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Quick overview of the history of caloric restriction


Aaron King
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Aaron, you call your video a "history," but you seem to think that history more or less ended in 1935, with a brief pop-up on tryptophan restriction in the 1970s. Does it really seem plausible to you that no one in the last 80 years had ever realized "fat rats" problem in McKay's paper and taken steps to control for it? Similarly, if you thought that all we had to go on on smoking and lung cancer was Franz Hermann Müller's roughly contemporaneous case-control study with a few score subjects in each group, you'd likely think we were wasting a lot of time pushing down a harmless little addiction.

The "fat rats" problem does continue to plague aging research(2) — and, indeed, much animal research generally(3-5) — but has been dealt with in high-quality CR (and lifespan generally) studies for decades by determining what the "true" stuff-your-face ad libitum intake of the mice is and then setting the "ad lib" control group to consume 80-90% of that, and then determining "%CR" based on that "ad libitum" intake.  Thus, "40% CR" is (in well-done studies) actually (0.85 x 0.6)= 51% of what true ad libitum feeding looks like. You can see this in any lifespan study by Spindler, Weindruch, or Walford from the 1980s on; see also (2) on lifespan study design generally, although it doesn't insist on this protocol specifically (only the importance of rigorously monitoring food intake).

Indeed, if you compare the control group in McKay's original study to any well-done modern study in rats, you'll see that his controls were rather short-lived — in part precisely because of the "fat rats" problem, as well as other limitations to animal nutrition at the time, the inability to control for colony infection, possibly the uncharacterized stock of "white rats," etc — problems that science has also moved to address in the ensuing eight decades.

Similarly with your issue about McKay's rats having been initiated at weaning . Again, this is not exactly a novel observation: for this reason, CR was largely considered to be a laboratory curiosity somehow related to development rather than aging (or, more goofily, that aging somehow was a programmed process proceeding on from development) up until 1982, when Weindruch and Walford finally proved that you could do it successfully in adult organisms.(1) They did it by (a) initiating CR gradually, and (b) being very careful to give the animals the full dose of vitamins, minerals, EFAs, and protein that they gave the AL animals (in weanlings, you can just feed the poor little bastards half of the same chow, which of course leads to them only getting half of all the nutrients).

Since then, multiple studies have demonstrated that CR not only works, but works in direct proportion of remaining life expectancy, when initiated in early middle age (eg, (1)) or even early seniority (7) -- and see review in (8)). It is desperately tiresome to keep hearing people claim otherwise.

CR works fine in females; there are too many studies to cite, but eg. (9) shows it for multiple strains of mice (and please don't try to stun us with the "news" that CR doesn't work well in DBA/2 mice). I just happened to have reason to run through a few of more studies in females recently here.

Tryptophan restriction does indeed lead to reduced food intak;ee, being a good example of this problem. It wasn't reported in all of Timiras' papers, perhas because of redundancy or perhaps because — as in too many lifespan studies — she may not always have monitored it. It's demonstrated in  PMID 933560.

It's a mistake to extrapolate from epidemiological studies on the relationship between BMI and life expectancy in humans to the CR data, as has been discussed on the Forum and elsewhere to death; I would point you particularly here.

Refernces

1: Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science. 1982 Mar 12;215(4538):1415-8. PMID: 7063854 [PubMed - indexed for MEDLINE]

2: Spindler SR. Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span. Age (Dordr). 2012 Feb;34(1):111-20. doi: 10.1007/s11357-011-9224-6. Epub 2011 Mar 22. Review. PubMed PMID: 21424790; PubMed Central PMCID: PMC3260350.

3: Martin B, Ji S, Maudsley S, Mattson MP. "Control" laboratory rodents are metabolically morbid: why it matters. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6127-33. doi: 10.1073/pnas.0912955107. Epub 2010 Mar 1. PubMed PMID: 20194732; PubMed Central PMCID: PMC2852022.

4: Festing MF. Fat rats and carcinogenesis screening. Nature. 1997 Jul 24;388(6640):321-2. PubMed PMID: 9237745.

5: Carey GB, Merrill LC. Meal-feeding rodents and toxicology research. Chem Res Toxicol. 2012 Aug 20;25(8):1545-50. doi: 10.1021/tx300109x. Epub 2012 Jun 13. PubMed PMID: 22642213.

6: Keenan KP, Laroque P, Ballam GC, Soper KA, Dixit R, Mattson BA, Adams SP, Coleman JB. The effects of diet, ad libitum overfeeding, and moderate dietary restriction on the rodent bioassay: the uncontrolled variable in safety assessment. Toxicol Pathol. 1996 Nov-Dec;24(6):757-68. Review. PubMed PMID: 8994307.

7: Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR. Temporal linkage between the phenotypic and genomic responses to caloric restriction. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5524-9. Epub 2004 Mar 25. PubMed PMID: 15044709; PubMed Central PMCID: PMC397416.

