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Ageing Research Reviews 9 (2010) 424430

Contents lists available at ScienceDirect

Ageing Research Reviews

j ou rna l homepage : www.e l sev i e r. com/ loca t e / a r r

Review

Commonly adopted caloric restriction protocols often involve malnutritionFernanda M. Cerqueira , Alicia J. KowaltowskiDepartamento de Bioqumica, Instituto de Qumica, Universidade de So Paulo, So Paulo, Brazil

a r t i c l e i n f o

Article history:Received 13 April 2010Received in revised form 10 May 2010Accepted 10 May 2010

Keywords:AgeingDietEnergy restrictionCalorie restrictionMicronutrientsVitamins

a b s t r a c t

Undernutrition without malnutrition is an intervention that enhances laboratory animal life span, andis widely studied to uncover factors limiting longevity. In a search of the literature over a course of fouryears, we found that most protocols currently adopted as caloric restriction do not meet micronutrient

standardsset by theNational ResearchCouncil forlaboratory rats and mice. We provide evidence that themost commonly adopted caloric restriction protocol, a 40%restrictionof theAIN-93 diet without vitaminor mineral supplementation, leads to malnutritionin both mice and rats. Furthermore,others and we ndthat every other dayfeeding, another dietary interventionoftenreferredto as caloricrestriction, does notlimit the total amount of calories consumed. Altogether, we propose that the term caloric restrictionshould be usedspecically to describedietsthat decreasecalorie intakebutnotmicronutrientavailability,and that protocols adopted should be described in detail in order to allow for comparisons and betterunderstanding of the effects of these diets.

2010 Elsevier B.V. All rights reserved.

1. Caloric restriction: early studies

McCay et al. rst demonstrated in 1935 that caloric restriction(CR)increasesmaximum lifespan( McCay, 1935 ), offering restrictedrats 20%less food than the ad libitumcontrols ingested. The authorsof this groundbreaking study were aware that micronutrient mal-nutrition could be associated with the restricted diet, and the CRrats received additional daily supplements of cod liver oil andyeast to prevent vitamin and mineral deciencies. Most CR stud-ies within the next decades kept micronutrient supplementation:Ross and colleagues used semi-puried diets in a series of stud-ies on longevity and cancer in rats, enriching the diets of CRrodents in contents of salts and vitamins ( Ross, 1961 ). Follow-ing Ross protocol, Weindruch and Walford developed a diet tostudy the inuences of CR and ageing on mitochondrial respiration(Weindruchet al., 1980 ), immunefunction( Weindruchet al., 1982 ),lifespan, and cancer incidence ( Weindruch and Walford, 1982a;Weindruch et al., 1986 ) in mice. The diets fed to the restricted

Disclaimer : Thefundershadno role in study design, data collection and analysis,decision to publish,or preparationof themanuscript.All animal experimentsfollowinternationalstandards andwere approved by the Comitde ticaem Cuidadose Uso Animal, an NIH accreditedethics committeewhich overseesanimal researchwithinthe Instituto de Qumicaof the Universidade de So Paulo, and follows standardsset by the Colgio Brasileiro de Experimentac o Animal. Rats and mice were breadand housed in the Biotrio de Produc o e Experimentac o da Faculdade de CinciasFarmacuticas e Instituto de Qumica, Universidade de So Paulo. Corresponding author at: Av. Prof. Lineu Prestes, 748, Cidade Universitria, So

Paulo, 05508-900, SP, Brazil. Tel.: +55 11 30913810; fax: +55 11 38155579.E-mail address:[email protected] (F.M. Cerqueira).

mice were also enriched, and solidied the term CR as a label for adietary intervention involving a decrease in calorie intake withoutmicronutrient limitation, which is associated with lifespan exten-sion in many animal models.

