restriçaõ calórica

restrição calórica

Origem: Wikipédia, a enciclopédia livre




A restrição calórica (CR ) , ou a restrição de calorias, é um regime dietético que restringe a ingestão de calorias , em que a linha de base para a restrição varia , geralmente sendo a entrada anterior , sem restrição, dos sujeitos. A restrição calórica sem desnutrição foi mostrado para melhorar a saúde relacionada com a idade e para retardar o processo de envelhecimento em uma ampla variedade de animais e alguns fungos .
CR é uma das poucas intervenções dietéticas mostrados para aumentar tanto o tempo de vida médio e máximo em uma variedade de espécies , entre elas de levedura , peixes, roedores e cães . Há estudos em andamento sobre se CR funciona em primatas não humanos , em seus efeitos sobre a saúde humana e sobre os parâmetros metabólicos associados à CR em outras espécies. Os resultados obtidos até agora são positivos , mas os estudos ainda não estão completos, devido ao longo tempo de vida das espécies . Entre os estudos atuais , um de UCSF , com o Prêmio Nobel Elizabeth Blackburn , como parte da equipe de investigação , está a olhar para os praticantes CR longo prazo , incluindo os fatores psicológicos que mantê-los motivados a permanecer em uma dieta CR . [3]A restrição calórica é uma característica de vários regimes alimentares , incluindo a dieta de Okinawa [4] e da dieta - cron.



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Em 1934, Mary Crowell e Clive McCay , da Universidade Cornell, observou que ratos de laboratório alimentados com uma dieta de calorias severamente reduzida , mantendo os níveis de micronutrientes resultou em vãos de até de vida para o dobro do tempo , caso contrário o esperado. Estes resultados foram explorados em detalhe por uma série de experiências com ratos realizados por Roy Walford e seu aluno Richard Weindruch . Em 1986, Weindruch relatado que a restrição da ingestão de calorias de ratos de laboratório proporcionalmente aumentado a sua vida útil em relação a um grupo de ratos com uma dieta normal. Os camundongos com restrição de calorias também manteve aparências juvenis e níveis de atividade mais longos e mostrou atrasos nas doenças relacionadas à idade . Os resultados de muitos experimentos de Walford e Weindruch foram resumidos no livro O retardo do envelhecimento ea doença de restrição dietética (1988).
Os resultados foram aceites e generalizada, uma vez que a uma série de outros animais. Os pesquisadores estão investigando a possibilidade de ligações paralelas fisiológicos em seres humanos. Entretanto , muitas pessoas têm adotado independentemente da prática de restrição de calorias de alguma forma.

 Efeitos sobre os seres humanos

 Os efeitos positivos

 Riscos cardiovasculares reduzidosAlgumas pesquisas mostraram CR para reduzir os fatores de risco para aterosclerose .

Um pequeno estudo de praticantes CR longo prazo estudaram os efeitos de uma dieta com 10-25% menos calorias do que a média de dieta "ocidental" . O índice de massa corporal (IMC) foi de 19,6 no grupo CR , o grupo acompanhado do IMC foi de 25,9, comparável ao IMC para as pessoas de meia-idade em os EUA .

A média do IMC do grupo CR caiu de 24 (intervalo de 19,4-29,6 ) para 19,5 (variação de 16,5-22,8 ) em períodos de 3-15 anos. Quase toda a diminuição no IMC e fatores de risco cardiovascular ocorreu no primeiro ano. Ajuste para a idade , o colesterol total e média LDL (mau colesterol) no grupo CR foram inferiores aos observados em todos, mas o menor de 10% da população. O HDL médio ( bom colesterol) estavam na faixa de 85o ao 90o percentil para os homens americanos de meia-idade normais.

O grupo de restrição calórica também se saiu muito melhor do que o grupo controle em termos de pressão arterial média ( 100/60 contra 130/80 mmHg) , glicemia de jejum , insulina de jejum (65 % de redução) , índice de massa corporal ( 19,6 ± 1,9 vs 25,9 ± 3,2 kg/m2) , porcentagem de gordura corporal (8,7% ± 7% vs 24% ± 8% ), proteína C -reativa, carótida IMT (40 % de redução) , e crescimento derivado das plaquetas fator AB.

O grupo CR apresentaram níveis de triglicérides tão baixo como o menor de 5% dos norte-americanos em seus 20 anos . ( O grupo CR idade - série foi 35-82 . ) Sistólica e pressão arterial diastólica no grupo CR eram cerca de 100/60 , um nível mais típico , de 10 anos de idade [carece de fontes ] . Concentração de insulina no plasma em jejum era de 65 % menor . A concentração de glicose no plasma em jejum foi também inferior.
O investigador principal do estudo observou uma menor taxa aparente de envelhecimento cardiovascular, com indicadores de progresso arteriosclerose particularmente lento.
As estatísticas do grupo de comparação alinhado aproximadamente com média nacional os EUA sobre as dimensões consideradas. [8 ] em jejum os níveis de insulina no plasma [9] e os níveis de glicose plasmática em jejum [10] são utilizados como testes para prever diabetes.
O estudo CALERIE americana começou em 2007 e investiga os efeitos de uma redução de 25% na ingestão de calorias em adultos saudáveis ​​durante um período de dois anos.O efeito de CR em IGF-1 níveis séricos observados em roedores parece só manifesta nos seres humanos quando a proteína ingestão não é muito maior do que a Recommended Dietary Allowance

  Melhora da memória

Uma pesquisa de 2009 mostrou que uma dieta de restrição de calorias pode melhorar a memória em idosos acima do peso normal . A dieta também resultou em diminuição dos níveis de insulina e sinais reduzidos de inflammation.Scientists acreditam que a melhoria da memória neste experimento foi causado pelos níveis mais baixos de insulina , porque os níveis elevados de insulina são normalmente associados com menor memória e cognitivos function.However , essa relação parece ter a idade específica desde um outro estudo , ao analisar pessoas com mais de 65 anos, aqueles que estavam abaixo do peso têm um risco maior de demência do que as pessoas normais ou com sobrepeso.

 preocupações com a saúdeEmbora os estudos mostram que a restrição de calorias pode melhorar a longevidade ea saúde em organismos modelo , e os estudos em humanos demonstram redução fatores de risco para doenças graves , os efeitos a longo prazo em seres humanos ainda são desconhecidos.

 perdas músculo-esqueléticasAlém dos benefícios , os estudos de curto prazo em humanos relatam a perda de massa muscular e da força muscular e diminuição da densidade mineral óssea.
Vários estudos revelaram que dieters que calorias restritas por 12 meses tiveram menor massa muscular e uma reduzida capacidade de realizar exercícios em comparação com aqueles que perderam quantidades similares de peso do exercício alon.Another estudo concluiu que aqueles que perderam peso com a ajuda das dietas CR são mais propensos a desenvolver uma perda de osso a nível da anca e coluna , a área de maior risco para os especialistas fractures.Some ósseas dizer que as perdas de minerais secundários podem ser evitados com suplementos de vitamina D e cálcio.

 ] Low BMI, alta taxa de mortalidade : um não-problema ?CR dietas geralmente levam à redução do peso corporal , e, em alguns estudos , peso corporal baixo tem sido associado com o aumento da mortalidade, particularmente em indivíduos de meia- idade ou idosos tardios. Um dos mais famoso desses estudos ligados um IMC inferior a 18 , para mulheres, com o aumento da mortalidade por causas de doenças não - cardiovasculares noncancer . [21] Os autores tentaram ajustar para fatores de confusão ( tabagismo , a falta de excluir pre- doenças existentes) , outros argumentam que os ajustes eram inadequados ." ... Epidemiologistas da ACS (American Cancer Society ) , American Heart Association , Harvard School of Public Health , e de outras organizações levantou questões metodológicas específicas sobre as recentes Centros de Controle e Prevenção de Doenças ( CDC) de estudos e análises apresentadas de outros dados conjuntos. a principal preocupação ... é que ele não levou em conta adequadamente a perda de peso de doenças graves , como câncer e doenças do coração ... [e] não conseguiu explicar de forma adequada para o efeito do tabagismo sobre o peso ... como resultado , o estudo Flegal subestimado os riscos de obesidade e superestimou os riscos da magreza " .A finura no idoso pode ser causado por condições que se causar a perda de peso (por exemplo, cancro, doença pulmonar obstrutiva crónica, ou depressão) ou da caquexia ( síndroma de desperdiçar ) e sarcopenia (perda de massa muscular , da estrutura e função) de envelhecimento .
Em qualquer caso , os estudos epidemiológicos de peso do corpo não são cerca de CR como utilizado em estudos anti-envelhecimento , pois eles não são sobre a ingestão de calorias , para começar, como o peso corporal é influenciado por muitos outros factores do que a ingestão de energia . Além disso, "a qualidade das dietas consumidas pelos indivíduos de baixa IMC são difíceis de avaliar, e pode faltar nutrientes importantes para a longevidade ". [16 ] típicas dietas de baixa caloria raramente fornecem as altas ingestões de nutrientes , que são uma característica necessária de um anti -envelhecimento dieta de restrição de calorias .