8: Rae M. It's never too late: calorie restriction is effective in older mammals. Rejuvenation Res. 2004 Spring;7(1):3-8. Review. PubMed PMID: 15256039.

9: Turturro A, Duffy P, Hass B, Kodell R, Hart R. Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction. J Gerontol A Biol Sci Med Sci. 2002 Nov;57(11):B379-89. PubMed PMID: 12403793.

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3 hours ago, Michael R said:

"The "fat rats" problem does continue to plague aging research(2) — and, indeed, much animal research generally(3-5) — but has been dealt with in high-quality CR (and lifespan generally) studies for decades by determining what the "true" stuff-your-face ad libitum intake of the mice is and then setting the "ad lib" control group to consume 80-90% of that, and then determining "%CR" based on that "ad libitum" intake.  Thus, "40% CR" is (in well-done studies) actually (0.85 x 0.6)= 51% of what true ad libitum feeding looks like. You can see this in any lifespan study by Spindler, Weindruch, or Walford from the 1980s on; see also (2) on lifespan study design generally, although it doesn't insist on this protocol specifically (only the importance of rigorously monitoring food intake)."

This only shifts the goalposts of the discrepancy between normal and obese.  It doesn't actually disprove what I said.  An extremely obese person is capable of consuming up to 6000 calories per day on average, whereas the supposed normal is 2000.  That's a 66% caloric restriction if we consider the obese person normal. 

In order to disprove the current obesity/maturation hypothesis, you'll need to introduce a new mechanism explaining how caloric restriction causes a reduction of aging.

Edited by Michael R
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1 hour ago, Aaron King said:

This only shifts the goalposts of the discrepancy between normal and obese.  It doesn't actually disprove what I said.  An extremely obese person is capable of consuming up to 6000 calories per day on average, whereas the supposed normal is 2000.  That's a 66% caloric restriction if we consider the obese person normal. 

No, it doesn't. Mice fed normal rodent chow (literally) ad libitum do not develop morbid obesity — they just get a bit chubbier than is good for them. To get morbid obesity, you have to feed them a hypercaloric high-fat, high-sugar diet, or a mutation to make them hyperphagic. Depending on the strain and the chow, a 10%-20% restriction of normal chow is quite sufficient to get a lean non-mutant mouse.

An additional line of evidence on this is the fact that CR female mice become infertile, and males develop extremely low sperm count and lose interest in mounting females; if this were a normal state of affairs for a merely nonobese mouse, the species would long since have gone extinct.

1 hour ago, Aaron King said:

In order to disprove the current obesity/maturation hypothesis, you'll need to introduce a new mechanism explaining how caloric restriction causes a reduction of aging.

No, I don't: the empirical demonstration that it still works in middle-aged and early-seniority mice proves the point decisively. A mechanistic explanation is secondary to the empirical observation, not the other way around.

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the empirical demonstration that [CR] still works in middle-aged and early-seniority mice proves the point decisively. A mechanistic explanation is secondary to the empirical observation, not the other way around.”

Worth mentioning that even the above is disputed, as CR does NOT work in the majority of mouse subtypes that have been tested.

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3 hours ago, Aaron King said:

For the infertile CR mice, and low sperm count male mice, can you provide sources

Because I haven't seen anything that implies that

Ovarian cycling was completely shut down in female mice on just 20% CR from  3.5-10.5 mo in  (1). Other studies report substantial but loss of cycling without a complete shutdown (eg. (2-5)). Note that these same studies also show that after refeeding later in life, fertility resumes in these animals, even at ages when AL females have completely or almost completely lost fertiility to degenerative aging changes.

Sperm counts: eg. (5,6).

"CR experiments do in fact restrict energy consumption beyond that typically experienced by mice in nature. Therefore, the retarded aging observed with CR is not due to eliminating the detrimental effects of overeating."(5)

References

1: Nelson JF, Gosden RG, Felicio LS. Effect of dietary restriction on estrous cyclicity and follicular reserves in aging C57BL/6J mice. Biol Reprod. 1985 Apr;32(3):515-22. PubMed PMID: 4039610.

2: Selesniemi K, Lee HJ, Tilly JL. Moderate caloric restriction initiated inrodents during adulthood sustains function of the female reproductive axis intoadvanced chronological age. Aging Cell. 2008 Oct;7(5):622-9. doi:10.1111/j.1474-9726.2008.00409.x. Epub 2008 Jul 24. PubMed PMID: 18549458; PubMedCentral PMCID: PMC2990913.

3: Holehan AM, Merry BJ. Lifetime breeding studies in fully fed and dietaryrestricted female CFY Sprague-Dawley rats. 1. Effect of age, housing conditionsand diet on fecundity. Mech Ageing Dev. 1985 Dec;33(1):19-28. PubMed PMID:4079476.

