heavy work such as farming, mining, forestry, lifting and many other types of work necessary to rebuild war-torn Europe.'"

So, if you choose caloric restriction, you might spend more years breathing, but would you call that living? Do we have a better way?

On the CR (Caloric Restriction) Society International website FAQ page you can find this:

“Are there any other ways of retarding biological aging or extending lifespan besides CR?

None known to science at this time. .. as of this writing, there is no reliable evidence to support the notion that anything besides CR is capable of retarding biological aging or extending maximum lifespan in adult mammals. “

Yet just above this statement, on the same page, you will find this:

Studies have shown that rodents fed all they can eat [emphasis added], but fasted every two, three or four days, also have an increase in longevity, though the increase is not quite as great as that of rodents on the standard kind of CR (when implemented in mature organisms). For some people, this might be an easier way of doing CR since hunger is limited to two or three days a week.

A humane approach to life extension research would look for a method that would not entail all of the harmful side effects listed above. I personally would not want to live a long, cold, depressed, constantly hungry, food-obsessed, neutered life having insufficient strength, muscle mass, or energy for activities I enjoy, and unable to heal wounds at a normal rate.

I think intermittent fasting can give you more life to live while preserving your ability to live it.

IF extends lifespans of Wistar Rats

In 1945, Anton J Carlson and Frederick Hoelzel of the department of physiology at the University of Chicago published “Apparent Prolongation of the Life of Rats by Intermittent Fasting” in the Journal of Nutrition. This paper detailed the results of their studies in which they put adult rats on intermittent fasting schedules of 1 fast day in 2 days, 1 in 3 days, and 1 in 4 days, compared to control animals allowed to eat ad libitum.

In this study, they fed the rats in four groups, three getting one of three different omnivorous diets and one getting a vegetarian diet.

The three omnivorous diets included:
1) A basic diet consisting of 61.5% cooked and dried whole veal (including practically all of the edible parts of calves, excepting excess fat and blood), 31 % corn starch, 2% powdered yeast, 1% cod liver oil, 1.5% inorganic salt mixture and 3% veal bonemeal. This diet provided 35% protein.
2) The basic diet (#1) plus 10% finely ground alfalfa stem meal.
3) The basic diet plus 5% psyllium seed husk and 5% specially prepared kapok fiber.

The one vegetarian diet consisted of 50% whole wheat flour, 10% peanut flour, 7% lima bean flour, 7% wheat gluten flour (containing 80% gluten), 7% corn gluten meal, 7% linseed meal, 5% powdered yeast, 5% alfalfa leaf meal and 2% NaCl. This diet provided approximately 30% proteins.

Hoelzel had previously performed a study in which he found that rats fasted every other day and fed a diet low in protein on non-fast days developed peptic ulcers within about 2 weeks, but rats fed adequate protein did not develop ulcers.

All groups got lettuce trimmings daily. During feeding periods, they supplied food continuously to all groups, so rats ate ad libitum when not fasting. Fasting began at 42 days (before which all rats received identical feed) and continued until the rats died.

Table 1 of the paper shows the effects on lifespan of fasting 1 day in 2, 3, or 4 days in male and female rats.

Fasting increased the average lifespan of males by 90 days, and that of females by 23 days.

Optimum fasting interval

Upon detailed analysis of their data, Carlson and Hoelzel found that rats fasting 1 day in 4 and 1 day in 2 displayed complications by “extraneous factors” more than either control rats eating ad libitum or rats fasting 1 day in 3. Those factors included:

1) The earliest male and female deaths occurred in the groups fasted 1 day in 4, and it appeared that other rats did not fare as well fasting 1 day in 4 as in 1 day in 3. Carlson and Hoelzel suggested that “Perhaps the amount of food consumed in 3 days of feeding, with increased voracity but without proportionately increased capacity after 1 day of fasting, constituted a greater physiological overstrain than the amount of food consumed by the controls or by the rats fasted 1 day in 3.”
2) Fasting 1 day in 2 produced both a greater mortality rate and the longest-lived rats. The males and females fasted 1 day in 2 also began dying earlier than the rats fasted 1 day in 3. Carlson and Hoelzel commented: “Evidently fasting 1 day in 2 and beginning this at the age of 42 days was too much fasting for some rats. One of the females fasted 1 day in 2 apparently died of a hemorrhage from a chronic duodenal ulcer.” Fasting 1 day in 2 produced the longest-lived male and female rats, 1052 and 1073 days respectively, but the average rat did very poorly on this level of fasting.