2. AIN diets and increased interest in CR: what happened tomicronutrient supplementation?

In 1977, the American Institute of Nutrition (AIN) Ad HocCom-mittee on Standards for Nutritional Studies released a report withrecommendations on nutritional methodology which would serveas a guideline for scientists who work with animal models. Fixed-formula diets, in which kinds and amounts of ingredients do notvary from batch to batch, areoften called open-formuladiets whenthe formula is openly declared. A xed-formula diet may containmultiple sources of protein, fat and carbohydrates, thereby reduc-ing the importance of variationin thecomposition of anyparticularingredient from batch to batch ( Knapka et al., 1974 ). The AIN-76xed-formula diet supported growth, reproduction and lactationcomparable to those observed using the best cereal-based diets.This diet was modied over the years, resulting nally in the AIN-93 diet, in two formulations: AIN-93G, for growth, pregnancy andlactation, andAIN-93M foradult maintenance ( Reeves et al., 1993 ).The criteria used for the AIN-93 formulations were (a) diets can beprepared from puried ingredients; (b) they conform to or exceednutrient requirements suggested by the National Research Council(NRC) (National Research Council, 1995 ); (c) they can be preparedwith readily available ingredients at a reasonable cost; (d) compo-sitions are consistent and reproducible; and (e) diets can be usedfor a wide range of applications ( Reeves, 1997 ). The AIN-93 diet is

1568-1637/$ see front matter 2010 Elsevier B.V. All rights reserved.

doi: 10.1016/j.arr.2010.05.002
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Table 1NRC micronutrient recommendations for mice and rats versus the micronutrient contents provided by AIN-93M and NIH-31 used in 40% DR. 1 NRC recommendation for ratsand mice ( National Research Council, 1995 ). 2 AIN-93M ( Reeves, 1997 ): a lower than recommended for rats; b lower than recommended for mice. 3 NIH-31 ( Pugh et al., 1999 ):a lower than recommended for rats; b lower than recommended for mice.

Micronutrients Growth recommendations 1 AIN-93M 2 NIH-31 3

unit/100 g rat (unit/100 g mouse) unit/100 g unit/60 g unit/100g unit/60 g

MineralsCalcium g 0.50 0.50 0.30 ab 1.01 0.61Chlorine g 0.05 0.16 0.09 0.42 0.25Magnesium g 0.05 0.05 0.03 ab 0.20 0.12Phosphorus g 0.30 0.30 0.18 ab 0.92 0.55Potassium g 0.05 (0.20) 0.60 0.31 0.59 0.35Sodium g 0.05 0.10 0.06 0.26 0.16Copper mg 0.50 (0.60) 0.60 0.36 ab 1.32 0.79Iron mg 3.50 3.50 2.10 ab 30.02 18.01Manganese mg 1.00 1.00 0.60 ab 15.28 9.17Zinc mg 1.50 (1.00) 3.00 1.80 5.04 3.02Molybdenium g 15.00 15.00 9.00 ab ND NDSelenium g 15.00 15.00 9.00 ab ND NDIodine g 15.00 20.00 12.00 ab 19.40 11.64 ab

Vitamins3-Hydroxy retinol mg 0.07 0.40 0.24 1.06 1.06Cholecalciferol g 2.00 2.50 1.50 ab 1.05 ab 1.05 ab

dl- -Tocopheryl acetate mg 1.80 (2.20) 5.00 3.00 3.83 3.83Menadione mg 0.10 0.08 a 0.06 ab 0.22 0.22Biotin mg 0.02 0.20 0.12 0.01 ab 0.01 ab

Choline mg 75.00 (200.00) 250.00 150.00 b 196 196Folic acid mg 0.10 (0.05) 0.20 0.12 0.17 0.17Niacin mg 1.50 3.00 1.80 9.22 9.22Pantothenic acid mg 1.00 (1.60) 1.50 0.96 ab 3.95 3.95Riboavin mg 0.30 (0.70) 0.60 0.36 b 0.78 0.78Thiamin mg 0.40 (0.50) 0.50 0.30 ab 7.73 7.73Pyridoxine mg 0.60 (0.80) 0.60 0.42 ab 1.02 1.02Cobalamin g 5.00 (1.00) 2.50 a 1.50 a 5.3 5.3

Abbreviations: American Institute of Nutrition (AIN); caloric restriction (CR); dietary restriction (DR); every other day feeding (EOD); National Institute of Aging (NIA);National Research Council (NRC).

