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Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study


Paul McGlothin

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In response to recent reports and articles referring to the calorie restriction lifestyle and the latest findings suggesting the discredit of the life extending qualities of the practice, The CR Society and the CR Way wish clarify the findings.

 

Nature.com published following paper:

 

Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study

 

Julie A. Mattison, George S. Roth, T. Mark Beasley, Edward M. Tilmont, April Handy, Richard L. Herbert, Dan L. Longo, David B. Allison, Jennifer E. Young, Mark Bryant, Dennis Barnard, Walter F. Ward, Wenbo Qi, Donald K.Ingram & Rafael de Cabo

 

Nature(2012)doi:10.1038/nature11432 Published online 29 August 2012

PMID: 22932268, NIH, NLM, PubMed access to Medline biomedical citations

 

 

Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function1, 2, motor coordination3 and resistance to sarcopenia4 in rhesus monkeys have recently been reported.

 

We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14years)5 and a preliminary report with a small number of CR monkeys6. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate.

 

Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents7, 8, 9, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.

 

The results state that rhesus monkeys fed a calorie-restricted diet didn't live any longer than monkeys on a higher-calorie diet. Regardless of the diet, the longest lifespan seems to hover around 40 years of age. Half the monkeys that began the study while young were still alive, but the researchers say, based on survival patterns, they forecast the lingering calorie-restrictors and controls will all live to be similar in age.

 

The CR Society and the CR Way, which advocate and practice calorie restricted lifestyle: respond to the latest study: we remind members that these monkeys are caged animals, housed in small wire spaces for their entire lives. Incarceration is torture. Human prisoners are well known to have shortened lifespans. So finding that caged living conditions do not produce the same results as the great body of research does that shows that calorie restriction extends life in all species, studied – including humans.

 

We asked Dr. Joseph Dhahbi, to comment:

 

"Housing of intelligent mammals in small cages is cruel. This affects the outcome more than diet."

 

 

Dr. Luigi Fontana voiced similar views:

 

“If you’re in a single cage for your whole life, and are a highly intelligent animal like a primate, deprived of contact with other peers, and on top of that you’re calorically restricted — can you imagine the psychological depression issues that will ensue?”

 

 

From the stockpile of evidence in support of calorie restriction for lifespan extension we share one example: the Okinawan elders. A 2007 study of elderly Okinawans who limited calories for 60 years by only 11% showed their life expectancy at age 65 to be the highest in Japan, possibly the world. Females had life expectancies that averaged 89.1 years and males, 83.5 years.

 

 

A decade of research, much of it involving CR Society members, at the School of Medicine at Washington University in St. Louis further confirms that human calorie restrictors show similar benefits to calorie-restricted animals.

 

Consider their 2009 paper: Fontana L: Modulating human aging and age-associated diseases. “… calorie restriction without malnutrition and moderate protein restriction with adequate nutrition may have additional beneficial effects on several metabolic and hormonal factors that are implicated in the biology of aging itself.”

 

 

These two examples are but a fraction of all the confirmatory data published in support of a calorie restricted lifestyle in extending lifespans. Caution should be used when considering recent reports suggesting results to the contrary.

 

Here is more:

 

http://calorierestri...ngevity-effect/

 

http://arc.crsociety...1800#msg-211800

 

http://arc.crsociety...81,211885#REPLY

 

 

Paul

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Guest Lindsay Edwards

Hi Paul,

 

I need to read the whole paper, but the abstract implies that both groups of animals were caged.

Thus simply discrediting the research on that basis is not terribly robust.

 

I'd also add that Nature is not prone to publishing articles that are so easy to discredit.

 

I'm not saying that CR doesn't work, just that interesting results such as these need to be taken seriously,

particularly when there is so little laboratory data on CR's effects in primates.

 

Best,

 

Lindsay Edwards.

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Hi Paul,

 

I need to read the whole paper, but the abstract implies that both groups of animals were caged.

Thus simply discrediting the research on that basis is not terribly robust.

 

I'd also add that Nature is not prone to publishing articles that are so easy to discredit.