 Como assim, " Os indivíduos de menor peso nos estudos não são CR porque a sua ingestão calórica reflete sua ad libitum indivíduo set-points , e não uma redução do que set-point ". [16]

 Provocando distúrbios alimentaresAs preocupações são muitas vezes levantada de que CR pode fazer as pessoas sentir fome o tempo todo e pode levar a obsessão por comida , causando transtornos alimentares. [18] No entanto, um estudo controlado de humano CR não encontrou nenhum aumento em sintomas de transtorno alimentar ou outros efeitos psicológicos nocivos , em linha com uma extensa pesquisa antes. [28] em aqueles que já sofrem de um transtorno da compulsão alimentar periódica , a restrição calórica pode precipitar um episódio de compulsão alimentar, mas não parece representar qualquer risco de outra forma .

 Não para os jovens , ou aqueles com baixo teor de gordura do corpoO efeito das dietas sobre as pessoas que querem perder peso é controverso. [ Carece de fontes? ] Embora a restrição calórica pode proporcionar perda de peso rápida , vários estudos têm demonstrado que o corpo se ajusta à nova dieta, a mais ou menos meio ano. [Citação necessitou] os pesquisadores argumentam que as pessoas que têm pouca gordura corporal não deve usar este método de perder peso , mas sim deve exercer mais porque a restrição de calorias neste caso pode ser prejudicial. [18] a razão para isto é que depois as reservas de gordura do corpo ter sido queimado para produzir energia , as proteínas dentro do tecido muscular será consumido . Em casos graves, onde as pessoas não reconhecem os perigos que estão se expondo a , eles podem sofrer séria perda de massa muscular.
Especialmente em crianças, adolescentes e adultos jovens (com menos de cerca de 21 ) , a restrição calórica não é aconselhável , pois este tipo de dieta pode interferir com o crescimento físico natural, tem sido observado em animais de laboratório . Além disso, o desenvolvimento físico e alterações mentais para o cérebro ter lugar no final da adolescência e início da idade adulta que poderiam ser afetados negativamente pela restrição calórica . [30] As mulheres grávidas são recomendados a não tentar perder peso com este método. Tem sido demonstrado que um IMC baixo é um fator de risco na gravidez , pois pode resultar em disfunção ovulatória ( infertilidade ) , e as mães que estão abaixo do peso são mais propensas a parto prematuro. [30]Os indivíduos que tentam perder peso em uma dieta CR inferior a 1500 calorias por dia devem ser monitorizados por um especialista , a fim de evitar os efeitos colaterais potenciais. [ 31]

 [editar ] preocupações DiversosTambém foi observado que pessoas que perdem peso em tais dietas risco de desenvolver sensibilidade a frio , irregularidades menstruais e até mesmo infertilidade e alterações hormonais. [20]Além disso, a restrição calórica foi avaliado em ratos para reduzir a sua capacidade para combater a infecção e, algumas evidências sugerem que em doentes com restrição de calorias esclerose amiotrófica lateral, acelera o início da doença . [32 ]
Restrição calórica excessiva pode resultar na fome , a menos que o metabolismo também é retardado por alguns meios. CR não deve ser confundido com anorexia nervosa ou outros distúrbios alimentares . Se esse padrão se repete por períodos prolongados , o corpo pode queimar o tecido magro (incluindo, mas não limitado a muscular e colágeno ), juntamente com as suas reservas de gordura restantes. [33] A combinação de fome e da letargia associados e diminuição da atividade física pode resultar em atrofia muscular , reduzindo a qualidade de vida [34] [35] .
Além de utilizar o tecido magro como fonte de energia , a presença de hormônios catabólicos , como o cortisol , e falta de uns anabólicos, tais como a insulina , interrompe a síntese de proteínas , a captação de aminoácidos e enfraquece o sistema imunitário. Comentando um estudo onde CR mostraram efeitos globalmente positivos, um pesquisador advertiu que " [i ] t é possível que a restrição calórica moderada mesmo pode ser prejudicial em populações de pacientes específicos, como pessoas magras que têm quantidades mínimas de gordura corporal ". [36 ]

 Efeitos da CR sobre diferentes organismos

 primatasUm estudo realizado em macacos rhesus , financiado pelo National Institute on Aging, foi iniciado em 1989 na Universidade de Wisconsin- Madison e ainda está em curso. Este estudo tem mostrado até agora que a restrição calórica em macacos rhesus desponta envelhecimento e atrasa significativamente o início de distúrbios relacionados com a idade , como câncer , diabetes, doença cardiovascular e atrofia cerebral . Os macacos foram incluídos no estudo com idades entre 7 e 14 anos, no ponto 20 anos 80% dos macacos de restrição calórica ainda estavam vivos , em comparação com apenas metade dos controles [37 ] Estes resultados levou a resultados mais cedo preliminares. que mostrou insulina menor jejum e os níveis de glicose , bem como maior sensibilidade à insulina e perfil de LDL associados com menor risco de aterogênese em animais sob restrição alimentar. [38]
O estudo mais recente realizado por J. Ricki Colman e Richard Weindruch na Universidade de Wisconsin usado macacos rhesus que vivem uma média de 27 anos e máxima de 40 anos, descobriu que os macacos dieta mostram muitos sinais benéficos da resistência calórica , incluindo significativamente menos diabetes , câncer e doenças cardíacas e cérebro. No entanto, como alguns dos macacos são esperados para viver outros 20 anos , os resultados ainda são inconclusivos. [39]
Os resultados até agora têm encontrado uma tendência em direção a uma taxa de mortalidade global reduzida , que ainda não atingiu significância estatística. Uma análise adicional , restrito a causas de mortalidade relacionada com o envelhecimento, foi observada redução significativa no número de mortes relacionadas com a idade . No entanto , a interpretação deste achado é incerto, uma vez que é hipoteticamente possível exclusão de óbitos por causas não -envelhecimento pode de alguma forma mascarar um envolvimento de CR em tais mortes. embora o tamanho da amostra é muito baixo para dizer com certeza . [1 ] [2]
Pesquisadores da Escola de Medicina Mount Sinai , em Nova York relatou em 2006 que em comparação com macacos alimentados com uma dieta normal, macacos-esquilo em uma dieta ao longo da vida de calorias restritiva tinham menos probabilidade de desenvolver alterações Alzheimer , como em seus cérebros . [40 ] Desde esquilo macacos são , conclusões relativamente longa duração definitivas sobre se são ou não de envelhecimento mais lento ainda não estão disponíveis.Moderado CR atenua sarcopenia relacionada à idade em primatas . [41]

 [editar ] RoedoresSetenta anos atrás , CM McCay , et al. , Descobriu que reduzir a quantidade de calorias na alimentação de roedores quase dobrou sua vida útil . A extensão da vida foi variada para cada espécie, mas, em média , houve um aumento de 30-40% na expectativa de vida em ambos os camundongos e ratos . [42] CR preserva uma série de parâmetros estruturais e funcionais no envelhecimento roedores. Por exemplo, estudos em ratinhos fêmea têm demonstrado que o estrogénio do receptor alfa - quedas no hipotálamo envelhecimento pré- óptico. Os ratos fêmeas que receberam uma dieta calórica restrita , durante a maior parte das suas vidas mantida níveis mais elevados de ERa no hipotálamo pré- óptica do que os seus homólogos restrita não- calóricos . [43 ]Estudos em ratos fêmeas demonstraram que tanto núcleo supra-óptico ( SON) e núcleo paraventricular ( PVN ) perdem cerca de um terço do IGF -1R imunorreactividade com o envelhecimento normal . Caloricamente restritas ( CR ) ratos velhos perder números mais elevados de células não- imunorreactivas de IGF- 1R , mantendo a contagem de células imunorreactivas semelhantes de IGF- 1R em comparação com os ratos velhos -Al . Consequentemente , os ratos velhos -CR mostram uma percentagem mais elevada de células imunorreactivas de IGF- 1R que reflectem o aumento da sensibilidade do hipotálamo ao IGF -1 , em comparação com os ratos normalmente envelhecimento . [44 ] [ 45]

