Kurt G. Harris MD

The PāNu approach to nutrition is grounded on clinical medicine and basic sciences disciplined by knowledge of evolutionary biology and paleoanthropology. The best evidence from multiple disciplines supports eating an animal-based diet high in fat, low in cereal grains and relatively low in carbohydrate.

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« Calorie Restricted Monkeys Part II | Main | Acetaminophen and the War on Drugs »
Tuesday
Jul142009

Calorie Restricted Monkeys Part I



No doubt many of you have seen mainstream media reports of this study, which just appeared in the journal Science. Here is the abstract:

Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys

Ricki J. Colman,1,* Rozalyn M. Anderson,1 Sterling C. Johnson,1,2,3 Erik K. Kastman,2,3 Kristopher J. Kosmatka,2,3 T. Mark Beasley,4 David B. Allison,4 Christina Cruzen,1 Heather A. Simmons,1 Joseph W. Kemnitz,1,2,5 Richard Weindruch1,2,3,*

Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.

This study was conducted over a 20-year period not more than a few hours from my home, at the Wisconsin National Primate Research Center in Madison, Wisconsin, USA. 

Caloric restriction (CR) has been studied in animal models since 1935, but only in the last two decades has there been serious experimentation with animal models to investigate CR as a method of prolonging life and ameliorating diseases associated with aging. Prior to the current study, (which I will hereafter abbreviate as CW09 after Coleman and Weindruch, the first author and research group leader, respectively) CR was demonstrated to increase lifespan in such organisms as yeast, worms, flies and mice. CW09 is the first published study claiming reduction in mortality and aging related diseases in a primate model.

The study began in 1989 with 30 male rhesus monkeys (macaca mulatta) and an additional 16 males and 30 females were added in 1994, for a total of 76 animals studied. All animals were adults aged 7-14 when entering the study. The monkeys first had their baseline ad libitum caloric intake established through observation over several months. This intake was highly variable between individuals (personal communication – RJC). They were then randomized to either the control (C) or calorie restricted (CR) groups. C animals continued to eat ad libitum, and this was ensured by adding an additional 20g of feed after any period where they ate all their allotment. (PC – RJC) In general, the C animals kept their caloric intake, once established, relatively constant over the duration of the study. (PC – RJC) The CR animals, after their baseline intake was established, had their allotments reduced by 10% per month for three months, with the final allocation of food 70% of their baseline caloric intake, a 30% reduction.  The CR monkeys were therefore on a calorically fixed diet for the remainder of the study. Note that they were not all on the same diet; each was on 30% less calories than their own established baseline.

The researchers performed periodic assessments over the 20 year period, including assessment of glucose and insulin metabolism using a frequently sampled intravenous glucose tolerance test (FSIGTT), assessment of physical parameters including abdominal circumference, adiposity, energy expenditure, and collection of the autopsy findings on all animals who died during the study period. They also performed high resolution brain MRIs on all animals with a 3.0 T MRI system.

The most impressive “data”, is not quantitative, yet familiar to anyone in the medical field who deals with “hard living” human patients who smoke or have diabetes. There was a very obvious differences in biological age judged simply by the animals’ appearance. The images of the two monkeys at the top of this article show two 28 year-old monkeys. The one on your left is a control animal and the one on your right is calorie-restricted. Note the skin and hair appearance as well as the facial appearances.

Measured physical differences included:

1)   Decreased adiposity (obesity) in the CR group which was maintained for the duration. No surprise to anyone as the researchers controlled intake completely. This is also achievable with very low carbohydrate (VLC) ad-lib diets in humans.

2)   Despite 30% lower calories, and lower average total weights, CR monkeys increased their lean body mass (LBM) in the early years of the study and then their LBM declined at a slower rate than the C monkeys as they aged. Loss of muscle with age is known as age-associated sarcopenia, and in humans accounts for significant morbidity in the elderly, leading to falls and difficulty with activities of daily living. This points to the anti-anabolic effects of high insulin levels at the muscle level. I believe this supports IF (intermittent fasting) and doing your workouts in the fasting state for optimal muscle anabolism. I and several of my more athletic colleagues have documented increased lean body mass despite decreased total weights with VLC ad lib diets - the monkeys had a similar effect on CR. I believe this was mediated via lower basal insulin levels.

3)   Of the original 38 C animals, 5 developed frank diabetes and 11 had pre-diabetes analogous to metabolic syndrome (metsyn) in humans, so 16/38 or fully 42% had abnormal glucose metabolism. By comparison, none of the 38 CR animals, including 2 who started with metabolic syndrome, ended with metabolic syndrome. The two originally metsyn monkeys on CR were “cured” and remained so for the duration of the study. The CW09 team has published other work looking at glucose homeostasis including this study which showed improvements in insulin sensitivity, lowering of basal glucose and especially insulin levels and evidence of decreased glycation of hemoglobin (lower HBA1c). These are all theoretically and empirically supported effects of VLC diets as well as caloric restriction. I am told by Dr. Coleman they will be publishing updated data on the monkeys with new HBA1c data soon.