enriched with a vitamin and mineral mix that supports the nutri-entrequirements suggestedby theNRC ( National ResearchCouncil,1995 ), and exceeds those in many, but not all, cases (compare therecommended vitamin and mineral amounts andcontent per100 g

AIN-93 diet in Table 1 ).The increased implementation of AINdiets wasparalleled by an

enhanced interest in CR studies. Unfortunately, the protocolsbeganto diverge withrespect to mineral and/or vitamin supplementation.Table2 listspapers added to thePubMed database betweenJanuary1st, 2006 and December 31st, 2009 with the widely adopted termcaloric restriction in the title, as well as the dietary interventionused. Surprisingly, 60% ofallarticlesuncoveredin oursearch do notspecify the use of micronutrient supplementation. Note that thepapers uncovered are a fraction of all publications involving somesort of dietary restriction during this period, since not all publica-tions include this exact term in their title. However, we believe thisfraction is representative of a general tendency to adopt diets thatdo not supplementmicronutrients. Indeed, a preliminarysearch for

papers usingenergyrestrictionor calorie restriction(a commonvariation of the term) reveals a similar pattern (not shown).The widespread use of diets without micronutrient supplemen-

tation may be due to the high content of vitamins and minerals inAIN formulations, which could lead researchers to believe supple-mentation was unnecessary. The use of ready-made commercialdiets may also have hampered the ease to obtain manipulatedenriched diets forCR studies. Furthermore,studies with animals onnon-supplemented dietary restricted diets presented some resultsexpected for CR animals ( Keenan et al., 1997; Yu et al., 1982 ).Unfortunately, no direct comparisons were made between dietaryrestriction (DR, a general limitation of diet, not necessarily associ-ated with enhanced lifespan)and CR,and it is thereforenot possibletoconclude that alleffects ofCR arereproducedin DR.Indeed,many

effects attributed to CR uncovered in DR models could, in fact, be

the result of decreased levels of micronutrients, even if these arestill above recommended daily needs.

As protocols changed, the terms (and acronyms) that describethem also diverged. Terms such as malnutrition, protein-energy

(calorie) malnutrition, starvation, food restriction, DR, undernutri-tion without malnutrition ( Weindruch and Walford, 1982b ), and,more recently, every other day feeding (EOD) are often used inter-changeably with CR. It is clear today that there is no consensusregarding the use of micronutrient supplementation in these stud-ies, that protocolsvarywidelyandthat theresults of these differentprotocols are not necessarily comparable. Furthermore, the extentof time in which animals are maintained on the diet also varies, asdescribed in Table 2 . Although short-term CR has a similar impacton gene expression as long-term CR ( Cao et al., 2001 ), the age atwhich CR is introduced affects changes in metabolic parameters(Colman et al., 2007 ), and the extent of time in which the animalsare kept on the diet most probably also affects these results.

In an example of one of the few well-controlled and detailed

protocols available that includes supplementation, the NationalInstitute on Aging formulated a specic diet, the NIH-31 Open-Formula Diet (see Table 1 f or micronutrient contents), and a dietimplementation protocol ( Pugh et al., 1999 ). The restricted NIH-31diet contains supplemental vitamins (but not minerals) to provideapproximately the same intake as that of the ad libitummice ( Pughet al., 1999 ) (see Table 2 ).

3. Micronutrient contents of diets versus NRCrecommendations

A nutritionally balanced diet is important both for the welfareof laboratory animals and to ensure that experimental results arenot biased by unintended nutritional factors ( National Research

Council, 1995 ). The NRC established diet contents based on maxi-


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micronutrient supplementation ( Pugh et al., 1999 ), although theperception that CR diets should account for this lack is reectedby NIA protocols. When we analyzed four years of original articlesusing the phrase caloric restriction ( Table 2 ), we found that theamount of calories/food restricted was most commonly 40% (butvaried from 8 to 60%), mostly without mentioning micronutrientsupplements anymicronutrient (60%of articles),even in long-termstudies ( Table 2 ). Most DR studies do not follow lifespans, so theeffect of a non-supplemented restricted diet on animal longevity isstillpoorlyknown.Although Keenanetal.(1996) sawa25%increasein the mean survival age for male rats eating 23% less of a unsup-plemented diet relative to ad libitumcontrols, Duffy et al. (2002)noted that DR of rats on AIN-93 diets did not result in the lifespanextension observed on NIH-31 diets, suggesting that micronu-trient supplementation is important for the long-term effectsof CR.