 [editar] YeastModelo fungos são muito fáceis de manipular e muitos passos importantes em direção à compreensão do envelhecimento foi feito com ele. Muitos estudos foram publicados em levedura de brotamento e levedura para analisar os mecanismos celulares por trás do aumento da longevidade devido à restrição calórica . Em primeiro lugar, a restrição calórica é muitas vezes chamado a restrição alimentar , porque os mesmos efeitos no tempo de vida pode ser alcançado somente mudando a qualidade nutritiva sem alterar a quantidade de calorias . Os dados do Dr Guarente , o Dr. Kennedy, Dr. Jazwinski , Dr Kaeberlein , o Dr. Longo, Dr. Shadel , Dr Nyström , o Dr. Piper e outros mostraram que as manipulações genéticas nas vias de sinalização de nutrientes pode imitar os efeitos da restrição dietética. Em alguns casos, a restrição dietética precisa respiração mitocondrial para aumentar a longevidade ( envelhecimento cronológico ) e em alguns outros casos não (envelhecimento replicativo ) . Sensoriamento de nutrientes em levedura controla defesa stress, funções mitocondriais , Sir2 e outros. Estas funções são todos conhecidos para regular o envelhecimento. Genes envolvidos nesses mecanismos são : TOR , PKA , SCH9 , MSN2 / 4, RIM15 , SIR2 , ... [46] [47] [48] [49] [50]

 [editar] DrosophilaResearch em 2003 por Mair et al . mostrou que a restrição calórica prolonga a vida das moscas da fruta de qualquer idade com efeitos instantâneos sobre as taxas de mortalidade . [51]

 [editar] Caenorhabditis elegansTrabalhos recentes sobre o Caenorhabditis elegans tem mostrado que a restrição do metabolismo da glucose se estende através do aumento da esperança de vida , principalmente o estresse oxidativo , finalmente, para exercer uma maior resistência contra o estresse oxidativo , um processo chamado ( Mito) hormesis . [ 52]

 [editar] Mecanismo de açãoMesmo que tenha havido pesquisa em CR há mais de 70 anos, o mecanismo pelo qual o CR funciona ainda não é bem compreendida. [1] Algumas explicações incluído reduzidos divisões celulares , as taxas de metabolismo mais baixo, reduziu a produção de radicais livres e hormesis . [53]

 hormesis



A investigação apontou para hormesis como uma explicação . Southam e Ehrlich (1943 ) relataram que um extracto de casca de que era conhecido por inibir o crescimento dos fungos , na verdade, estimularam o crescimento , quando administrado em concentrações muito baixas . Que cunhou o termo " hormesis " para descrever essas ações benéficas resultantes da resposta de um organismo a um estressor biológico de baixa intensidade. A palavra " hormesis " é derivado da palavra grega " hormaein ", que significa " excitar " .
A hipótese de CR hormesis ( Mito) propõe que a dieta impõe um esforço de baixa intensidade biológica no organismo , o que provoca uma resposta de defesa que ajuda a protegê-lo contra as causas do envelhecimento. Em outras palavras , CR coloca o organismo num estado defensiva de modo que possa sobreviver às adversidades , e isto resulta na melhoria da saúde e vida mais longa. Esta mudança para um estado defensivo pode ser controlada por genes da longevidade ( ver abaixo). [54 ]

 hormesis mitocondrialO hormesis mitocondrial era um conceito puramente hipotético até final de 2007 , quando o trabalho pelo grupo de Michael Ristow em um pequeno verme chamado Caenorhabditis elegans sugere que a restrição do metabolismo da glicose aumenta a vida útil principalmente pelo aumento do estresse oxidativo para estimular o organismo para ter uma última análise, o aumento da resistência a mais estresse oxidativo. [52] Esta é provavelmente a primeira evidência experimental para hormesis ser a razão para a expectativa de vida estendida seguindo CR .Embora o envelhecimento pode ser conceituado como o acúmulo de dano, o mais recente determinação de que os radicais livres participar de sinalização intracelular fez a equação categórico de seus efeitos com "dano" mais problemática do que era comumente apreciado nos últimos anos. Foi proposto anteriormente em uma base hipotética de que os radicais livres, podem induzir uma resposta endógena culminando em adaptações mais eficazes que protegem contra os radicais exógenas ( e, possivelmente, outros compostos tóxicos ) [55]. Evidências experimentais recentes sugerem fortemente que este é de facto o caso, e que tal indução da produção de radicais livres endógenos prolonga a vida útil de um organismo modelo e mitohormetically exerce prolongar a vida e promover a saúde efeitos. Estresse mitocondrial subletais com um aumento estequiométrica atendente de espécies reativas de oxigênio podem precipitar muitas das alterações benéficas na fisiologia celular produzido pela restrição calórica. [56] [57] [58]

  Evolução

Foi recentemente argumentou que durante anos de fome , pode ser evolutivamente desejável para um organismo para evitar a reprodução e upregulate mecanismos enzimáticos de proteção e reparação para tentar garantir que ele está apto para a reprodução em anos futuros. Este parece ser suportada pelo trabalho recente estudo hormonas. [59 ] Um estudo realizado em ratinhos macho descobriu que CR geralmente feminizes expressão génica e muitos dos genes individuais mais alterados significativamente estão envolvidos no envelhecimento , a sinalização da hormona, e p53 associado regulação da o ciclo celular e apoptose , concluiu-se que os efeitos de prolongamento da vida de CR pode surgir em parte a partir de um deslocamento para um perfil de expressão do gene mais comum das mulheres . [ 60] prolongada CR grave reduz a testosterona no soro e livre total, enquanto que o aumento das concentrações de SHBG em seres humanos , estes efeitos são independentes de adiposidade . [61 ]

A redução da concentração de insulina e as substâncias que estão relacionadas com insulina, por exemplo, Insulin-like Growth Factor 1 e hormona de crescimento tem sido mostrado para sobrerregular autofagia , o mecanismo de reparação da célula. [62 ] Uma hipótese sugere que a RC relacionado funciona através da diminuição dos níveis de insulina e , assim, upregulating autofagia , [62 ] [ 63], mas a RC afecta muitos outros indicadores de saúde , e se a insulina é a principal preocupação é ainda pendentes. [42 ] a restrição calórica foi mostrada para aumentar a DHEA em primatas, no entanto, não foi demonstrado que o aumento de DHEA em primatas pós- púberes . [64 ] [65 ] a medida em que estes resultados se aplicam aos seres humanos ainda está sob investigação .

 ] Cromatina e PHA -4Evidências sugerem que os efeitos biológicos da CR estão intimamente relacionados com a função da cromatina. [66] Um estudo realizado pelo Instituto Salk para Estudos Biológicos e publicado na revista Nature maio 2007 determinou que o gene PHA -4 é responsável pela longevidade atrás restrição calórica em lombrigas ", com resultados similares que se espera em seres humanos " . [67]

 Os radicais livres ] e glicaçãoDuas explicações propostas muito importantes do envelhecimento que têm uma influência sobre a restrição calórica é a teoria dos radicais livres ea teoria glicação . Com grandes quantidades de energia disponível , as mitocôndrias não operam de forma muito eficiente e gerar mais superóxido. Com CR , a energia é conservada e há menos geração de radicais livres . Um organismo CR terá menos gordura e requerem menos energia para suportar o peso , o que significa também que não tem necessidade de ser tão grande de glicose na corrente sanguínea.
Menos de glicose no sangue significa menos adjacentes a glicação de proteínas e menos gordura para oxidar na corrente sanguínea para causar blocos pegajosas , resultando em aterosclerose. Os diabéticos do tipo II são as pessoas com a insensibilidade à insulina causadas por exposição de longo prazo à glicose sanguínea elevada. A obesidade leva a diabetes tipo 2. Diabetes tipo 2 e descontrolada diabetes tipo 1 são muito parecidos " envelhecimento acelerado " , devido aos efeitos acima . Pode até haver um continuum entre CR e da síndrome metabólica .
Restrição calórica com nutrição ideal não foi testado em comparação com calorias em excesso com a nutrição ideal . Pode ser que, com calorias extra , nutrição deve ser aumentado de forma semelhante aos rácios comparáveis ​​às de restrição de calorias para proporcionar benefícios antienvelhecimento semelhantes. Níveis declarados de necessidades calóricas pode ser inclinado para indivíduos sedentários . A restrição calórica pode não ser mais do que a adaptação da dieta para as necessidades do corpo .