Carlson and Hoelzel concluded that the optimum amount of fasting for the average rat in their study was 1 day in 3, or about twice weekly. This fasting frequency produced a 15% increase of average lifespan for females and 20% for males.

Of interest, in their raw data (Table 1), the average lifespan of male rats fasted 1 day in 4 did not significantly differ from those fasted 1 day in 3. Females fasted 1 day in 3 actually on average lived longer than those fasted 1 day in 2, but the reverse for males.

Another way to interpret this: Fasting 1 day in 2 produced a restriction of calories that proved too harmful for the majority of rats. Fasting 1 day in 3 or 4 produced the optimum result without daily caloric restriction.

Taking the average lifespan of 75 years in the U.S., this would mean IF twice weekly could increase the span to 86 to 90.

IF did not affect growth

Whereas 40% CR adversely affects muscle growth and mass, in this study, Carlson and Hoelzel found no or only small effects on growth or body mass in rats fasted 1 day in 4 or 1 day in 3.

Under unrestricted feeding conditions, male Wistar rats reach 450-520 g, and females reach 250-300 g.

In this study Carlson and Hoelzel compared littermates fed ad libitum to those fasted 1 day in 2, 3, or 4 days.

Using litter mate controls, male rats fasted 1 day in 4 attained body mass 91% of males fed ad libitum (413 v. 449 g), those fasted 1 day in 3 attained 85% of the mass of ad libitum males (339 v 397 g), and males fasted 1 day in 2 attained 74% of the body mass of ad libitum littermates (265 v. 356 g).

Female rats fasted 1 day in 4 attained body mass 89% of ad libitum females, those fasted 1 day in 3 attained 89% of ad libitum females, and those fasted 1 day in 2 attained body mass 85% of ad libitum females.

Again using litter mate controls, in some cases fasted rats actually had longer femurs than rats fed ad libitum, illustrating that intermittent fasting did not impair healthy tissue growth. In contrast, as stated by the CR Society's Risks Page, "Physical growth may be impaired by calorie restriction, as observed in lab animals."

Genetic controls

Carlson and Hoelzel found a large variation in response to fasting and feeding regimens. All rats were Wistar variety, and regardless of regime, 67% of all rats died between ages of 550 and 850 days, and 85% between 400 and 900 days. Further, “Some littermate rats, after having been kept from 400 to 1000 days on widely differing nutritional regimens, died within 24 hours or a few days of one another. Four of the twelve rats that lived to be over 1000 days old belonged to one of the seventeen litters.” Thus, genetic factors played a strong role in mortality.

IF influence on development of disorders leading to death

Carlson and Hoelzel also found that fasting rats had retarded development of mammary tumors, both in terms of age of onset and size of tumor, proportional to the amount of fasting. The following table from their paper displays the data.

Mammary tumors occurred in 37% of ad libitum female rats, compared to 29% of females fasted 1 day in 4 , 36% of those fasted 1 day in 3, and only 7% of those fasted 1 day in 2.

Average weight of tumors in ad libitum females equaled 193 g, versus only 67 g in rats fasted 1 day in 4 and 36 g in those fasted 1 day in 3.

Rate of tumor growth was +134 g/100 days in ad libitum rats, +48 g/100 d in rats fasted 1 day in 4, +42 g/100 d in rats fasted 1 day in 3, and +13 g/100 d in rats fasted 1 day in 2.

IF extends healthy lifespan

Carlson and Hoelzel thus showed in 1945 that intermittent fasting 1 in 3 days extends healthy lifespan of rats by 15-20% compared to ad libitum feeding, without daily food restriction (hunger), restriction of protein intake (these rats had 30-35% protein diets), impairing healthy lean tissue growth, or causing extreme loss of body mass.

It looks to me like IF offers a rational alternative to daily caloric restriction.

Monday, December 21, 2009

High dietary animal protein links to lower population growth and greater longevity

Roger Williams, the biochemist who first identified, isolated, and synthesized pantothenic acid, wrote a book titled Nutrition Against Disease (Pitman, 1971), in which he has a chapter titled "How Can We Delay Old Age?" In this chapter he discusses human population growth, because the goal of extending life span conflicts a bit with the growth of population. He points out that if life spans get extended and population growth also continues, in 200 years "Tokyo, New York, and London would each have populations several times that of the entire present world population."

