Tuesday, October 5, 2010

The China Study II: Does calorie restriction increase longevity?

The idea that calorie restriction extends human life comes largely from studies of other species. The most relevant of those studies have been conducted with primates, where it has been shown that primates that eat a restricted calorie diet live longer and healthier lives than those that are allowed to eat as much as they want.

There are two main problems with many of the animal studies of calorie restriction. One is that, as natural lifespan decreases, it becomes progressively easier to experimentally obtain major relative lifespan extensions. (That is, it seems much easier to double the lifespan of an organism whose natural lifespan is one day than an organism whose natural lifespan is 80 years.) The second, and main problem in my mind, is that the studies often compare obese with lean animals.

Obesity clearly reduces lifespan in humans, but that is a different claim than the one that calorie restriction increases lifespan. It has often been claimed that Asian countries and regions where calorie intake is reduced display increased lifespan. And this may well be true, but the question remains as to whether this is due to calorie restriction increasing lifespan, or because the rates of obesity are much lower in countries and regions where calorie intake is reduced.

So, what can the China Study II data tell us about the hypothesis that calorie restriction increases longevity?

As it turns out, we can conduct a preliminary test of this hypothesis based on a key assumption. Let us say we compared two populations (e.g., counties in China), based on the following ratio: number of deaths at or after age 70 divided by number deaths before age 70. Let us call this the “ratio of longevity” of a population, or RLONGEV. The assumption is that the population with the highest RLONGEV would be the population with the highest longevity of the two. The reason is that, as longevity goes up, one would expect to see a shift in death patterns, with progressively more people dying old and fewer people dying young.

The 1989 China Study II dataset has two variables that we can use to estimate RLONGEV. They are coded as M005 and M006, and refer to the mortality rates from 35 to 69 and 70 to 79 years of age, respectively. Unfortunately there is no variable for mortality after 79 years of age, which limits the scope of our results somewhat. (This does not totally invalidate the results because we are using a ratio as our measure of longevity, not the absolute number of deaths from 70 to 79 years of age.) Take a look at these two previous China Study II posts (here, and here) for other notes, most of which apply here as well. The notes are at the end of the posts.

All of the results reported here are from analyses conducted using WarpPLS. Below is a model with coefficients of association; it is a simple model, since the hypothesis that we are testing is also simple. (Click on it to enlarge. Use the "CRTL" and "+" keys to zoom in, and CRTL" and "-" to zoom out.) The arrows explore associations between variables, which are shown within ovals. The meaning of each variable is the following: TKCAL = total calorie intake per day; RLONGEV = ratio of longevity; SexM1F2 = sex, with 1 assigned to males and 2 to females.



As one would expect, being female is associated with increased longevity, but the association is just shy of being statistically significant in this dataset (beta=0.14; P=0.07). The association between total calorie intake and longevity is trivial, and statistically indistinguishable from zero (beta=-0.04; P=0.39). Moreover, even though this very weak association is overall negative (or inverse), the sign of the association here does not fully reflect the shape of the association. The shape is that of an inverted J-curve; a.k.a. U-curve. When we split the data into total calorie intake terciles we get a better picture:


The second tercile, which refers to a total daily calorie intake of 2193 to 2844 calories, is the one associated with the highest longevity. The first tercile (with the lowest range of calories) is associated with a higher longevity than the third tercile (with the highest range of calories). These results need to be viewed in context. The average weight in this dataset was about 116 lbs. A conservative estimate of the number of calories needed to maintain this weight without any physical activity would be about 1740. Add about 700 calories to that, for a reasonable and healthy level of physical activity, and you get 2440 calories needed daily for weight maintenance. That is right in the middle of the second tercile.

In simple terms, the China Study II data seems to suggest that those who eat well, but not too much, live the longest. Those who eat little have slightly lower longevity. Those who eat too much seem to have the lowest longevity, perhaps because of the negative effects of excessive body fat.

Because these trends are all very weak from a statistical standpoint, we have to take them with caution. What we can say with more confidence is that the China Study II data does not seem to support the hypothesis that calorie restriction increases longevity.

Reference

Kock, N. (2010). WarpPLS 1.0 User Manual. Laredo, Texas: ScriptWarp Systems.

Notes

- The path coefficients (indicated as beta coefficients) reflect the strength of the relationships; they are a bit like standard univariate (or Pearson) correlation coefficients, except that they take into consideration multivariate relationships (they control for competing effects on each variable). Whenever nonlinear relationships were modeled, the path coefficients were automatically corrected by the software to account for nonlinearity.

