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Dean Pomerleau

A Pessimistic Model of Human CR Longevity Benefits

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Al Pater posted this older paper [1] that I don't believe has been discussed here before - perhaps on the email list, but unfortunately those archives aren't available...  :(xyz

 

It has the pessimistic title: "Why dietary restriction substantially increases longevity in animal models but won't in humans". 

 

In it, the authors develop a simple (simplistic?) linear model of the impact of calorie restriction on rodent longevity - as long as calories remain above a certain minimum needed for survival, their model say a given percentage decrease in calories will result in the same percentage increase in lifespan. They use rodent CR data from a range of experiments to create this model, and claim their model fits the data pretty well - which isn't too surprising. Although recent data and analysis discussed here, suggests that in rodents (and primates) that a disproportionate fraction of CR longevity benefits may be achieved via modest (e.g. 10%) restriction, suggesting such a linear model of benefits may not be appropriate.

 

Then they try to apply the same model to humans, by fitting a linear model to three different populations of Japanese people whose calorie intake and lifespan information we know - long-lived male Okinawans who eat ~1900kcal/day, medium-lived average Japanese men who eat 2300kcal/day, and short-lived Sumo wrestlers who eat 5500kcal/day.

 

By their best estimate, fitting a line between the Sumo wrestlers and the normal japanese men, they come up with a very modest, 7% (or 5 year) lifespan extension for lifelong, maximal CR (which they estimated to be 1500kcal/day) relative to lifespan eating a normal diet of 2300 kcal/day. 

 

They argue that the reason rodents see such a large benefit (up to 64% life extension) from CR while humans will likely enjoy such a small benefit is because of the different fractions of energy the two species devote to reproduction. In short, relative to "normal" fecund & well-fed rodents, CRed rodents can tolerate a crushing 66% CR (yes - only 33% of "normal" calorie intake), because of all the energy they can save by not 'wasting' energy on reproductive functions. In contrast, humans devote a much smaller fraction of our energy budget to reproduction, and so can tolerate a much smaller degree of CR than rodents. Not to mention we have free access to food and the rodents can only eat what the cruel researchers put in their cages - one rodent per cage to avoid cannibalism...  :(xyz

 

They go on to editorialize about the relatively futility of human CR, saying:

 

Caloric restriction is likely to be almost universal in its beneficial effects on longevity.
This does not, however, warrant an expectation that there will be a quantitative equivalence
between DR in humans and DR in rodents. Instead, if our quantitative analysis is to be
taken at face value, the quantitative benefit to humans from caloric restriction is going to be

small, even if human subjects restrict their caloric intake substantially and over long
periods of time...

 

To undergo decades of CR, suffering chronically reduced fertility and increased hunger,
for the sake of a much smaller proportionate increase in longevity than is seen in rodents
seems unappealing and ill-advised.
Our conclusion is that it is reasonably prudent
assuming that caloric restriction is unlikely to be a panacea for human aging.

 

Boy they are Debbie Downers aren't they...

 

--Dean

 

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[1] Ageing Res Rev. 2005 Aug;4(3):339-50.

 

Why dietary restriction substantially increases longevity in animal models but
won't in humans.

 

Phelan JP(1), Rose MR.

 

Author information:
(1)Life Sciences Core Curriculum Program, UCLA, Los Angeles, CA 90095-1606, USA.
jay@ucla.edu

 

Full text: http://roselab.bio.uci.edu/Publications/75%20Phelan%20Rose%202005.pdf

 

Caloric restriction (CR) extends maximum longevity and slows aging in mice, rats,
and numerous non-mammalian taxa. The apparent generality of the
longevity-increasing effects of CR has prompted speculation that similar results
could be obtained in humans. Longevity, however, is not a trait that exists in a
vacuum; it evolves as part of a life history and the physiological mechanisms
that determine longevity are undoubtedly complex. Longevity is intertwined with
reproduction and there is a cost to reproduction. The impact of this cost on
longevity can be age-independent or age-dependent. Given the complexity of the
physiology underlying reproductive costs and other mechanisms affecting life
history, it is difficult to construct a simple model for the relationship between
the particulars of the physiology involved and patterns of mortality.
Consequently, we develop a hypothesis-neutral model describing the relationship
between diet and longevity. Applying this general model to the special case of
human longevity and diet indicates that the benefits of caloric restriction in
humans would be quantitatively small.

PMID: 16046282

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You apparently don't remember, but I hacked this one to shit when it came out.

Briefly, the main points are that:

1. They take too seriously the notion, based on very indirect data, that the Okies were on severe, lifelong CR. As Willcox & co. were able to document,(1) however, they were actually only on about 10% CR, and their environmentally-imposed CR was alleviated by rising prosperity starting in the period between 1949 and 1961 if not before, when the famed centenarian cohorts were in their 50s-70s.

2. They are also unaware of the influence of the Okinawans' mild malnutrition, also documented in (1), and ignore or were unaware of the poor medical care they received relative to the people to whom they are compared (the mainland Japanese (who have excellent health care), mainstream Americans, and sumo wrestlers (whose care is in most respects, I assume, even better than the Japanese population at large, since they're highly-paid elite athletes, as likely is their nutrition outside of energy intake).

 

3. They also take obesity/overfeeding as a straightforward extension of the energy continuum between severe CR, mild CR, and nonobese AL, which is problematic.

 

Reference

1. Willcox BJ, Willcox DC, Todoriki H, Fujiyoshi A, Yano K, He Q, Curb JD, Suzuki M. Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world's longest-lived people and its potential impact on morbidity and life span. Ann N Y Acad Sci. 2007 Oct;1114:434-55. PMID: 17986602

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Thanks Michael,

 

You apparently don't remember, but I hacked this one to shit when it came out.

 

I figured you would have. As I said, I really wish the CR email list archives were available... [Edit by Brian: discussion of archives continued here.]

 

I agree that there linear extrapolation of lifespan from both the high end (sumo wrestlers) and the low end (Okinawans) of the calorie intake continuum, without accounting for the very different life circumstances (e.g. healthcare and diet quality) of the different groups seems quite naive. 

 

--Dean

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