 Miméticos da restrição calóricaTrabalho sobre os mecanismos de CR deu esperança ao sintetizar drogas futuros para aumentar a expectativa de vida humana através da simulação dos efeitos da restrição calórica . No entanto, MIT biólogo Leonard Guarente advertiu que " (tratamento) não será um substituto para um estilo de vida saudável. Você ainda vai precisar ir ao ginásio " . [68] Sir2 ou " silent information regulator 2" é uma sirtuin , descobertos nas células de fermento de padeiro , que é a hipótese de suprimir a instabilidade DNA. [69] nos mamíferos Sir2 é conhecido como SIRT1 . David Sinclair da Harvard Medical School, Boston é um dos principais defensores da opinião de que o Sir2 gene pode estar por trás do efeito da restrição calórica em mamíferos , protegendo as células morram sob estresse. [70] Sugere-se uma dieta de baixa caloria que requer menos nicotinamida adenina para metabolizar pode permitir SIRT1 ser mais ativo em seus processos de vida que se estende . Um artigo na edição da revista Nature junho 2004 mostrou que a SIRT1 lançamentos de gordura a partir de células de armazenamento. [ 71]

 [editar] Sir2/SIRT1 e resveratrolEstão sendo feitas tentativas para desenvolver CR miméticos intervenções. [72] Resveratrol tem sido relatado para ativar Sir2/SIRT1 e prolongar a vida útil de fermento, [73 ] vermes nematóides , moscas de frutas, [ 74 ] e os ratos que consumiram uma dieta calórica elevada . [ 75 ] Resveratrol não estender o tempo em ratos normais . [76]O efeito do resveratrol na vida em C. elegans e Drosophila foi re- investigado por D. Gems e L. Partridge, eles concluíram anteriormente relatados aumenta expectativa de vida era de fato devido à variabilidade natural em C. elegans expectativa de vida [77] Um estudo recente descobriu resveratrol prolonga a vida útil de um peixe vertebrado de 59% . [78] no leveduras, vermes , moscas e estudos , o resveratrol não prolongar sua vida útil , se o gene Sir2 foi mutado. Um estudo de 2010 concluiu que SRT1720 e resveratrol não são ativadores diretos da SIRT1 . [79]Matt Kaeberlein e Brian Kennedy , da Universidade de Washington, Seattle acreditam que o trabalho de Sinclair em resveratrol é um artefato e que o gene Sir2 não tem relevância para CR , eles propuseram que a restrição calórica aumenta a expectativa de vida , diminuindo a atividade do alvo da rapamicina ( TOR ) quinase . [80 ] [81]Gurarente publicou recentemente que o comportamento associado com restrição calórica não ocorreu quando SIRT1 camundongos knockout foram colocados em uma dieta de restrição calórica , o que implica que SIRT1 é necessário para mediar os efeitos da restrição calórica. No entanto , o mesmo jornal informou também que os parâmetros bioquímicos pensado para mediar a vida efeitos da restrição calórica estende ( reduzida de insulina , IGF1 e glicemia de jejum ) , não eram diferentes em ratos normais e ratos que faltam Sirt1 . Se o efeito que prolonga vida útil de CR ainda era evidente em SIRT1 camundongos knockout não foi relatado neste estudo . De acordo com dados de Sinclair , Sirtuins ( SirT1 , Sir2 , ... ) estão por trás do efeito putativo da restrição calórica na longevidade , [82] no entanto, algumas pesquisas têm dúvidas sobre isso. [81] [83] [84] [85] Um ensaio clínico do SRT501 formulação resveratrol foi suspensa. [86]

 objeções

 Nenhum benefício para moscas , organismos-modelo superalimentadosUm conjunto de experiências mostram que CR não tem benefícios na mosca doméstica . [87 ] Os autores sugerem que os efeitos pretendidos de CR amplamente pode ser porque uma dieta contendo mais calorias pode aumentar a proliferação bacteriana , ou que o tipo de dietas de alto teor calórico utilizados em experiências passadas têm uma viscosidade , a composição geral, ou a textura que reduz a longevidade.
Outra teoria relacionada diz que alguns dos efeitos de restrição de calorias são manufacturados, porque os organismos modelo de laboratório são mantidos a não fisiológicas dietas de alto teor calórico . Isto significa que a restrição calórica significa simplesmente imitando uma fonte de energia ambiente natural [88] .

 Atividade física preconceitos testesEnquanto alguns testes de restrição de calorias demonstraram aumento do tecido muscular nos indivíduos do teste de restrição calórica , como isso ocorreu é desconhecido. O tecido muscular cresce quando estimulados , de modo que é possível que os animais de teste com restrição de calorias exercido mais do que os seus companheiros de calorias elevadas. As razões por trás disso pode ser que os animais entram em um estado de forrageamento durante a restrição calórica . A fim de controlar a esta variável, tais testes terá de ser monitorizada para assegurar que os níveis de actividade física são iguais entre os grupos.

 Calorias suficientes e aminoácidos para o exercícioO exercício também tem sido demonstrado que o aumento da saúde e vida e reduzir a incidência de várias doenças . Restrição calórica entra em conflito com as necessidades dos atletas de alto teor calórico , e não pode dar-lhes níveis adequados de energia ou aminoácidos suficientes para a reparação , embora isso não é uma crítica de CR , por si só , já é certamente possível ser um atleta saudável , ou um atleta destinado a morrer em uma idade jovem , devido à má alimentação, estresse , etc Além disso, em experimentos comparando CR para o exercício, os animais CR viver muito mais tempo do que os animais exercido [89] .

 O Calorie Restriction só beneficiam os jovens?Há algumas evidências que sugerem que o benefício da CR em ratos só pode ser colhida nos primeiros anos. Um estudo em ratos que foram introduzidas gradualmente para um estilo de vida CR aos 18 meses não apresentaram melhora em relação a média de vida do grupo ad libitum. [90 ] Este ponto de vista , no entanto, é contestada por Spindler , Dhahbi , e seus colegas , que mostraram que no final de idade adulta, aguda CR parcial ou completamente revertida alterações relacionadas com a idade de proteínas no fígado , cérebro e coração e que ratos colocados em CR aos 19 meses de idade mostram aumentos na expectativa de vida . [ 91] O Wisconsin estudo em macacos rhesus mostrou aumento das taxas de sobrevida e redução de doenças do envelhecimento da restrição calórica , embora o estudo começou com macacos adultos . [37]

 ] Midlife início da restrição calórica como um meio de prolongar a vida útilEste é um tema muito controverso de se e como começar como na meia-idade em humanos. Veja os livros de vida restrição calórica Roy Walford pesquisador que oferecem evidências inconclusivas , mas de apoio para esta tese.

 possíveis contra-indicaçõesAmbos animais e humanos sugerem BUD CR pode ser contra-indicado para pessoas com esclerose lateral amiotrófica (ELA). Investigação sobre um modelo de ratinho transgénico de esclerose lateral amiotrófica demonstra que CR pode acelerar o aparecimento de morte em ALS . Hamadeh et ai. Por conseguinte, conclui : "Estes resultados sugerem que o CR de dieta não é uma estratégia de protecção para os pacientes com esclerose lateral amiotrófica ( ALS) e, portanto, é contra-indicada . " [ 92 ] Hamadeh et ai. também notar dois estudos em humanos [93] [94] que indicam mostrar " baixo consumo de energia se correlaciona com a morte em pessoas com ELA. "

Calorie restriction

From Wikipedia, the free encyclopedia

Caloric restriction (CR), or calorie restriction, is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects. Calorie restriction without malnutrition has been shown to improve age-related health and to slow the aging process in a wide range of animals and some fungi.

CR is one of the few dietary interventions shown to increase both median and maximum lifespan in a variety of species, among them yeast, fish, rodents and dogs. There are ongoing studies on whether CR works in nonhuman primates, on its effects on human health, and on the metabolic parameters associated with CR in other species. The results so far are positive, but the studies are not yet complete, due to the long lifespan of the species. Among the current studies, one at UCSF, with Nobel laureate Elizabeth Blackburn as part of the investigation team, is looking at long-term CR practitioners, including the psychological factors that keep them motivated to stay on a CR diet.^[3]
Calorie restriction is a feature of several dietary regimens, including the Okinawa diet ^[4] and the CRON-diet.