- Only two data points per county were used (for males and females). This increased the sample size of the dataset without artificially reducing variance, which is desirable since the dataset is relatively small (each county, not individual, is a separate data point is this dataset). This also allowed for the test of commonsense assumptions (e.g., the protective effects of being female), which is always a good idea in a multivariate analyses because violation of commonsense assumptions may suggest data collection or analysis error. On the other hand, it required the inclusion of a sex variable as a control variable in the analysis, which is no big deal.

- Mortality from schistosomiasis infection (MSCHIST) does not confound the results presented here. Only counties where no deaths from schistosomiasis infection were reported have been included in this analysis. The reason for this is that mortality from schistosomiasis infection can severely distort the results in the age ranges considered here. On the other hand, removal of counties with deaths from schistosomiasis infection reduced the sample size, and thus decreased the statistical power of the analysis.

21 comments:

Ned Kock said...

Just a quick note for those who are coming from Denise's blog. The claim that calorie restriction increases longevity has been made based on data from China and other Asian countries and regions (e.g., Okinawa), but not by Dr. Campbell in the China Study book. That book pretty much dismisses that notion that calorie restriction increases longevity, and at points argues the opposite.

Scott W said...

Ned, Dr. Kurt Harris did a very interesting breakdown of the primate calorie-restriction studies that you might find interesting:

Calorie Restricted Monkeys Part 1

His bottom line was that the calorie restriction was most likely just compensating for the horrible quality of the monkey chow.

Scott W

john said...

Hi Ned,

As you know, there's obviously many variables for which to control when trying to show something like this, so large-scale observations have little meaning.

I doubt that calorie restriction extends life solely due to poor quality food. Calorie restricted animals have a few interesting characteristics that are also shared with other examples of life extension (dwarf mouse, metabolic supermice, glucose restricted nematode): low respiratory quotient, low fasting insulin, high free fatty acids, low triglycerides. Of course, those are all connected/related and would imply a greater oxidation of fat, compared to glucose.

It's also interesting that calorie restricted animals actually eat more per unit mass, so they actually end up with a proportionally faster metabolism. This could be related to Nick Lane's idea on aging due to mtDNA stress: higher uncoupling protein activity reduces it while causing one to use calories as heat instead of ATP--ie, a "faster" metabolism.

Ned Kock said...

Hi Scott, thanks.

Right, more conclusive would be primate studies of CR where the controls were living in the wild.

Ned Kock said...

Hi john.

Yes, it is difficult to tell exactly what is going on here. Still, we have one negative piece of evidence, and more research is needed.

Very good point you make: "... calorie restricted animals actually eat more per unit mass". I would add to that that they eat significantly more per unit of fat mass.

Ned Kock said...

Here is another interesting piece of news, related to this post, that may be useful as a basis for discussion:

http://www.memebox.com/futureblogger/show/1588-the-myth-of-calorie-restriction-and-life-extension

Ned Kock said...
This comment has been removed by the author.
Ned Kock said...

And another one:

http://www.livescience.com/health/090127-bad-calorie-restriction.html

john said...

I really don't know what to make of that study. I've never read the full text, and the idea of relating "naturally chubby" vs "naturally lean" mice to humans is difficult.

I don't think there is anything special with reducing calories in and of itself, at least in the context of lower "wear and tear." From what I can gather, low fasting insulin and respiratory quotient (implying high comparative fat oxidation) are important, perhaps by simply reducing mtDNA damage (which Peter theorizes in his post, "Metabolism Nuts and Bolts"). If mtDNA is reduced with more fat oxidation, then there should be the answer; but, even without definitive evidence, the fact that all animal models (that I know of) of life extension share this property [low RQ, low insulin] is noteworthy.

Ned Kock said...

Hi john.

In my opinion, there is too much of a focus on insulin as a possible cause of aging and disease. In humans, leptin resistance seems to precede insulin resistance. And we don't know if leptin is really that important either. For example, adiponectin also regulates glucose and fatty acid utilization, and it circulates at levels that are 1,000 times higher than leptin.

In birds, diabetes is often associated with increased glucagon secretion, which overwhelms insulin. That is, it is not primarily an insulin problem.