5)   Total deaths in the two groups were 21/38 or 55% for C and 14/38 or 37% for CR. This was not statistically significant, with a p-value of 0.16, but the “trend” would look pretty exciting if this were a phase I drug trial, I suppose. Figure 1 (c) below.


6)   The researchers excluded deaths not due to aging related diseases for analysis to arrive at “age related disease mortality”. There were 9 non-age-related deaths in the CR animals and 7 in the C animals. Many of these deaths were due to anesthesia for data collection (apparently ketamine and diazepam are pretty hazardous if you are a rhesus monkey). This gave “age related” mortality data with 14/38 or 37% deaths in C and 5/38 or 13% CR. This was statistically significant at p = .03 and the hazard ratio was 3.0, meaning the effect is probably large. (Compare this to hazard ratios of 1.2 or 1.4  in lots of the epidemiology garbage implicating various foods, but I digress) These data gave the impressive looking mortality curve in figure 1(b) above.

Now, one could argue that susceptibility to anesthetic misadventure should be included in age related deaths, as who knows a priori how the dietary intervention should affect susceptibility to death by anesthesia. It personally think it is a failure of laboratory science that we can’t factor in the photos of the animals. A chimpanzee or baboon could see that the CR animals are biologically younger, so maybe it is legitimate to take out the anesthesia deaths. Maybe anesthesia hazards are more akin to motorcycle riding than some age-related thing if you are rhesus monkey

So how did the monkeys die?

1)   Cancer – 8 cases in C, 4 cases in CR for a 50% reduction with CR. Not statistically significant but suggestive. Also, 7 of 8 control cancers and 2 of 4 CR cancers were GI tract adenocarcinoma. These most commonly were at or near the ileocecal valve. (PC –RJC) In humans, adenocarcinoma of the colon is one of the common cancers we suspect is related to insulin or glucose metabolism, so this supports the carcinogenesis being attenuated by CR, mediated via insulin effects.

2)   Diabetes, cardiovascular disease. Cardiovascular disease at autopsy included mitral regurgitation (leaky heart valve), valvular endocardiosis, cardiomyopathy, and myocardial fibrosis. Unfortunately, they do not provide a table with the individual causes of death for each monkey, We are left to take their word that each death was “age related”.

They also give the following survival table in Figure 2 (b) showing remaining animals without an age related disease, essentially by adding all the diabetic and metsyn animals to any that acquired or died of cancer, or cardiovascular disease. Nearly three quarters of animals on CR survive with no age-related disease versus less than one quarter of the C animals. They are still not giving us the raw data of who died of what, but if you think of this as “did not die of nor acquire an age-related diagnosis”, this is what most of us would hope for from our diets anyway. Even if we don’t live longer, we want to last longer without bypass surgery or diabetic retinopathy.

Altogether, this a very impressive study. It takes great patience to perform a carefully controlled study of primates over 20 years. The study results are the first evidence of reduced aging-related morbidity and increased survival in a non-human primate. Findings included virtual elimination of diabetes and a very suggestive reduction in insulin-sensitive neoplasia with caloric restriction. Most readers of this blog will note that there is good theoretical and empirical evidence that the same effects can be acheived in humans with low carbohydrate diets.

I would like to acknowledge Ricki J. Coleman for very kindly answering my many questions via an email interview.

I will engage in some speculative discussion about the applicability of this trial to human diets in my next post.

Stay Tuned!


Reader Comments (4)

Kurt,

Do you have any idea about the incidence of metabolic syndrome, diabetes and cancer for monkeys in the wild? I assume its close to nothing. (I admit I have no idea.) If that's the case, then one might further assume that the monkeys in the trial developed these diseases because were being fed the monkey equivalent of the SAD - perhaps abundant veggie oils and refined sugar. I am curious if the CR monkeys would have outperformed the control monkeys by such a large margin if the monkeys were fed a healthier "monkey paleo" diet. Put another way, does CR help someone who is eating well, or only someone who is eating the SAD?

July 14, 2009 | Unregistered CommenterTodd Hargrove

Sandy Szwarc recently covered this study on her Junkfood Science blog:

http://junkfoodscience.blogspot.com/2009/07/calorie-restrictive-eating-for-longer.html

July 14, 2009 | Unregistered CommenterJohn

Hello John

It's easier to be a muckraker than than a real critic, I guess. Her review indicates that she might have read the paper , but she obviously did not read any of the other papers by the Weindruch group. The effects on glucose homeostasis alone are quite convincing.

But then I wonder if she really did read the paper, as her description of the methodology makes no sense. An ad lib feeding monkey cannot be overfed without forcing it to eat more, and this was not done.

Whether Weindruch is motivated to sell resveratrol does not affect the metabolic insights gained by this study, IMO.

Todd

See part II

July 14, 2009 | Registered CommenterKurt G. Harris MD

Great posts Kurt, excellent site! You really broke this down in an easily digested format.

July 14, 2009 | Unregistered CommenterDanny Roddy
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