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New mouse study suggests CR may only benefit the obese


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#1 tedsez

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Posted 23 January 2009 - 07:48 PM


I'd be interested to know what everyone thinks of this study.


Eating Less May Not Extend Human Life: Caloric Restriction May Benefit Only Obese Mice

ScienceDaily (Jan. 22, 2009) — If you are a mouse on the chubby side, then eating less may help you live longer.

For lean mice – and possibly for lean humans, the authors of a new study predict – the anti-aging strategy known as caloric restriction may be a pointless, frustrating and even dangerous exercise.

"Today there are a lot of very healthy people who look like skeletons because they bought into this," said Raj Sohal, professor at the University of Southern California's School of Pharmacy.

He and Michael Forster, of the University of North Texas Health Science Center, compared the life span and caloric intake of two genetically engineered strains of mice.

The "fat" strain, known as C57BL/6, roughly doubles in weight over its adult life. That strain benefited from caloric restriction, Sohal said.

The "lean" strain, DBA/2, does not become obese. Caloric restriction did not extend the life of these mice, confirming previous work by Forster and Sohal.

"Our study questions the paradigm that caloric restriction is universally beneficial," Sohal said. "Contrary to what is widely believed, caloric restriction does not extend (the) life span of all strains of mice."

By measuring the animals' metabolic rate, Sohal and his colleagues came to a deceptively simple conclusion: Caloric restriction is only useful when, as in the case of the obese mice, an animal eats more than it can burn off.

"Your energy expenditure and your energy intake should be in balance," Sohal said. "It's as simple as that. And how do you know that? By gain or loss of weight.

"The whole thing is very commonsensical."

For humans of normal weight, Sohal strongly cautions against caloric restriction. In a 2003 study, he and Forster found that caloric restriction begun in older mice – both in DBA and leaner C57 individuals – actually shortened life span.

However, Sohal said that obese individuals are probably better off cutting calories than increasing their exercise to make up for overeating. Overly vigorous exercise can lead to injuries and long-term wear and tear.

In other words, it is better to skip the double cheeseburger than to turn up the treadmill after binging at Carl's Jr.

Sohal's study is not the first to question the allegedly universal benefits of caloric restriction. A study by Ross et al. published in Nature in 1976 ("Dietary practices and growth responses as predictors of longevity") found that caloric restriction works best in mice that gain weight rapidly in early adulthood, Sohal said.

Studies of caloric restriction in wild types of mouse strains have shown minimal life span extension, he added.

Next, the researchers want to understand why the obese mice have a lower metabolic rate that promotes weight gain.

The other members of the research team were Melissa Ferguson and Barbara Sohal of the USC School of Pharmacy.

Funding for the study came from the National Institute on Aging, part of the National Institutes of Health.

http://www.scienceda...90123101224.htm


Abstract:

Life Span Extension in Mice by Food Restriction Depends on an Energy Imbalance1,2

Rajindar S. Sohal3,*, Melissa Ferguson3, Barbara H. Sohal3 and Michael J. Forster4

3 Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089 4 Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107

In this study, our main objective was to determine whether energy restriction (ER) affects the rate of oxygen consumption of mice transiently or lastingly and whether metabolic rate plays a role in the ER-related extension of life span. We compared rates of resting oxygen consumption between C57BL/6 mice, whose life span is prolonged by ER, and the DBA/2 mice where it is not, at 6 and 23 mo of age, following 40% ER for 2 and 19 mo, respectively. Mice of the 2 strains that consumed food ad libitum (AL) had a similar body mass at the age of 4 mo and consumed similar amounts of food throughout the experiment; however, the body weight subsequently significantly increased (20%) in the C57BL/6 mice but did not increase significantly in the DBA/2 mice. The resting rate of oxygen consumption was normalized as per g body weight, lean body mass, organ weight, and per mouse. The resting rate of oxygen consumption at 6 mo was significantly higher in AL DBA/2 mice than the AL C57BL/6 mice for all of the criteria except organ weight. A similar difference in AL mice of the 2 strains was present at 23 mo when resting oxygen consumption was normalized to body weight. Resting oxygen consumption was lowered by ER in both age groups of each strain according to all 4 criteria used for normalization, except body weight in the C57BL/6 mice. The effect of ER on resting oxygen consumption was thus neither transient nor age or strain dependent. Our results suggest that ER-induced extension of life span occurs in the mouse genotype in which there is a positive imbalance between energy intake and energy expenditure.

http://jn.nutrition....jn.108.100313v1

#2 Johan

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Posted 23 January 2009 - 08:33 PM

Does anyone have the full PDF-availed paper? I would like to know how the energy restriction was carried out, i.e. if it was induced suddenly or gradually, whether adequate micronutrient intake was ensured, etc.