 

I'm not saying that CR doesn't work, just that interesting results such as these need to be taken seriously,

particularly when there is so little laboratory data on CR's effects in primates.

 

 

 

Thank you for your comments, Leslie.

 

 

 

Noting cruel confinement of the monkeys is a serious response to the study, a reason for dismissal by many in the research field.

 

 

 

A great deal more should be pointed out about the study:

 

 

The NIA monkeys ate 17% protein. In healthy CR folk that could send IGF-1 to very high levels, which is normally low in calorie restricted animal studies. The paper states: [O]nly the CR males had somewhat lower triglycerides compared to respective controls (P50.051) (Fig. 2d)". When triglycerides are not lower in a CR'd human, it is cause for concern about their practice and often for exclusion from a research study.

 

 

 

Then there is this information from researchers from the same department that produced the Wisconsin Monkey study:

 

 

Hypervitaminosis A in experimental nonhuman primates: evidence, causes, and the road to recovery.

 

Am J Primatol. 2009 Oct;71(10):813-6.

 

 

 

Dever JT, Tanumihardjo SA.

 

 

Source

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

 

 

Abstract

One of the great underlying assumptions made by all scientists utilizing primate models for their research is that the optimal nutritional status and health of the animals in use has been achieved. That is, no nutrient deficiency or excess has compromised their health in any detectable way. To meet this assumption, we rely on the National Research Council's (NRC's) nutritional recommendations for nonhuman primates to provide accurate guidance for proper dietary formulations. We also rely on feed manufacturers to follow these guidelines. With that in mind, the purpose of this commentary is to discuss three related points that we believe have significant ramifications for the health and well being of captive primates as well as for their effective use in biomedical research. First, our laboratory has shown that most experimental primates are likely in a state of hypervitaminosis A. Second, it is apparent that many primate diets are providing vitamin A at levels higher than the NRC's recommendation. Third, the recommendation itself is based on inadequate information about nutrient needs and is likely too high, especially when compared with human requirements.

 

PMID: 19484706

 

 

Here are some additional points made by Society members and excerpted from the Society archives:

 

 

 

Dr. Alan Pater:

 

This study in question showed many odd features

that make me think that it might not represent the

truth of the matter.

 

 

* The study incorporated monkeys that had

previously been used in military research and 20

out of the 26 animals seemed to die before age of

12 years. In order not to taint the research, they

tagged the results with an origin label and then

adjusted to remove these animals. Could this have

had an effect on the other animals too that was

not controlled for?

 

 

Twenty of the 26 adult-onset females were obtained

from a military research facility, and 19 of these

monkeys developed severe and rapidly progressing

endometriosis. The twentieth monkey of this group

died at the age of 12 years from renal necrosis.

 

 

It seemed apparent that this cohort was

differentially affected in terms of long-term

health, and thus, an indicator variable that

designated the source of this monkey group as

Aberdeen™ was created and was included in most

analyses to control statistically for the effects

of these animals on the outcomes of interest.

 

 

* The animals didn't exhibit "CR normal" fasting

blood glucose profiles vs. age compared to prior CR

animal studies.

 

 

* The animals didn't exhibit "CR normal"

triglyceride profile vs. age compared to prior CR

animal studies.

 

 

* The female animals didn't live as long as the

male animals in either CR or control groups. This

is contrary to what we experience in humans where

females average 5+ years more than males.

 

 

Richard Schulman:

 

It's also important to note that the NIA study featured a mixed lot of

both Chinese and Indian rhesus monkeys, whereas the Wisconsin/NPRC

study comprised a relatively homogeneous, well-studied, and well-cared

for collection of Indian rhesus monkeys. As noted in Joseph W. Kemnitz's

 

2011 study, "Calorie Restriction and Aging in Nonhuman Primates,"

 

[www.ncbi.nlm.nih.gov]

 

the NIA's Chinese-origin monkeys were not only genetically and

behaviorally different from the Indian monkeys used in Wisconsin, they

could even be regarded as having become brain damaged. I quote from

the Kemnitz study:

 

"[T]here is deep divergence in mitochondrial and nuclear genomes

between Indian and Chinese rhesus, including sequences for the major

histocompatibility complex (Kanthaswamy et al. 2008). Phenotypic

differences, including behavioral differences such as less

aggressiveness in Indian versus Chinese rhesus, have also been

reported (see Kanthaswamy et al. 2008).