To add to the confusion regarding the denition of CR, recentstudies have adopted other restriction strategies. An increasinglypopular strategy is EODfeeding, where animals arefed on alternatedays. Thirteen percent of feeding strategies employed in the four-year period analyzed are EOD ( Table 2 ). Some EOD studies providead libitumfood on the feeding day ( Anson et al., 2003; Pearson etal., 2008a; Caro et al., 2008 ), while others give a dened amount of food, limiting total consumption to less than that of control animals(Shimokawa et al., 2003; Zha et al., 2008 ). The diet is not vitaminand mineral enriched in anyEOD protocol uncovered in our search.Furthermore, in ouranimal facilities, EODfeedings resulted in totalfood ingestion levels equal to those in control animals. This is inagreement with previous studies demonstrating that food inges-tion in EOD protocols varies very slightly from that of controls(Anson et al., 2003; Hipkiss, 2007 ), although at least two groupsreport a 3040% decrease in food intake in EOD feedings ( Caro etal., 2008; Nisoli et al., 2005 ). Most EOD studies involve short-terminterventions, and we found only two which follow full lifespans:in one study ( Goodrick et al., 1990 ), both mean and maximal lifes-pan were enhanced,while the second paper ( Pearson et al., 2008b )shows no increment in lifespan associated with EOD feedings. Inall, EOD is an interesting protocol in many aspects, although directcomparisons between the effectsof thisregimen and traditional CRmust be made with caution, since it is not clear that this regimenis associated with prolonged life.

More complexity is added by the nding that some authorsrefer to EOD as intermediate feeding, while other authors useintermediate feeding to describe other feeding strategies such asoffering food on specic days (Mondays, Wednesdays and Fridays(Tatsumi et al., 2008 )). The effectsof such rarer protocols on animallongevity are unknown.

5. Potential impact of DR on animal development

It rst became clear to us that non-supplemented DR proto-cols could be nutritionally decient when we submitted adultSwiss mice on AIN-93M diets to 40% food restriction ( Fig. 1A) andobserved pronounced ( 20%)weightloss.A signicant weightgain( p< 0.001) was observed in these animals after the supplemen-tation of micronutrients. Weight loss was less than 10% duringthe same period with the same level of restriction of the dietsupplemented with vitamins and minerals, to equal micronutri-ent ingestion in controls (CR, results not shown). Furthermore, wefound that Sprague-Dawley rats on long-term dietary restrictionpresented signicantly larger weight gains over time when theyreceived micronutrient supplementation ( p= 0.04, Fig. 1B). Ourresults demonstrate that non-supplemented DR in young rodentsdoes not only limit calories, but also involves micronutrient mal-

nutrition.

Fig.1. Rodent growth onsupplemented versusnon-supplemented diets. (A)FemaleSwiss outbred albino mice, purchased originally from Taconic Farms, were bred(5mice/cage)andlodgedatthe Biotriode Produc oe Experimentac oda FaculdadedCincias Farmacuticas e Instituto de Qumica, under controlled temperature (22 C),humidity, light (12 h light/dark cycles) and pressure conditions. Starting at 9 weeksofage,theControlgroup waskept on ad libitumAIN-93Mdiets (produced by Rhoster Indstria e Comrcio, Arac oiaba da Serra, So Paulo, Brazil), while 40% of ad libitumdietary restriction (DR) was initiated for DR mice, initially without micronutrientsupplementation. At 15 weeks, where indicated by the arrow, vitamin and mineral