Research history

In 1934, Mary Crowell and Clive McCay of Cornell University observed that laboratory rats fed a severely reduced calorie diet while maintaining micronutrient levels resulted in life spans of up to twice as long as otherwise expected. These findings were explored in detail by a series of experiments with mice conducted by Roy Walford and his student Richard Weindruch.

 In 1986, Weindruch reported that restricting the calorie intake of laboratory mice proportionally increased their life span compared to a group of mice with a normal diet. The calorie-restricted mice also maintained youthful appearances and activity levels longer and showed delays in age-related diseases. The results of the many experiments by Walford and Weindruch were summarized in their book The Retardation of Aging and Disease by Dietary Restriction (1988) .

The findings have since been accepted and generalized to a range of other animals. Researchers are investigating the possibility of parallel physiological links in humans. In the meantime, many people have independently adopted the practice of calorie restriction in some form.

Effects on humans

Positive effects

Cardiovascular risks reduced

Some research has shown CR to reduce atherosclerosis risk factors.

A small study of long-term CR practitioners studied the effects of a diet with 10-25% less calorie intake than the average "Western" diet. Mean Body mass index (BMI) was 19.6 in the CR group; the matched group BMI was 25.9, comparable to the BMI for middle-aged people in the US.

The mean BMI in the CR group dropped from 24 (range of 19.4 to 29.6) to 19.5 (range of 16.5 to 22.8) over periods of 3–15 years. Nearly all the decrease in both BMI and cardiovascular risk factors occurred in the first year. Adjusting for age, the average total cholesterol and LDL (bad) cholesterol levels in the CR group were below those seen in all but the lowest 10% of the population. The average HDL (good) cholesterol levels were in the 85th to 90th percentile range for normal middle-aged US men.

The calorie-restricted group also fared much better than the control group in terms of average blood pressure (100/60 vs. 130/80 mm Hg), fasting glucose, fasting insulin (65% reduction), body mass index (19.6 ± 1.9 vs. 25.9 ± 3.2 kg/m²), body fat percentage (8.7% ± 7% vs. 24% ± 8%), C-reactive protein, carotid IMT (40% reduction), and platelet-derived growth factor AB.^[7]

The CR group had triglyceride levels as low as the lowest 5% of Americans in their 20s. (The CR group age-range was 35-82.) Systolic and diastolic blood pressure levels in the CR group were about 100/60, a level more typical of 10-year-olds^{[citation needed]}. Fasting plasma insulin concentration was 65% lower. Fasting plasma glucose concentration was also lower.

The principal investigator in this study noted an apparent lower rate of cardiovascular aging, with arteriosclerosis progress indicators particularly slowed.

The comparison group's statistics aligned approximately with the US national average on the dimensions considered.^[8] Fasting plasma insulin levels^[9] and fasting plasma glucose levels^[10] are used as tests to predict diabetes.

The American CALERIE study began in 2007 and investigates the effects of a 25% reduction in calorie intake on healthy adults over a period of two years.The effect of CR on IGF-1 serum levels seen in rodents appears to only manifest in humans when protein intake is not much higher than the Recommended Dietary Allowance

 Improved memory

A 2009 research paper showed that a calorie restricted diet can improve memory in normal to overweight elderly. The diet also resulted in decreased insulin levels and reduced signs of inflammation.Scientists believe that memory improvement in this experiment was caused by the lower insulin levels, because high insulin levels are usually associated with lower memory and cognitive function.However, that relation seems to be age-specific since another study, when analyzing people older than 65, those who were underweight had a higher dementia risk than normal or overweight people.

Health concerns

Although studies show that calorie restriction can improve longevity and health in model organisms, and studies in humans demonstrate reduced risk factors for major diseases, the long-term effects on humans are still unknown.

Musculoskeletal losses

In addition to the benefits, short-term studies in humans report loss of muscle mass and muscle strength, and reduced bone mineral density.

Several studies revealed that dieters who restricted calories for 12 months had lower muscle mass and a reduced capacity to perform exercise compared with those who lost similar amounts of weight from exercise alon.Another study concluded that those who lost weight with the help of the CR diets are more prone to develop a loss of bone at the level of hip and spine, the area most at risk for bone fractures.Some specialists say that minor mineral losses can be prevented with supplements of vitamin D and calcium.

] Low BMI, high mortality: a non-issue?

CR diets typically lead to reduced body weight, and in some studies, low body weight has been associated with increased mortality, particularly in late middle-aged or elderly subjects. One of the more famous of such studies linked a BMI lower than 18, for women, with increased mortality from noncancer, non−cardiovascular disease causes.^[21] The authors attempted to adjust for confounding factors (cigarette smoking, failure to exclude pre-existing disease); others argued that the adjustments were inadequate.

"... epidemiologists from the ACS (American Cancer Society), American Heart Association, Harvard School of Public Health, and other organizations raised specific methodologic questions about the recent Centers for Disease Control and Prevention (CDC) study and presented analyses of other data sets. The main concern ... is that it did not adequately account for weight loss from serious illnesses such as cancer and heart disease ... [and] failed to account adequately for the effect of smoking on weight ... As a result, the Flegal study underestimated the risks from obesity and overestimated the risks of leanness."

Thinness in the elderly can be caused by conditions that themselves cause weight loss (such as cancer, chronic obstructive pulmonary disorder, or depression) or of the cachexia (wasting syndrome) and sarcopenia (loss of muscle mass, structure, and function) of aging.

In any case, epidemiological studies of body weight are not about CR as used in anti-aging studies; they are not about calorie intake to begin with, as body weight is influenced by many factors other than energy intake. Moreover, "the quality of the diets consumed by the low-BMI individuals are difficult to assess, and may lack nutrients important to longevity."^[16] Typical low-calorie diets rarely provide the high nutrient intakes that are a necessary feature of an anti-aging calorie restriction diet.

 As well, "The lower-weight individuals in the studies are not CR because their caloric intake reflects their individual ad libitum set-points, and not a reduction from that set-point."^[16]

Triggering eating disorders

Concerns are sometimes raised that CR can make people feel hungry all the time and may lead to obsessing about food, causing eating disorders.^[18] However, a controlled study of human CR found no increase in eating disorder symptoms or other harmful psychological effects, in line with extensive earlier research.^[28] In those who already suffer from a binge-eating disorder, calorie restriction can precipitate an episode of binge eating, but it does not seem to pose any such risk otherwise.

Not for the young, or those with low body fat

The effect of these diets on people who want to lose weight is controversial.^{[citation needed]} Although calorie restriction may provide quick weight loss, several studies have shown that the body adjusts to the new diet in more or less half a year.^{[citation needed]} Researchers argue that people who have little body fat should not use this method of losing weight but rather should exercise more because calorie restriction in this case can be harmful.^[18] The reason for this is that after the body's fat reserves have been burned for energy, the proteins within muscle tissue will be consumed. In severe cases where individuals do not acknowledge the dangers they are exposing themselves to, they may suffer serious loss of the muscle mass.