...

"The [NIA] group that underwent CR in early adulthood exhibited

increased activity, particularly oral behaviors and rocking (usually

regarded as manifestations of neurosis), compared to the younger

groups. Interestingly, animals exhibiting stereotypies were those

imported from China, suggesting that the behavioral difference may

have a genetic basis or result from different early experiences."

 

Here is Wikipedia's entry on stereotypy:

 

"A stereotypy is a repetitive or ritualistic movement, posture, or

utterance. Stereotypies may be simple movements such as body rocking,

or complex, such as self-caressing, crossing and uncrossing of legs,

and marching in place. They are found in people with mental

retardation, autism spectrum disorders, tardive dyskinesia and

stereotypic movement disorder;[1] studies have shown stereotypies

associated with some types of schizophrenia.[2] Frontotemporal

dementia is also a common neurological cause of repetitive behaviors

and stereotypies.

...

"Stereotypies also occur in non-human animals. It is considered an

abnormal behavior and is sometimes seen in captive animals,

particularly those held in small enclosures with little opportunity to

engage in more normal behaviors. These behaviors may be maladaptive,

involving self-injury or reduced reproductive success, and in

laboratory animals can confound behavioral research.[15] Examples of

stereotypical behaviors include pacing, rocking, swimming in circles,

excessive sleeping, self-mutilation (including feather picking and

excessive grooming), and mouthing cage bars. Stereotypies are seen in

many species, including primates, birds, and carnivores.

 

"Stereotypical behaviors are thought to be caused ultimately by

artificial environments that do not allow animals to satisfy their

normal behavioral needs. Rather than refer to the behavior as

abnormal, it has been suggested that it be described as 'behavior

indicative of an abnormal environment.[18] Stereotypies are correlated

with altered behavioral response selection in the basal ganglia.[15]

As stereotypies are frequently viewed as a sign of psychological

distress in animals, there is also an animal welfare issue involved.

 

"Stereotypical behavior can sometimes be reduced or eliminated by

environmental enrichment, including larger and more stimulating

enclosures, training, and introductions of stimuli (such as objects,

sounds, or scents) to the animal's environment. The enrichment must be

varied to remain effective for any length of time. Housing social

animals with other members of their species is also helpful. But once

the behavior is established, it is sometimes impossible to eliminate

due to alterations in the brain.[18]"

 

 

 

# # #

Thank you for your reply. It is important for the Society to discuss this issue.

 

Paul

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Guest Ian Ross

Hi Paul,

I'm a biologist (research scientist) and I have followed the CR issue with interest for a long time (1985). I am neither advocating nor opposing CR but I wanted to make a few points about this study. First, science proceeds by experiments which need to be thoughtfully discussed rather than simply rebutted. Second, it is very rare for a single experiment to prove conclusive in any area, and this one is no exception. Third, it speaks volumes for CR advocates if they are prepared to discuss the data with genuine curiosity and preparedness to accept the results, given that they maintain that their interest is evidence based. After all, things are as they are - time will tell who is right. No point in arguing about it in a polemical way. So I'd be strongly advocating that the CR Society should not dismiss this study, but try to understand what it might imply. Now for the study itself. The journal "Nature" doesn't publish poor quality studies (not usually, anyway) but every study like this is open to several interpretations. My first thought upon reading it (the whole thing, not just the abstract) is that the non-restricted group is NOT an "ad libitum" group and thus does not compare to the control group in the Wisconsin study. And the authors themselves point out that even a 10% restriction can have an effect, so this may affect the "control-ness" of their control group. Luigi Fontana raises the issue of protein content in the diet, but regardless of how valid this is, it's a side issue. The reality is that as the biology of CR is unravelled, there will always be a need to reconsider assumptions and adjust preconceptions; that's how science progresses. The endpoint is to understand what regime will yield the greatest and healthiest lifespan, and this study makes a contribution that is important. In particular, the "control" group in the NIA study is eating a diet that is about as good as it's possible to have (apart from the CR element) which is NOT the case for "ad libitum" fed Americans. So to take the message (as some commenters have) that "CR has been disproved, lets go eat pizza" is simply foolish. I think this is a very interesting study and will help advance the field, no matter what the biology turns out to be.