#3 kismet

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Posted 23 January 2009 - 08:39 PM

Personally I wouldn't care about any rodent studies anymore. The primate studies are under way, let's wait for their conclusion. If I remember correctly DBA/2 are known to be poor responders to CR, but it still provides benefits proportional to the level of restriction to many different strains of mice - which does not fit the headline. Even the CR tests in wild mice were not that negative (actually not negative at all), although the employed methodology was flawed.

I say re-test wild mice or just wait for the results in primates. DBA/2 mice are messed up on so many levels.

Maybe one of our CR experts will chime in. Sorry, Johan, I don't have access to it.

Edited by kismet, 23 January 2009 - 08:40 PM.


#4 Anthony

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Posted 23 January 2009 - 08:40 PM

This post might have fit better under an already constructing topic group; however, I'll answer here. Personally, I don't think that this result does much to discredit the potential benefits of caloric restriction. For one thing, the mice were engineered to be leaner; the scientists didn't keep them lean through diet. This genetic change might have given the mice an advantage vis a vis other mice. For instance, the altered mice may have stored fat in a different way (can't find post now but there is on Ourobos linking fat storage and aging). Additionally, one can find thousands of published reports on caloric restriction. When looked at in that perspective, one null result doesn't do much to discredit the majority of positive ones. Furthermore, limited research on CR humans and monkeys is positing good results, which also points to CR having a beneficial effect on "normal" sized individuals. Even if CR doesn't extend maximum lifespan, it almost certainly (to my knowledge) both improves and extends healthspan. This is a huge plus.

For what it's worth, I don't think that caloric restriction in and of itself is of much use to society. Few people will attempt this diet even if one could guarantee them extra years. As has often been said (by others), scientists, by and large, do CR research in the hopes that the information they obtain will allow them to find therapeutic means to slow aging by allowing them to isolate genes, biologic processes, etc. which mediate aging in mammals. For example, CR mice have a lower level of IGF-1 than do their non-CR peers. Using this information (or maybe using it to correllate other information), scientists hypothesized that lower levels of IGF-1 might have a positve impact on lifespan. Low and behold, people with below normal levels of IGF-1 tend to live longer (don't have time to find references but google Valter Longo, Ashekani Jews, centenarians). Perhaps more important to us in the long run, researchers used CR findings to help them isolate the sirtuin family of proteins and NF-KB.

#5 Mind

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Posted 23 January 2009 - 09:31 PM

There are people who are naturally lean and even seem to have stunted growth (naturally lower IGF) and this study would lead me to believe they are not going to get a whole lot of benefit from CR, however, this is not most people. Most of the research into CR show healthspan extension, even in primates. Even most research on eating less calories (but not all the way to CR) shows benefits, so the weight of the evidence is in favor.

In the long run, obviously, we still have to rely on something other than CR for indefinite lifespan extension.

#6 Matt

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Posted 24 January 2009 - 12:09 AM

I'm still reading the paper, but I got to this part and I thought it was a bit to fast the way they were put on 40% CR.

"At 14 wk of age, one-half of the mice from each strain were placed
under the ER regimen, which entailed a 10% decrease in the amount of
food consumed by the mice during the first week, followed by 20% in wk
2, and 40% in wk 3 and thereafter"

I don't know much about the DBA mouse strain, but I see that it's shorter lived with a lifespan of around 20 months or so.

"Long life-span in SPF fostered conditions (12/17 = 629 days in males, 15/17 = 719 days in females) with 6-35% liver and 1-23% lung tumours (Festing and Blackmore, 1971). Long life-span in conventional conditions (21/22 = 707 days in males, 20/22 = 714 days in females) (Storer, 1966). Life-span 722_30 days in males and 683_26 days in females (Goodrick, 1975)."
http://www.informati.....tinget al1971

Edited by Matt, 24 January 2009 - 12:17 AM.


#7 Matt

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Posted 24 January 2009 - 12:45 AM

Heres a related study which the articles mention from 2003

Genotype and age influence the effect of caloric intake on mortality in mice.
Forster MJ, Morris P, Sohal RS.