Especially in children, adolescents and young adults (under approximately 21), calorie restriction is not advised because this type of diet may interfere with the natural physical growth, as it has been observed in laboratory animals. In addition, mental development and physical changes to the brain take place in late adolescence and early adulthood that could be negatively affected by calorie restriction.^[30] Pregnant women are recommended not to try losing weight with this method. It has been shown that a low BMI is a risk factor in pregnancy as it may result in ovulatory dysfunction (infertility), and mothers who are underweight are more prone to preterm delivery.^[30]
Individuals trying lose weight on a CR diet of less than 1,500 calories a day need to be monitored by a specialist in order to prevent potential side effects.^[31]

[edit] Miscellaneous concerns

It has also been noted that people losing weight on such diets risk developing cold sensitivity, menstrual irregularities and even infertility and hormonal changes.^[20]
Moreover, calorie restriction has been reported in mice to hinder their ability to fight infection, and some evidence suggests that in patients with amyotrophic lateral sclerosis calorie restriction accelerates the onset of the disease.^[32]

Excessive calorie restriction may result in starvation, unless metabolism is also slowed by some means. CR should not be confused with anorexia nervosa or other eating disorders. If such a pattern is repeated for prolonged periods, the body may burn lean tissue (including but not limited to muscle and collagen) along with its remaining fat reserves.^[33] The combination of starvation and the associated lethargy and decreased physical activity can result in muscular atrophy, reducing quality of life.^[34][35]

Beyond using lean tissue as energy source, the presence of catabolic hormones, such as cortisol, and lack of anabolic ones, such as insulin, disrupts protein synthesis, amino acid uptake and weakens the immune system. Commenting on a study where CR showed generally positive effects, one researcher warned that "[i]t is possible that even moderate calorie restriction may be harmful in specific patient populations, such as lean persons who have minimal amounts of body fat."^[36]

Effects of CR on different organisms

Primates

A study on rhesus macaques, funded by the National Institute on Aging, was started in 1989 at the University of Wisconsin–Madison and is still ongoing. This study has so far shown that caloric restriction in rhesus monkeys blunts aging and significantly delays the onset of age related disorders such as cancer, diabetes, cardiovascular disease and brain atrophy. The monkeys were enrolled in the study at ages of between 7 and 14 years; at the 20 year point 80% of the calorically restricted monkeys were still alive, compared to only half of the controls.^[37] These results bore out earlier preliminary results that showed lower fasting insulin and glucose levels as well as higher insulin sensitivity and LDL profiles associated with lower risk of atherogenesis in dietary restricted animals.^[38]

The most recent study conducted by Ricki J. Colman and Richard Weindruch at the University of Wisconsin used rhesus monkeys that live an average of 27 years and a maximum of 40, found that the dieting monkeys show many beneficial signs of caloric resistance, including significantly less diabetes, cancer, and heart and brain disease. However, as some of the monkeys are expected to live another 20 years, the findings are still inconclusive.^[39]

Results to date have found a trend toward a reduced overall death rate, which has not yet reached statistical significance. An additional analysis, restricted to causes of death related to aging, did find a significant reduction in age-related deaths. However, the interpretation of this finding is uncertain, as it is hypothetically possible exclusion of deaths due to non-aging causes may somehow mask an involvement of CR in such deaths. although the sample size is too low to say for certain.^[1][2]

Researchers at New York's Mount Sinai School of Medicine reported in 2006 that compared to monkeys fed a normal diet, squirrel monkeys on a life-long calorie-restrictive diet were less likely to develop Alzheimer's-like changes in their brains.^[40] Since squirrel monkeys are relatively long-lived, definitive conclusions regarding whether or not they are aging slower are not yet available.
Moderate CR attenuates age-related sarcopenia in primates.^[41]

[edit] Rodents

Seventy years ago, McCay CM, et al., discovered that reducing the amount of calories fed to rodents nearly doubled their lifespans. The life extension was varied for each species but on average, there was a 30-40% increase in lifespan in both mice and rats.^[42] CR preserves a range of structural and functional parameters in aging rodents. For example, studies in female mice have shown that estrogen receptor-alpha declines in the aging pre-optic hypothalamus. The female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.^[43]
Studies in female mice have shown that both Supraoptic nucleus (SON) and Paraventricular nucleus (PVN) lose about one-third of IGF-1R immunoreactivity with normal aging. Old calorically restricted (CR) mice lose higher numbers of IGF-1R non-immunoreactive cells while maintaining similar counts of IGF-1R immunoreactive cells in comparison to Old-Al mice. Consequently, Old-CR mice show a higher percentage of IGF-1R immunoreactive cells reflecting increased hypothalamic sensitivity to IGF-1 in comparison to normally aging mice.^[44][45]

[edit] Yeast

Fungi model are very easy to manipulate and many crucial steps toward the understanding of aging has been done with it. Many studies were published in budding yeast and fission yeast to analyse the cellular mechanisms behind the increased longevity due to calorie restriction. First, calorie restriction is often called dietary restriction because the same effects on life span can be reached by only changing the nutrient quality without changing the amount of calories. The data from Dr Guarente, Dr Kennedy, Dr Jazwinski, Dr Kaeberlein, Dr Longo, Dr Shadel, Dr Nyström, Dr Piper and others showed that genetic manipulations in nutrient signaling pathways could mimic the effects of dietary restriction. In some case dietary restriction needs mitochondrial respiration to increase longevity (chronological aging) and in some other case not (replicative aging). Nutrient sensing in yeast controls stress defense, mitochondrial functions, Sir2 and others. These functions are all known to regulate aging. Genes involved in these mechanisms are: TOR, PKA, SCH9, MSN2/4, RIM15, SIR2,...^{[46][47][48][49][50]}

[edit] Drosophila

Research in 2003 by Mair et al. showed that calorie restriction extends the life of fruit flies of any age with instantaneous effects on death rates.^[51]

[edit] Caenorhabditis elegans

Recent work in Caenorhabditis elegans has shown that restriction of glucose metabolism extends life span by primarily increasing oxidative stress to exert an ultimately increased resistance against oxidative stress, a process called (mito)hormesis.^[52]

[edit] Mechanism of Action

Even though there has been research on CR for over 70 years the mechanism by which CR works is still not well understood.^[1] Some explanations included reduced cellular divisions, lower metabolism rates, reduced production of free radicals and hormesis.^[53]

Hormesis

Research has pointed toward hormesis as an explanation. Southam and Ehrlich (1943) reported that a bark extract that was known to inhibit fungal growth, actually stimulated growth when given at very low concentrations. They coined the term "hormesis" to describe such beneficial actions resulting from the response of an organism to a low-intensity biological stressor. The word "hormesis" is derived from the Greek word "hormaein" which means "to excite".

The (Mito)hormesis hypothesis of CR proposes that the diet imposes a low-intensity biological stress on the organism, which elicits a defense response that helps protect it against the causes of aging. In other words, CR places the organism in a defensive state so that it can survive adversity, and this results in improved health and longer life. This switch to a defensive state may be controlled by longevity genes (see below).^[54]

Mitochondrial hormesis

The mitochondrial hormesis was a purely hypothetical concept until late 2007 when work by Michael Ristow's group in a small worm named Caenorhabditis elegans suggests that restriction of glucose metabolism extends life span primarily by increasing oxidative stress to stimulate the organism into having an ultimately increased resistance to further oxidative stress.^[52] This is probably the first experimental evidence for hormesis being the reason for extended life span following CR.
Although aging can be conceptualized as the accumulation of damage, the more recent determination that free radicals participate in intracellular signaling has made the categorical equation of their effects with "damage" more problematic than was commonly appreciated in years past. It was previously proposed on a hypothetical basis that free radicals may induce an endogenous response culminating in more effective adaptations which protect against exogenous radicals (and possibly other toxic compounds).^[55] Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free radical production extends life span of a model organism and mitohormetically exerts life extending and health promoting effects. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction.^[56][57][58]

[edit] Evolution

It has been recently argued that during years of famine, it may be evolutionarily desirable for an organism to avoid reproduction and to upregulate protective and repair enzyme mechanisms to try to ensure that it is fit for reproduction in future years. This seems to be supported by recent work studying hormones.^[59] A study in male mice has found that CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis, it concluded that CR's life-extension effects might arise partly from a shift toward a gene expression profile more typical of females.^[60] Prolonged severe CR lowers total serum and free testosterone while increasing SHBG concentrations in humans, these effects are independent of adiposity.^[61]

Lowering of the concentration of insulin and substances which are related to insulin, e.g. Insulin-like growth factor 1 and Growth hormone has been shown to upregulate autophagy, the repair mechanism of the cell.^[62] A related hypothesis suggests that CR works by decreasing insulin levels and thereby upregulating autophagy,^[62][63] but CR affects many other health indicators and whether insulin is the main concern is still undecided.^[42] Calorie restriction has been shown to increase DHEA in primates, however it has not been shown to increase DHEA in post-pubescent primates.^[64][65] The extent to which these findings apply to humans is still under investigation.

] Chromatin and PHA-4

Evidence suggests that the biological effects of CR are closely related to chromatin function.^[66] A study conducted by the Salk Institute for Biological Studies and published in the journal Nature in May 2007 determined that the gene PHA-4 is responsible for the longevity behind calorie restriction in roundworms, "with similar results expected in humans".^[67]

] Free radicals and glycation

Two very prominent proposed explanations of aging which have a bearing on calorie restriction are the free radical theory and the glycation theory. With high amounts of energy available, mitochondria do not operate very efficiently and generate more superoxide. With CR, energy is conserved and there is less free radical generation. A CR organism will have less fat and require less energy to support the weight, which also means that there does not need to be as much glucose in the bloodstream.