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  • 4 weeks later...
Guest Bret Jondaughter

All I have to say is... uh oh. I thought we were pretty sure this would work in humans. It was showing lots of promise, and it really seems to improve health as it relates to age (i.e. making your body genuinely "younger" as compared to those on a normal diet). Granted, the study was done on caged animals that are more intelligent than rats, but I'm not convinced that this stressful environment is enough to shorten an organism's lifespan by more than a very small amount. I am beginning to think that eating a highly nutritious diet combined with plenty of exercise is the best way to go for myself. I certainly won't overeat, but I may not restrict as much as I'd originally planned (1,800 calories), either.

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All I have to say is... uh oh. I thought we were pretty sure this would work in humans. It was showing lots of promise, and it really seems to improve health as it relates to age (i.e. making your body genuinely "younger" as compared to those on a normal diet). Granted, the study was done on caged animals that are more intelligent than rats, but I'm not convinced that this stressful environment is enough to shorten an organism's lifespan by more than a very small amount. I am beginning to think that eating a highly nutritious diet combined with plenty of exercise is the best way to go for myself. I certainly won't overeat, but I may not restrict as much as I'd originally planned (1,800 calories), either.

The impact that CR has on health cannot be duplicated by exercise and reasonable diet. The NIA study had complete absence of cancer for the young initiated CR group so far. The WNPRC study had complete absence of diabetes for young initiated CR. Both studies showed significant reduction in risks for heart disease. One should not draw the conclusion from the NIA study that CR doesn't work at all, just that a cloud of uncertainty exists over the life extension part. The healthspan benefits are indeed represented in the results and even though they were not as good as many CRONIES expected, they are certainly statistically significant.

 

If one doesn't do full CR, then one should implement a lesser version. We all know how life goes if you don't do anything. My advice is to implement a 10 % reduction in calories and eat a nutritionally dense diet along with modest exercise.

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Guest Bret Jondaughter

The impact that CR has on health cannot be duplicated by exercise and reasonable diet. The NIA study had complete absence of cancer for the young initiated CR group so far. The WNPRC study had complete absence of diabetes for young initiated CR. Both studies showed significant reduction in risks for heart disease. One should not draw the conclusion from the NIA study that CR doesn't work at all, just that a cloud of uncertainty exists over the life extension part. The healthspan benefits are indeed represented in the results and even though they were not as good as many CRONIES expected, they are certainly statistically significant.

 

If one doesn't do full CR, then one should implement a lesser version. We all know how life goes if you don't do anything. My advice is to implement a 10 % reduction in calories and eat a nutritionally dense diet along with modest exercise.

 

 

I'm not sure exactly what you're refuting here. Hmm... After all, I made a point of mentioning CR's positive effect on health as it relates to age. However, I had also hoped it would have some sort of life-extension benefit, and this study is definitely giving me pause when it comes to that.

Not to mention the benefits of exercise are something that can't be ignored in humans. CR does seem to be very beneficial for maintaining good health and avoiding certain diseases, and that's exactly why I will still probably cut back, just not to the point I was planning on originally. I was really hoping for a considerable effect on life-extension, and I'm starting to doubt that we'll ever see that effect materialize.

I'm still wondering why you thought I was implying that CR doesn't work in any way, shape or form.

Eh, unless you weren't refuting my post at all.

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  • 4 weeks later...

I'm not sure exactly what you're refuting here.

 

Keith was pretty clear-

"The impact that CR has on health cannot be duplicated by exercise and reasonable diet."