Long-term caloric restriction (CR) has been repeatedly shown to increase life span and delay the onset of age-associated pathologies in laboratory mice and rats. The purpose of the current study was to determine whether the CR-associated increase in life span occurs in all strains of mice or only in some genotypes and whether the effects of CR and ad libitum (AL) feeding on mortality accrue gradually or are rapidly inducible and reversible. In one experiment, groups of male C57BL/6, DBA/2, and B6D2F1 mice were fed AL or CR (60% of AL) diets beginning at 4 months of age until death. In the companion study, separate groups of mice were maintained chronically on AL or CR regimens until 7, 17, or 22-24 months of age, after which, half of each AL and CR group was switched to the opposite regimen for 11 wk. This procedure yielded four experimental groups for each genotype, namely AL-->AL, AL-->CR, CR-->CR, and CR-->AL, designated according to long-term and short-term caloric regimen, respectively. Long-term CR resulted in increased median and maximum life span in C57BL/6 and B6D2F1 mice but failed to affect either parameter in the DBA/2 mice. The shift from AL-->CR increased mortality in 17- and 24-month-old mice, whereas the shift from CR-->AL did not significantly affect mortality of any age group. Such increased risk of mortality following implementation of CR at older ages was evident in all three strains but was most dramatic in DBA/2 mice. Results of this study indicate that CR does not have beneficial effects in all strains of mice, and it increases rather than decreases mortality if initiated in advanced age.


heres the full paper http://www.fasebj.or...nt/02-0533fjev1

#8 Matt

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Posted 24 January 2009 - 12:59 AM

As for the Wild type mouse, Michael talks about it here, which indicates that actually CR probably does work and mght need to be looked at again. (comment 1).

http://ouroboros.wor...e-in-wild-mice/

#9 nameless

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Posted 24 January 2009 - 01:56 AM

There are people who are naturally lean and even seem to have stunted growth (naturally lower IGF) and this study would lead me to believe they are not going to get a whole lot of benefit from CR, however, this is not most people.

I was under the impression (possibly a false impression) that lower IGF could be a reason for longer lifespans.

http://www.scienceda...80527084252.htm

This article states that men with a higher IGF-1 appear to have a longer lifespan and less cardiovascular risk. I am not doing the CR thing, but I am interested in the science behind it, and why it may work (or not work) in people. So... is IGF-1 good or bad? Or perhaps it plays little to no role in regard to CR and humans?

#10 sUper GeNius

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Posted 24 January 2009 - 02:04 AM

For what it's worth, I don't think that caloric restriction in and of itself is of much use to society. Few people will attempt this diet even if one could guarantee them extra years.


No doubt you are correct. Food is like an addiction. I know people with emphysema who can't quit smoking. Very few have what it takes to do CR.

#11 Forever21

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Posted 24 January 2009 - 03:51 AM

What were they fed with?

#12 Matt

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Posted 24 January 2009 - 03:59 AM

I believe CR mice consumed a fortified diet to match ad lib nutrient levels when they were restricted.

See here; NIH-31 http://www.teklad.com/pdf/7109.pdf

#13 Johan

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Posted 24 January 2009 - 08:43 AM

For one thing, the mice were engineered to be leaner; the scientists didn't keep them lean through diet.

Does anyone know which genetic changes are made in DBA/2 mice to make them leaner? That might provide a clue as to why CR didn't work for them in this study. Perhaps the mechanisms of CR are competitive or inhibitive to these genetic changes?

Also, has any study tried using an all-natural diet (i.e. no supplementation) to provide adequate nutrition for CR:ed mice? Is it possible?

Edited by Johan, 24 January 2009 - 08:48 AM.


#14 Michael

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Posted 25 January 2009 - 02:49 AM

[Basically cross-posted from CR Society ...).

These guys have really made some extremely unreasonable leaps of reasoning.

First, yes, it's true that DBA/2 mice are resistant to the effects of CR on lifespan -- that's been shown repeatedly, since at least the early 80s, and not just by Sohal; and (per this study) yes, they apparently have some aesthetically happy genetic perk, that allows them to eat ad libitum without gaining any weight, while other mice gain weight as one would expect.

But so what? First, as Anthony noted, while they have demonstrated these two facts, they haven't done anything to prove that this resistance to weight gain in response to an AL diet is what *causes* their resistance to the age-retarding effects of CR in this strain.