Less blood glucose means less glycation of adjacent proteins and less fat to oxidize in the bloodstream to cause sticky blocks resulting in atherosclerosis. Type II Diabetics are people with insulin insensitivity caused by long-term exposure to high blood glucose. Obesity leads to type 2 diabetes. Type 2 diabetes and uncontrolled type 1 diabetes are much like "accelerated aging", due to the above effects. There may even be a continuum between CR and the metabolic syndrome.

Calorie Restriction with Optimal Nutrition has not been tested in comparison to Calorie Excess with Optimal Nutrition. It may be that with extra calories, nutrition must be similarly increased to ratios comparable to that of Calorie Restriction to provide similar antiaging benefits. Stated levels of calorie needs may be biased towards sedentary individuals. Calorie restriction may be no more than adapting the diet to the body's needs.

Caloric restriction mimetics

Work on the mechanisms of CR has given hope to the synthesising of future drugs to increase the human lifespan by simulating the effects of calorie restriction. However, MIT biologist Leonard Guarente cautioned that "(treatment) won't be a substitute for a healthy lifestyle. You'll still need to go to the gym".^[68] Sir2 or "silent information regulator 2" is a sirtuin, discovered in baker's yeast cells, which is hypothesized to suppress DNA instability.^[69] In mammals Sir2 is known as SIRT1. David Sinclair at Harvard Medical School, Boston is a leading proponent of the view that the gene Sir2 may underlie the effect of calorie restriction in mammals by protecting cells from dying under stress.^[70] It is suggested a low-calorie diet that requires less Nicotinamide adenine dinucleotide to metabolize may allow SIRT1 to be more active in its life-extending processes. An article in the June 2004 issue of the journal Nature showed that SIRT1 releases fat from storage cells.^[71]

[edit] Sir2/SIRT1 and resveratrol

Attempts are being made to develop CR mimetics interventions.^[72] Resveratrol has been reported to activate Sir2/SIRT1 and extend the lifespan of yeast,^[73] nematode worms, fruit flies,^[74] and mice consuming a high caloric diet.^[75] Resveratrol does not extend lifespan in normal mice.^[76]
The effect of resveratrol on lifespan in C. elegans and Drosophila was re-investigated by D. Gems and L. Partridge, they concluded previously reported lifespan increases were in fact due to natural variability in C. elegans lifespans^[77] A recent study found resveratrol extends the lifespan of a vertebrate fish by 59%.^[78] In the yeast, worm, and fly studies, resveratrol did not extend lifespan if the Sir2 gene was mutated. A 2010 study concluded that SRT1720 and resveratrol are not direct activators of SIRT1.^[79]
Matt Kaeberlein and Brian Kennedy at the University of Washington Seattle believe that Sinclair's work on resveratrol is an artifact and that the Sir2 gene has no relevance to CR, they have proposed that the caloric restriction increases lifespan by decreasing the activity of the Target of Rapamycin (TOR) kinase.^[80][81]
Gurarente has recently published that behavior associated with caloric restriction did not occur when Sirt1 knockout mice were put on a calorie restricted diet, the implication being that Sirt1 is necessary for mediating the effects of caloric restriction. However, the same paper also reported that the biochemical parameters thought to mediate the lifespan extending effects of calorie restriction (reduced insulin, igf1 and fasting glucose), were no different in normal mice and mice lacking Sirt1. Whether the lifespan-extending effect of CR was still evident in Sirt1 knockout mice was not reported in that study. According to Sinclair's data, Sirtuins (SirT1, Sir2, ...) are behind the putative effect of calorie restriction on longevity,^[82] however some research has cast doubt on this.^{[81][83][84][85]} A clinical trial of the resveratrol formulation SRT501 was suspended.^[86]

Objections

No benefit to houseflies, overfed model organisms

One set of experiments shows that CR has no benefits in the housefly.^[87] The authors hypothesize that the widely purported effects of CR may be because a diet containing more calories can increase bacterial proliferation, or that the type of high calorie diets used in past experiments have a stickiness, general composition, or texture that reduces longevity.

Another related theory says that some of the calorie-restriction effects are artifacts, because the laboratory model organisms are kept at non-physiological high calorie diets. This would mean that calorie restriction simply means mimicking a natural environment energy supply.^[88]

Physical activity testing biases

While some tests of calorie restriction have shown increased muscle tissue in the calorie-restricted test subjects, how this has occurred is unknown. Muscle tissue grows when stimulated, so it is possible that the calorie-restricted test animals exercised more than their companions on higher calories. The reasons behind this may be that animals enter a foraging state during calorie restriction. In order to control this variable, such tests would need to be monitored to make sure that levels of physical activity are equal between groups.

Insufficient calories and amino acids for exercise

Exercise has also been shown to increase health and lifespan and lower the incidence of several diseases. Calorie restriction comes into conflict with the high calorie needs of athletes, and may not provide them adequate levels of energy or sufficient amino acids for repair, although this is not a criticism of CR per se, since it is certainly possible to be an unhealthy athlete, or an athlete destined to die at a young age due to poor diet, stresses, etc. Moreover, in experiments comparing CR to exercise, CR animals live much longer than exercised animals.^[89]

Does Calorie Restriction only benefit the young?

There is some evidence to suggest that the benefit of CR in rats might only be reaped in early years. A study on rats which were gradually introduced to a CR lifestyle at 18 months showed no improvement over the average lifespan of the Ad libitum group.^[90] This view, however, is disputed by Spindler, Dhahbi, and colleagues who showed that in late adulthood, acute CR partially or completely reversed age-related alterations of liver, brain and heart proteins and that mice placed on CR at 19 months of age show increases in lifespan.^[91] The Wisconsin rhesus monkey study showed increased survival rates and decreased diseases of aging from caloric restriction even though the study started with adult monkeys.^[37]

] Midlife Onset of Calorie Restriction as a Means of Prolonging Lifespan

This is a highly controversial topic of if and how to start such in Midlife in humans. See the books by lifetime calorie restriction researcher Roy Walford which offer inconclusive but supportive evidence for this thesis.

Possible contraindications

Both animal and human research suggest BUD CR may be contraindicated for people with amyotrophic lateral sclerosis (ALS). Research on a transgenic mouse model of ALS demonstrates that CR may hasten the onset of death in ALS. Hamadeh et al. therefore concluded: "These results suggest that CR diet is not a protective strategy for patients with amyotrophic lateral sclerosis (ALS) and hence is contraindicated."^[92] Hamadeh et al. also note two human studies^[93][94] that they indicate show "low energy intake correlates with death in people with ALS." However, in the first study, Slowie, Paige, and Antel state: "The reduction in energy intake by ALS patients did not correlate with the proximity of death but rather was a consistent aspect of the illness." They go on to conclude: "We conclude that ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake."^[93]

Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits.^[95] Suggesting that a calorically dense diet may slow ALS, a ketogenic diet in the ALS mouse model has been shown to slow the progress of disease.^[96] More recently, Mattson et al. opine that the death by ALS of Roy Walford, a pioneer in CR research and its antiaging effects, may have been a result of his own practice of CR.^[97] However, as Mattson et al. acknowledge, Walford's single case is an anecdote that by itself is insufficient to establish the proposed cause-effect relation.

Negligible effect on larger organisms

Another objection to CR as an advisable lifestyle for humans is the claim that the physiological mechanisms that determine longevity are very complex, and that the effect would be small to negligible in our species.^[98]

[edit] Intermittent fasting as an alternative approach

Studies by Mark P. Mattson, Ph. D., chief of the National Institute on Aging's (NIA) Laboratory of Neurosciences, and colleagues have found that intermittent fasting and calorie restriction affect the progression of diseases similar to Huntington's disease, Parkinson's disease, and Alzheimer's disease in mice (PMID 11119686). In one study, rats and mice ate a low-calorie diet or were deprived of food for 24 hours every other day.^[99] Both methods improved glucose metabolism, increased insulin sensitivity, and increased stress resistance. Researchers have long been aware that calorie restriction extends lifespan, but this study showed that improved glucose metabolism also protects neurons in experimental models of Parkinson's and stroke.