 

No combination of exercise and dietary composition alone can duplicate anything whatsoever like the maximum life span extension of CR in any animal thus far studied.

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  • 2 weeks later...
Guest Bret_Jondaughter

Keith was pretty clear-

"The impact that CR has on health cannot be duplicated by exercise and reasonable diet."

 

No combination of exercise and dietary composition alone can duplicate anything whatsoever like the maximum life span extension of CR in any animal thus far studied.

 

 

No, because the current study does not find that benefit, and now we're talking about primates. When you look to older studies, too, it casts a considerable amount of doubt. Because the rats and monkeys in the non-CR'd groups are also allowed to eat as much as they want...something that many non-CR'd humans (as well as the monkeys in the non CR group here) don't even do. When you compare these two groups of monkeys, the only benefits remaining in the CR'd group versus eating a normal, healthful but non-CR'd diet are the lower incidences of cancer and diabetes - NOT life extension, which was the whole point if you read the study or the thread.

 

Also, I believe kethsc was talking about these aforementioned benefits when he argued with my post. These are things I never argued with in the first place, so I don't find his post "clear" because I don't know why he quoted me at all if I had never argued with those facts. I only stated what I think is best for me based on the available research, especially considering that CR won't really work well for someone like me who is going to need to be very active and can't afford to lose any more bone or muscle than I already have - ESPECIALLY at my young age. (MY BMI is 17.3 btw).

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No, because the current study does not find that benefit, and now we're talking about primates. When you look to older studies, too, it casts a considerable amount of doubt. Because the rats and monkeys in the non-CR'd groups are also allowed to eat as much as they want...something that many non-CR'd humans (as well as the monkeys in the non CR group here) don't even do. When you compare these two groups of monkeys, the only benefits remaining in the CR'd group versus eating a normal, healthful but non-CR'd diet are the lower incidences of cancer and diabetes - NOT life extension, which was the whole point if you read the study or the thread.

 

Also, I believe kethsc was talking about these aforementioned benefits when he argued with my post. These are things I never argued with in the first place, so I don't find his post "clear" because I don't know why he quoted me at all if I had never argued with those facts. I only stated what I think is best for me based on the available research, especially considering that CR won't really work well for someone like me who is going to need to be very active and can't afford to lose any more bone or muscle than I already have - ESPECIALLY at my young age. (MY BMI is 17.3 btw).

Perhaps Taurus has muddied the waters here with his choice of words. His sentence:

No combination of exercise and dietary composition alone can duplicate anything whatsoever like the maximum life span extension of CR in any animal thus far studied.

isn't what I would have said since the NIA study throws that conclusion into doubt. Bret, my original reply to your message was meant to counter the impression that your message leaves in the minds of someone who merely scans these messages. I didn't intend to refute your statements, but instead to clarify the important conclusions from CR research. The animal studies, including the NIA and WNPRC studies, show a significant benefit with respect to the diseases of aging. The human data also points in the same direction, but cannot be the subject of a longevity experiment due to time, cost and ethical considerations. Never the less, the research over the last decade on human subjects from Dr. Luigi Fontana et. al. shows that those who do follow a CR lifestyle are a much healthier bunch than those who don't. That statement also includes people who are careful with their diets and exercise a lot.

 

Perhaps I should state my assertion more bluntly: If you don't follow a CR like diet, you will be accepting the risks for the diseases of aging like everyone else around you. If you happen to have an excellent set of genes like Jean Calment did, then you don't really need to worry much at all anyway. You need to get past the diseases of aging to have any chance at longevity, so think about it. Regarding your young age and low BMI, assuming you're fully grown, CR is a great choice for a young man. Those young years do disappear rather quickly (perception), and the sooner you start preventing the damage from aging, the better. With your low BMI you need to concentrate on tuning the number of calories for your lifestyle. It sounds like you already have some ideas about that, so great!

 

The fact that you're thinking about it now indicates that you're miles ahead of your peers. I sure that eventually you'll agree with the CRSociety members that a CR lifestyle is a healthy way to go through life.

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