4: BALL ZB, BARNES RH, VISSCHER MB. The effects of dietary caloric restriction onmaturity and senescence, with particular reference to fertility and longevity. AmJ Physiol. 1947 Sep;150(3):511-9. PubMed PMID: 20265851.

5: Chapin RE, Gulati DK, Fail PA, Hope E, Russell SR, Heindel JJ, George JD, Grizzle TB, Teague JL. The effects of feed restriction on reproductive function in Swiss CD-1 mice. Fundam Appl Toxicol. 1993 Jan;20(1):15-22. PubMed PMID: 8432424.

6: Brinkworth MH, Anderson D, McLean AE. Effects of dietary imbalances on spermatogenesis in CD-1 mice and CD rats. Food Chem Toxicol. 1992 Jan;30(1):29-35. PubMed PMID: 1544603.

7:Austad SN, Kristan DM. Are mice calorically restricted in nature? Aging Cell.2003 Aug;2(4):201-7. PubMed PMID: 12934713.

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The data in the papers on female fertility as well as other papers I found while searching for this clearly points to a reduction of fertility on a CR diet.

I was about to concede the point, but then I thought of something - what would happen if a human woman got pregnant and didn't alter her feeding pattern at all.  I did some preliminary searching which backs up the concept that if a woman doesn't alter her diet at all, she will experience hardships during pregnancy.  That is, the 'normal' diet for an average woman would cause infertility risk unless she increases food intake during pregnancy, as they do for all of these mice studies.  I'll have to dig deeper to see if any formal studies have been done on this topic.

So far, the number being mentioned seems to be +300 calories per day, which is a 15% increase based on a 2000 calorie diet.  Obviously, the ratios are going to be different between a human female who has 1 child vs. a mouse that is giving birth to an entire litter.  

I can't see how this would be extrapolated to the sperm count though, that point may still stand.

Edited by Aaron King
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5 hours ago, Aaron King said:

The data in the papers on female fertility as well as other papers I found while searching for this clearly points to a reduction of fertility on a CR diet.

I was about to concede the point, but then I thought of something - what would happen if a human woman got pregnant and didn't alter her feeding pattern at all.   [...] So far, the number being mentioned seems to be +300 calories per day, which is a 15% increase based on a 2000 calorie diet....

This would contribute to a low rate of live and viable offspring, but not  likely for the dramatic reductions in pregnancies per se; and, again, CR also substantially reduces ovarian cycling — in one case, even shutting it down completely at just 20% CR — which you'll agree requires very little energy (indeed, less than spermatogenesis).

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This paper implies that mice can achieve pregnancies during CR, but the offspring are not viable.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990913/pdf/acel0007-0622.pdf

"It should be mentioned here that fertility of CR females while on the restriction protocol (i.e. between 10 and 15.5 months of age) was poor, with a total of 9 pregnancies achieved by the 11 CR females (7 females pregnant once, 1 female pregnant twice). Furthermore, all offspring were delivered dead or died very shortly after birth (data not shown)."

These were mice at 25% CR, and I believe that due to the difference in reproduction methods - litters vs. individual births - that the effect is much more pronounced in mice.

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I went through this paper:

"EFFECTS OF DIETARY IMBALANCES ON SPERMATOGENESIS IN CD-1 MICE AND CD RATS" 1992

I would really encourage you to read the papers you cite.  In particular, take a look at the results section.  The sperm count did dramatically change - when they did 85% caloric restriction, which is borderline starvation.  Another notable reduction occurred when they gave a protein free diet.  Sperm are mostly protein, so this makes sense.  There was also a reduction with a carbohydrate free diet.  I'm not exactly sure why that would be, but fatty acids do take longer to convert to energy than carbohydrates so that may have something to do with it.  They did not test 'normal' caloric restriction of something like ~30% across the board.  

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In my (5):

"using adult mice that were maintained at 90, 80, and 70% of concurrent control body weight (CBW) for up to 21 weeks ... there was a significant decrease in the number of epididymal sperm and in the number of testicular spermatids in the 70% CBW groups."

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Also from the paper:

"Two points about the intratesticular testosterone deserve mention: (a) the decrease in the 70% group was severe, and (b) this magnitude of decrease still allowed for a functional reproductive system, as shown by the ability of the animals to make sperm and sire litters. If this lowered intratesticular testosterone also reflects serum values, then this might explain some of the decrease in accessory organ weights. How much of those weight decreases are due to "generalized body weight effects" and how much is due specifically to lowered testosterone cannot be determined."

It still allows for functional reproduction.  The results are significant though, they clearly have reduced litter size.

I think that it would be more convincing to see the same type of experiment done on an animal that reproduces in a similar way as humans.  Any mammal that has 1-2 offspring at a time, rather than a litter.  Then the litter-based reproductive mechanics could be separated from the CR mechanics.

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