In this context he remarks that in The Geography of Hunger, the author Josue d Castro states that he thinks that "hunger, particularly protein deficiency, is an important factor in creating the problem of overpopulation." To support his hypothesis, de Castro cites several observations that support, such as the fact that cattle become sterile if overfattened. de Castro also produced the following table indicating that human populations display an inverse relationship between birth rates and amount of dietary animal protein.

Williams comments on this data (collected before the introduction of hormonal contraception):

"There seems, however, to be an interesting principle involve which should be further explored. Nature does take measures to prevent the extinction of a species, and when extinction is threatened––by starvation for example––it may be that an exaggerated sex urge is one of he devices used to perpetuate the race. It may be that this contributes to the high birth rate among people who are ill fed. A parallel is found in the area of plant physiology where t has been observed that plants often grow vegetatively as long as well fertilized, and tend to go to seed (reproduce) only when conditions become adverse.

The contrary possibility that a decrease in human birth rates could automatically be brought about by the provision of certain nutritional factors is at least worthy of study.”

Of interest, international data from 2004 also indicate that healthy life expectancy may also correlate inversely with animal protein intake. The following table based on WHO data shows that nations with lower animal protein intake and higher birth rates (e.g. Mexico, China, Thailand, India) generally have lower life expectancy than nations with higher animal protein intake and lower birth rates (e.g. Japan, Sweden, Switzerland, Italy).

These data suggest that vegetarian diets both increase population growth and decrease life expectancy. It does look like these two phenomena (increased birth rate and decreased life expectancy) arise from a common biological condition, and quite possibly de Castro and Williams have named it: animal protein (and perforce, methionine) deficiency.

Addendum 11/18/11:

I made a couple of important errors in my reasoning in this post:

1.  The reduced fertility found in modern nations with higher protein intake could equally be interpreted as an indication that high intake of animal protein might increase the prevalence of infertility in humans. Thus, the data may indicate that low animal protein intake improves fertility.

In fact, we have data indicating that high animal protein intake poisons the uterus with ammonia, reducing the viability of embryos.

“These data show that consumption of a high protein [25%] diet results in the excess accumulation of ammonium in the fluid of the female reproductive tract of mice. These high levels of ammonium subsequently impair the formation of the fetal progenitor cells and increase cell death at the blastocyst stage. These data from in vivo-developed mouse blastocysts are similar to those for blastocysts developed in culture in the presence of 300 uM ammonium. Therefore, it is not advisable to maintain mice on a high protein diet. These data have significant implications for animal breeding, and for patients attempting IVF treatment.”
Gardner, D. K., Stilley, K. S., Lane, M., 2004. High protein diet inhibits inner cell mass formation and increases apoptosis in mouse blastocysts developed in vivo by increasing the levels of ammonium in the reproductive tract (abstract). Reprod. Fertil. Dev. 16(2):190.

…amino acid inclusion, especially that of glutamine, significantly increases the level of
ammonia within embryo culture media systems. It was shown that the benefits of amino
acid addition could be annulled by the effect of ammonia build-up, partly from degradation of glutamine over the course of embryo culture, and partly as a result of deamination of amino acids during metabolism. Early embryos appear to be sensitive to levels of ammonia as low as 100 mM and levels above 300 mM yield significant detrimental effects.”
Thompson, J. G., Lane, M., Robertson, S., 2006. Adaptive responses of early embryos to their microenvironment and consequences for post-implantation development. In: Wintour, E. M., Owens, J. A. (Eds.), Early Life Origins of Health and Disease. Adv. Exp. Med. Biol. 573. Springer, New York, NY, pp. 58–69.

2.  At the time the data was collected, the populations with low animal protein intake, high fertility, and low life expectancy also had relatively high infant mortality rates, which drives down the average the life expectancy.  Thus, this data does NOT show that high animal protein intake increases longevity.   Further, although most consider high infant mortality a terrible thing, in fact it is a pretty normal biological phenomenon; most organisms produce far more fertile seeds than surviving offspring.  Modern medical care reduces infant mortality, possibly by preserving lives of weaker, more disease-prone individuals.