supplementation were added to the restricted diet, in order to reach micronutrientlevels equal to controls, but maintaining 40% food restriction. Food quantities wereadjusted weekly by weight, based on ad libitum food consumption of the Controlgroup, and animals were weighted weekly. Restricted diets were offered daily at18:00. Values are mean SEM, n =10. (B) Male Sprague-Dawley albino rats pur-chased originally from Taconic Farms were bred (3 rats/cage) and lodged underthe same conditions as described for Panel A, on ad libitumAIN-93M diets. Start-ing at week 12, the Control group was kept on the ad libitumAIN-93M diet, while40% dietary restriction (DR) without supplementation (calculated based on weeklymeasurements of Control animal ingestion), 40% dietary restriction with vitaminandmineral supplementation (CR)or non-supplemented ad libitumevery other day(EOD) feedings were introduced to the other experimental groups. These dietaryinterventions were maintained during the following 15 weeks, and the weightgain over this experimental period was recorded. DR and CR food quantities wereadjusted weekly by weight, based on ad libitum food consumption of the Controlgroup. Restricted diets were offered daily at 18:00, the same time in which the dietwas removed or placed for the EOD group. Results are expressed as mean SEM,n = 6.

In our animal facilities, as well as in others ( Anson et al.,2003; Hipkiss, 2007 ), ad libitum EOD intake did not signicantlydecrease total food ingestion (22.8 2.4gday 1 animal 1 versus20.15 0.9gday 1 animal 1 for ad libitumversus EOD), althoughthe weight gainof EOD rats was smaller ( Fig. 1B), indicating a lowerefciency of energy conversion. Together, these results suggestthat, although it may present some metabolic changes observedin CR, EOD is not necessarily a form of calorie restriction, and theterms should not be used interchangeably.

6. A proposal for nomenclature and protocols

Our data mining indicates clearly that a large diversity of pro-tocols is adopted as caloric restriction in the literature ( Table 2 ).In addition to differing widely, these protocols are often imple-mented with little knowledge regarding their long-term effects.The consequence of this variability in the literature is that exper-imental results cannot be compared adequately, and often cannotbe directly related to a positive lifespan effect.

Other researchers have proposed care in respect to CR nomen-clature. Piper et al. (2005) proposed the use of dietary restrictionas a term of choice, arguing that it is difcult to quantify useableenergy (calories) in a diet. Masoro (2009) suggests the use of foodrestrictioninstead,because dietarycan referto anything, includ-ing the restriction of a single nutrient.

We would like to propose that the terms calorie restriction

andcaloricrestriction retaintheiroriginalmeaning ofenergy, but


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428 F.M. Cerqueira, A.J. Kowaltowski / Ageing Research Reviews9 (2010) 424430

not micronutrient limitation, and be used to refer to diets in whichtotal calories are limited, with vitamin and mineral supplementa-tion. Fully supplemented diets should be the standard interventionstudied in longevity research due to their well-established lifespaneffects in rodents. Diets such as non-supplemented chow restric-tion, EOD and other variants should perhaps more precisely bereferred to as dietary restriction or food restriction, and theirlifespan effects should be closely evaluated.

Most importantly, all work in the area should include detailedmethodology describing the animal model, genotype, type of dietadopted, restriction levels and how these were calculated, the agein which the diet was introduced, length of time in which the ani-mals were maintained on the diet, supplements included, housingconditions and methods of feeding. With such standards and infor-mation, research in the area will certainly gain more signicantinsight into the mechanistic effects of diets on longevity.

Contributors

FMCdesigned, conducted andanalyzed thedatapresented. FMCand AJK reviewed the literature and prepared the manuscript.

Conict of interest

None.

Acknowledgements

Theauthors arein debtto Camille C. Caldeira-da-Silva forexperttechnical assistanceand SilvaniaM.P.Neves,RenataS. Fontes, FlaviaM.P. Ong and Maria de Ftima Rodrigues for excellent animal care.This work is supported by grants from the Fundac o de Amparo Pesquisa do Estado de So Paulo(FAPESP), Instituto Nacional deCincia e Tecnologia de Processos Redox em Biomedicina(Redox-oma), Conselho Nacional de Desenvolvimento Cientco e Tecnolgico(CNPq) and the John Simon Guggenheim Memorial Foundation.

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