Second, as Matt notes, these are sickly mice to begin with: in the NIA's massive Biomarkers of Aging Program (BAP),

ad lib-fed D2 mice were markedly shorter lived (median life span, 540 and 616 days for females and males, respectively) than C57BL/6s (median 816 and 843 days for females and males, respectively) or B6C3F1 or B6D2F1 hybrids. The differential between the sexes in the effects of caloric restriction in the BAP study was greater than for other mouse strains ... Maximum life span (MLS) in days [were] AL-F, 1015 (33.83 months); CR-F, 1060 (35.33 months); AL-M, 934 (31.13 months); CR-M, 1069 (35.63 months) [for C57BL/6, the maximum lifespan for AL male or female mice is more like 40 months -MR]

DBA/2 mice are homozygous for a mutation for aging-related hearing loss (ah1), resulting in detectable high-frequency impairment (and progressive cochlear pathology) by the time of weaning and severe impairment by 2 to 3 months of age. Young individuals are prone to audiogenic seizures. Adults develop progressive visual abnormalities, including iris aberrations, resembling hereditary glaucoma in humans; these are generally seen in both sexes by 9 months of age. This strain is particularly intolerant of alcohol and morphine. In addition, these mice may not be suitable for studies of normal aging-related changes in behavior or cognition, because they have a low brain weight on average and perform poorly in general on a number of standard psychological tests, including forced swimming tests. (1)



It's unreasonable to draw any conclusions about "normal" aging from animals that are clearly fucked up to begin with; indeed, C57BL/6 mice are amongst the most commonly used for biogerontology studies precisely because they ARE long-lived, healthy mice, not prone to early pathology.

Third: CR has been pretty clearly shown to work as a continuous variable, right up to the point of starvation, and not just as obesity-avoidance: you get the maximum extensioin of youthful lifespan at nearly 70% CR -- and just a tiny hair more, you starve 'em to death PDQ. The dose-response effect is illustrated here:
Posted Image

Redrawn from (2).

... and, here (graphs reproduced from (3)).

(More on CR not being about body weight or in these 2 posts:

http://www.caloriere...3328#msg-113328

http://www.caloriere...9191#msg-169191

And fourth: these mice eat all they want from early adulthood, spend every day of their lives locked in a cage with no exercise equipment available, and never put on any weight! Does that sound like most humans that you know of? And they do so because of an abnormally high resting metabolic rate; by contrast, while some humans are thin, this is not because of a magic, super-high metabolism, despite the widespread belief in people who can eat all day and just 'naturally' stay thin. Studies in humans clearly show that weight can be consistently and directly extrapolated from measured anthropometry, energy intake, and energy output as physical activity: with vanishingly rare exceptions, no one 'just burns it off', and nearly all genes discovered to date that are associated with obesity regulate the reward systems and taste preferences -- ie, the association is almost certainly through increased food intake, not a metabolism so slow that their bearers can gain weight on a diet of celery sticks.

In other words, the CR-recalcitrant DBA/2 mice respond to AL feeding in exactly the way that humans DON'T, and CR-responsive C57BL/6 mice respond in exactly the way that humans ( *typically* ) DO! So what kind of headline is "Caloric restriction may not extend human life after all"??

For humans of normal weight, Sohal strongly cautions against caloric restriction. In a 2003 study, he and Forster found that caloric restriction begun in older mice -- both in DBA and leaner C57 individuals -- actually shortened life span.


Yeah, well, in that study, they violated almost every rule of adult-onset CR in the book: they administered CR as shock therapy instead of stepwise to allow for gradual adaptation, and they didn't boost the %protein in the diet to ensure that they got the full rodent 'RDA' of the AL mice. Weindruch and Walford's big 1982 breakthru', showing that you COULD actually make CR work in adults, was based precisely on not making those mistakes -- and it's been repeated numerous times since. O, the other hand:

I'm still reading the paper, but I got to this part and I thought it was a bit to fast the way they were put on 40% CR.

"At 14 wk of age, one-half of the mice from each strain were placed
under the ER regimen, which entailed a 10% decrease in the amount of
food consumed by the mice during the first week, followed by 20% in wk
2, and 40% in wk 3 and thereafter"

That actually is just fine in mice this young: 14 weeks is still a juvenile, and CR works fine even as total 'shock therapy' at such ages. It's only in mice getting more up past teh 6 month mark that you have to ease them into it.

But the current study doesn't come anywhere close to proving what Sohal is evidently asserting about it.