3.  The most long-lived nation on the second table is Japan, but Japanese do not have a 'liberal' animal food intake by U.S. standards, although it is higher than in Mexico, China, Thailand, etc..  However, here again Japan has a low infant mortality rate compared to developing nations, making it look as though adults live longer in Japan than in those developing nations, when in reality the main difference is fewer deaths in infants in Japan versus developing nations.

Thursday, December 17, 2009

Fructose makes bellies fat

Thanks to Eric for alerting me to this article.

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans

Not much time to comment on it, so a quick look. The research team fed people diets in which 25% of calories came from either a glucose- or a fructose- sweetened beverage.

The results: "Consumption of fructose-sweetened but not glucose-sweetened beverages for 10 weeks increased DNL [denovolipogenesis], promoted dyslipidemia, decreased insulin sensitivity, and increased visceral adiposity in overweight/obese adults."

Small dense LDL results: The glucose-consumers had no net increase in the apparently harmfull small-dense LDL. "In contrast, fasting sdLDL concentrations increased progressively in subjects consuming fructose."

Mean 24 hour triglycerides increased 2.5% in glucose-consumers, 18.2% in fructose-consumers.

For glucose consumers, 23 hour triglyceride area under curve decreased by 32%, whereas for fructose consumers it increased by 99%.

Fasting oxidized LDL increased by 0.7% in glucose consumers, but 12.8% in fructose-consumers.

Cane sugar (white or brown) and high fructose corn syrup both provide about 50% of their carbohydrate as fructose. Honey consumed occasionally by hunter-gatherers has less fructose, at about 39%.

This study gives some indication why diets based on starch (primarily glucose) but containing little fructose do less health damage than diets containing plenty of sugars.

Wednesday, December 9, 2009

McDougall on Mammography

I certainly don't agree with John McDougall's dietary philosophy, but I do agree with his recent article on Huffington Post "ACS Chief Sends Mixed Messages On Mammography."

A choice observation he makes:

"The burden of proof of 'the benefits outweighing the harms' rests with those making the recommendations--the American Cancer Society and its Chief Medical Officer in this case. Dr. Brawley has voiced doubt about the benefits of mammography, and now appears conflicted by communicating two opposing stands in less than a month. The American Cancer Society, on the other hand, has remained steadfast in a position that enhances the profits of breast cancer-related businesses, regardless of the effects on women."

As he points out, a typical breast tumor has been growing for ten years (going from one cell to 1 cm in diameter) before a mammogram can detect it:

"Adequate scientific evidence to stop mass screening programs, such as mammography, has been readily available for more than three decades. In 1976 Pietro M. Gullino presented his findings on the natural history of cancer, showing 'early detection' is really 'late detection,' at the Conference on Breast Cancer: A Report to the Profession, sponsored by the White House, the National Cancer Institute, and the American Cancer Society. He explained: 'If the time required for a tumor to double its diameter during a known period of time is taken as a measure of growth rate, one can calculate by extrapolation that two-thirds of the duration of a breast cancer remains undetectable by the patient or physician. Long before a breast carcinoma can be detected by present technology, metastatic spread may occur and does in most cases.' This report was subsequently published in the journal representing the American Cancer Society (Cancer 1977 Jun;39(6 Suppl):2697-703)."

The drive for so-called "early" detection does serve people who have invested in expensive radiologic equipment. If your physician recommends early mammograms, you might want to find out if s/he has investments in or business ties with radiology centers.

It also leads to a lot of unnecessary medical intervention:

"Just as tragic is the devastation to the lives of millions of women with indolent cancers (the latent forms) that would have never appeared in their lifetime if no one had been busy looking for them with screening programs. Once found, these nonthreatening lesions are aggressively treated with life-changing surgeries, radiation treatments, and/or chemotherapies."

Having studied it for about 20 years now, the "science" of cancer treatment in the U.S. has about as much "science" to it as the lipid hypothesis. I can only conclude that it has more commercial than scientific basis. And all dissenters, such as Max Gerson, who produced evidence of cancer reversal with dietary intervention, are labeled nutcases, etc.

Imagine if it became commonly known that cancer can be cured by dietary interventions. What would happen to all those cushy jobs for those searching for cures? The ACS etc. have perverse incentive. So long as the cure is elusive, they continue to have cushy jobs and lots of donations.

Why is this relevant on a paleo blog? Because cancer is a disease of civilization, largely caused by neolithic foods and insulin levels, and we have evidence that paleo diets can prevent and probably reverse some if not all cancers.