Interestingly, birds have very high levels of blood glucose, and yet tend to live longer than mammals of comparable size. Taking the glucose level used to diagnose diabetes in humans as a baseline, we could say that all birds are diabetic. The blood glucose threshold for a diabetes diagnosis in birds is 4 times higher than that for a human.

Our bodies have mechanisms to deal with injury (e.g., glycation, inflammation, oxidation); mechanisms that have been evolved. Sometimes too much of a good thing is bad, as it fails to stimulate health-promoting compensatory adaptation (or hormesis) processes.

CarbSane said...

Great post Ned! Happy to have stumbled across your blog. Actually my research (literature, not lab) trends towards many of the "risks" of aging as associated with the natural development of insulin resistance that in turn leads to rising insulin levels. Insulin's inhibitory effects on the release of potentially harmful free fatty acids seems the critical lynch pin in the cascade. It is not the insulin per se that is the issue, it is the loss of sensitivity to its action.

Anecdotal evidence and some studies would seem to point to CR being of mixed use for life extension for humans in the modern world. A few extra pounds seem to help survival rates of hospitalization for example.

john said...

Ned,

I agree somewhat, as insulin is just a piece--typically, adiponectin [inversely], fasting insulin, fasting leptin, etc all go hand in hand. I obviously don't know what causes slower aging in the animals, but the idea of lower mtDNA is well-supported by references in Power, Sex, Suicide. So, how do we lower it? One could guess using fat is better from associations, but we don't know if it is in fact the cause--Peter's "Metabolism Nuts and Bolts" post helps.

Birds are very interesting. What about the blood glucose levels of carnivorous/hunter birds? Or, can we find a comparison of rates of aging between a "hunter" birds and a "gatherer" birds.

CarbSane,

Are you saying that general free fatty acids are harmful or that it's just certain types? Either way, that's hard to support: free fatty acids are higher in calorie restricted animals who live longer and who consume sizeable amounts of corn oil.

gibby1979 said...

question regarding your first and second tercile. Are those points different in a statistically significant way?

Ned Kock said...

Hi CarbSane, thanks. I like your blog!

Ned Kock said...

Hi john.

Carnivorous birds, like falcons and vultures, seem better able to maintain high glucose levels. A bird will typically enter a hypoglycemic state if blood glucose goes below 200 mg/dl.

In falcons, blood glucose rises gradually after feeding, reaching a peak level around 16 h from feeding. This rise is fueled by dietary protein, of course.

Ned Kock said...

Hi gibby1979.

Good question. I am pretty sure that a comparison of means between the 1st and 2nd tercs. would not yield a significant difference. But one between the 2nd and 3rd might yield a significant difference at the 0.05 level.

Ned Kock said...

Here is a interesting ref. on a comparison between carnivorous and granivorous birds:

http://www.ncbi.nlm.nih.gov/pubmed/204201

Michal said...
This comment has been removed by a blog administrator.
Ned Kock said...

Spam comment above deleted.

Comments that contribute to the discussion, and include links, are usually kept.

One-liners like "get XXX pills online" get deleted immediately.

thomas t samaras said...

I have found a number of human studies showing CR reduces chronic disease and mortality rates. These include the following researchers: Vallejo, Kagawa, Willcox, Fontana, and Murray. Granados found that mortality rates for most ages also dropped during the Great Depression, including infants. A Dutch famine study found adults that experienced the famine in their last trimester, had about 23% lower mortality vs those who were conceived or born after the famine. Okinawan children ate almost 40% fewer calories vs. mainland Japan but lived longer. Song also studied the Chinese Great Leap Forward Famine and found that people born during the famine had a longer life expectancy than those born after the famine ended.

Most studies of areas noted for exceptionally high numbers of centenarians have found that they are short and light and consume low to moderate amounts of calories. For example an Italian report based on 2500 centenarians found them to be short and lean. They didn't follow a CR diet but you don't get short and light eating a high calorie diet.

It is hard to accept the findings that CR doesn't extend longevity in view of 80 years of studies showing nematodes, mice, rats, dogs, and cows live longer on a well balanced CR diet.

For more information on nutrition, body size, chronic disease and longevity see website: http://www.humanbodysize.com

Steven Dawson said...

Hi, thanks for this Article! Finally some Non-bs site about nutrition. First of thanks for your statistical analyses, I have something to learn here. This piece right here is yet another piece of the puzzle and alsoI was surprised with the outcome. I really enjoyed reading it and on a last note I want to add that Carbohydrate calories are not stored and used as efficiently as fat calories. Thanks