-Michael

References
1. Holmes DJ.
DBA/2 Mouse .
Sci. Aging Knowl. Environ., Vol. 2003, Issue 44, pp. as3, 5 November 2003

2. Weindruch R, Walford RL, Fligiel S, Guthrie D.
The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake.
J Nutr. 1986 Apr;116(4):641-54.
PMID: 3958810 [PubMed - indexed for MEDLINE]

3. Merry BJ.
Molecular mechanisms linking calorie restriction and longevity.
Int J Biochem Cell Biol. 2002 Nov;34(11):1340-54. Review.
PMID: 12200030 [PubMed - indexed for MEDLINE]

#15 hormoneman

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Posted 18 August 2009 - 02:57 PM

To investigate whether mice genetically unaltered by many generations of laboratory selection exhibit similar hormonal and demographic responses to caloric restriction (CR) as laboratory rodents, we performed CR on cohorts of genetically heterogeneous male mice which were grandoffspring of wild-caught ancestors. Although hormonal changes, specifically an increase in corticosterone and decrease in testosterone, mimicked those seen in laboratory-adapted rodents, we found no difference in mean longevity between ad libitum (AL) and CR dietary groups, although a maximum likelihood fitted Gompertz mortality model indicated a significantly shallower slope and higher intercept for the CR group. This result was due to higher mortality in CR animals early in life, but lower mortality late in life. A subset of animals may have exhibited the standard demographic response to CR in that the longest-lived 8.1% of our animals were all from the CR group. Despite the lack of a robust mean longevity difference between groups, we did note a strong anticancer effect of CR as seen in laboratory rodents. Three plausible interpretations of our results are the following: (1) animals not selected under laboratory conditions do not show the typical CR effect; (2) because wild-derived animals eat less when fed AL, our restriction regime was too severe to see the CR effect; or (3) there is genetic variation for the CR effect in wild populations; variants that respond to CR with extended life are inadvertently selected for under conditions of laboratory domestication.

http://www3.intersci...14022/HTMLSTART



But it might also be, as the authors point out, that lab mice have been inadvertently selected for some trait that enhances the benefits of CR. Wild populations may be a mix of some mice that benefit from CR and some that don’t (e.g., the early-mortality subjects in this study).

This is the possibility that’s of particular concern for humans. Via the emerging field of pharmacogenomics, we’re becoming increasingly aware of the impact that genetic variation can play on the efficacy of therapeutics: Sometimes a drug will benefit only 20% of the trial population, but it later turns out that 100% of those 20% had the same haplotype at a particular locus, making the drug great for them and lousy for everyone else. This phenomenon isn’t limited to drugs; it extends (e.g.) to the benefits people reap from exercise and the risk of getting cancer after a lifetime of smoking.

What if calorie restriction is the same? I would argue that we’re more like wild mice than lab mice, and that there are going to be existing variants in the human population that benefit differently from CR (just like any other course of treatment). What do we do if it turns out that CR confers both early mortality (on one subset of the population) and delayed aging (in another, or in everyone who survives the increased early-mortality risk)?

We’ve based a lot of our optimism about CR in humans on data from rodents, and while the human and primate data is promising so far, it’s also limited in statistical power and temporal depth. Simple intellectual honesty mandates that these results give us pause, and encourage rational reflection about all the possibilities that might result from being our own guinea pigs.

http://ouroboros.wor...e-in-wild-mice/




Eating Less May Not Extend Human Life: Caloric Restriction May Benefit Only Obese Mice

He and Michael Forster, of the University of North Texas Health Science Center, compared the life span and caloric intake of two genetically engineered strains of mice.

The "fat" strain, known as C57BL/6, roughly doubles in weight over its adult life. That strain benefited from caloric restriction, Sohal said.

The "lean" strain, DBA/2, does not become obese. Caloric restriction did not extend the life of these mice, confirming previous work by Forster and Sohal.

"Our study questions the paradigm that caloric restriction is universally beneficial," Sohal said. "Contrary to what is widely believed, caloric restriction does not extend (the) life span of all strains of mice."

For humans of normal weight, Sohal strongly cautions against caloric restriction. In a 2003 study, he and Forster found that caloric restriction begun in older mice – both in DBA and leaner C57 individuals – actually shortened life span.

http://www.scienceda...90123101224.htm

#16 kismet

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Posted 19 August 2009 - 12:08 PM

Your post is redundant. We have discussed the study to death. Just read the ouroboros article... it does not even prove that CR does not work.  ;)

EDIT: I guess that makes my post redundant too.

Edited by kismet, 19 August 2009 - 01:43 PM.


#17 Brainbox

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Posted 19 August 2009 - 01:09 PM

Thanks for posting the information!

I did merge it into this topic that already existed about this subject.

One thing that is good to do before posting is a quick search. Use the search tab in the upper right. When searching, select the "search titles only" option. This will result in a very fast search of the Imminst forums. This is especially useful for historical perspective and reference - especially with regard to new biotech and pharma advances. Adding to a previous discussion will resurrect past thoughts on the issue and will help everyone see how things have changed.




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