Another NIA study found that intermittent fasting and calorie restriction delays the onset of Huntington's disease-like symptoms in mice and prolongs their lives.^[100] Huntington's disease (HD), a genetic disorder, results from neuronal degeneration in the striatum. This neurodegeneration results in difficulties with movements that include walking, speaking, eating, and swallowing. People with Huntington's also exhibit an abnormal, diabetes-like metabolism that causes them to lose weight progressively.

This NIA study compared adult HD mice who ate as much as they wanted with HD mice who were kept on an intermittent fasting diet during adulthood. HD mice possess the abnormal human gene huntingtin and exhibit clinical signs of the disease, including abnormal metabolism and neurodegeneration in the striatum. The mice on the fasting program developed clinical signs of the disease about 12 days later and lived 10 to 15% longer than the free-fed mice.

The brains of the fasting mice also showed less degeneration. Those on the fasting program also regulated their glucose levels better and did not lose weight as quickly as the other mice. Researchers found that fasting mice had higher brain-derived neurotrophic factor (BDNF) levels. BDNF protects neurons and stimulates their growth. Fasting mice also had high levels of heat-shock protein-70 (Hsp70), which increases cellular resistance to stress.

Another NIA study compared intermittent fasting with cutting calorie intake. Researchers let a control group of mice eat freely (ad libitum). Another group was fed 60% of the calories that the control group consumed. A third group was fasted for 24 hours, then permitted to free-feed. The fasting mice didn't cut total calories at the beginning and the end of the observation period, and only slightly cut calories in between. A fourth group was fed the average daily intake of the fasting mice every day. Both the fasting mice and those on a restricted diet had significantly lower blood sugar and insulin levels than the free-fed controls. Kainic acid, a toxin that damages neurons, was injected into the dorsal hippocamnavigation, search dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects. Calorie restriction without malnutrition has been shown to improve age-related health and to slow the [1]aging process in a wide range of animals and some fungi.[1]

Calorie restriction

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Caloric restriction (CR), or calorie restriction, is a
CR is one of the few dietary interventions shown to increase both median and maximum lifespan in a variety of species, among them yeast, fish, rodents and dogs. There are ongoing studies on whether CR works in nonhuman primates, on its effects on human health, and on the metabolic parameters associated with CR in other species. The results so far are positive, but the studies are not yet complete, due to the long lifespan of the species. Among the current studies, one at
Calorie restriction is a feature of several

1 Research history 2 Effects on humans 2.1 Positive effects 2.1.1 Cardiovascular risks reduced 2.1.2 Improved memory 2.2 Health concerns 2.2.1 Musculoskeletal losses 2.2.2 Low BMI, high mortality: a non-issue? 2.2.3 Triggering eating disorders 2.2.4 Not for the young, or those with low body fat 2.2.5 Miscellaneous concerns 3 Effects of CR on different organisms 3.1 Primates 3.2 Rodents 3.3 Yeast 3.4 Drosophila 3.5 Caenorhabditis elegans 4 Mechanism of Action 4.1 Hormesis 4.1.1 Mitochondrial hormesis 4.2 Evolution 4.3 Chromatin and PHA-4 4.4 Free radicals and glycation 5 Caloric restriction mimetics 5.1 Sir2/SIRT1 and resveratrol 6 Objections 6.1 No benefit to houseflies, overfed model organisms 6.2 Physical activity testing biases 6.3 Insufficient calories and amino acids for exercise 6.4 Does Calorie Restriction only benefit the young? 6.4.1 Midlife Onset of Calorie Restriction as a Means of Prolonging Lifespan 6.5 Possible contraindications 6.6 Negligible effect on larger organisms 7 Intermittent fasting as an alternative approach 8 See also 9 Notes 10 References

[ Research history

In 1934,
The findings have since been accepted and generalized to a range of other animals. Researchers are investigating the possibility of parallel physiological links in humans. In the meantime, many people have independently adopted the practice of calorie restriction in some form.

Effects on humans

 Positive effects

 Cardiovascular risks reduced

Some research has shown CR to reduce
A small study of long-term CR practitioners studied the effects of a diet with 10-25% less calorie intake than the average "Western" diet. Mean

The mean BMI in the CR group dropped from 24 (range of 19.4 to 29.6) to 19.5 (range of 16.5 to 22.8) over periods of 3–15 years. Nearly all the decrease in both BMI and cardiovascular risk factors occurred in the first year. Adjusting for age, the average total

The calorie-restricted group also fared much better than the control group in terms of average blood pressure (100/60 vs. 130/80 mm Hg), fasting glucose, fasting insulin (65% reduction), body mass index (19.6 ± 1.9 vs. 25.9 ± 3.2 kg/m²), body fat percentage (8.7% ± 7% vs. 24% ± 8%), C-reactive protein, carotid IMT (40% reduction), and platelet-derived growth factor AB.

The CR group had
The principal investigator in this study noted an apparent lower rate of cardiovascular aging, with arteriosclerosis progress indicators particularly slowed.

The comparison group's statistics aligned approximately with the US national average on the dimensions considered. Fasting plasma insulin levels and fasting plasma glucose levels are used as tests to predict

A 2009 research paper showed that a calorie restricted diet can improve memory in normal to overweight elderly. The diet also resulted in decreased

Health concerns

Although studies show that calorie restriction can improve

Musculoskeletal losses

Several studies revealed that dieters who restricted calories for 12 months had lower muscle mass and a reduced capacity to perform exercise compared with those who lost similar amounts of weight from exercise alone. Another study concluded that those who lost weight with the help of the CR diets are more prone to develop a loss of bone at the level of

[ Low BMI, high mortality: a non-issue?

CR diets typically lead to reduced body weight, and in some studies, low body weight has been associated with increased mortality, particularly in late middle-aged or elderly subjects. One of the more famous of such studies linked a BMI lower than 18, for women, with increased mortality from noncancer, non−cardiovascular disease causes. The authors attempted to adjust for confounding factors (cigarette smoking, failure to exclude pre-existing disease); others argued that the adjustments were inadequate.

"... epidemiologists from the ACS (

Thinness in the elderly can be caused by conditions that themselves cause weight loss (such as cancer, chronic obstructive pulmonary disorder, or depression) or of the
In any case, epidemiological studies of body weight are not about CR as used in anti-aging studies; they are not about calorie intake to begin with, as body weight is influenced by many factors other than energy intake. Moreover, "the quality of the diets consumed by the low-BMI individuals are difficult to assess, and may lack nutrients important to longevity." Typical low-calorie diets rarely provide the high nutrient intakes that are a necessary feature of an anti-aging calorie restriction diet As well, "The lower-weight individuals in the studies are not CR because their caloric intake reflects their individual ad libitum set-points, and not a reduction from that set-point."

Triggering eating disorders

Concerns are sometimes raised that CR can make people feel

[ Not for the young, or those with low body fat

The effect of these diets on people who want to lose weight is controversial.^[] Although calorie restriction may provide quick
Especially in
Individuals trying lose weight on a CR diet of less than 1,500 calories a day need to be monitored by a specialist in order to prevent potential side effects.

[ Miscellaneous concerns

It has also been noted that people losing weight on such diets risk developing
Moreover, calorie restriction has been reported in mice to hinder their ability to fight
Excessive calorie restriction may result in starvation, unless
Beyond using lean tissue as energy source, the presence of catabolic hormones, such as

Effects of CR on different organisms

Primates

A study on
The most recent study conducted by Ricki J. Colman and Richard Weindruch at the University of Wisconsin used rhesus monkeys that live an average of 27 years and a maximum of 40, found that the dieting monkeys show many beneficial signs of caloric resistance, including significantly less diabetes, cancer, and heart and brain disease. However, as some of the monkeys are expected to live another 20 years, the findings are still inconclusive.
Results to date have found a trend toward a reduced overall death rate, which has not yet reached statistical significance. An additional analysis, restricted to causes of death related to aging, did find a significant reduction in age-related deaths. However, the interpretation of this finding is uncertain, as it is hypothetically possible exclusion of deaths due to non-aging causes may somehow mask an involvement of CR in such deaths. although the sample size is too low to say for certain.^{[2][40]sarcopenia in primates.[41]edit][42]estrogen receptor-alpha declines in the aging pre-optic hypothalamus. The female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.[43]Supraoptic nucleus (SON) and Paraventricular nucleus (PVN) lose about one-third of IGF-1R immunoreactivity with normal aging. Old calorically restricted (CR) mice lose higher numbers of IGF-1R non-immunoreactive cells while maintaining similar counts of IGF-1R immunoreactive cells in comparison to Old-Al mice. Consequently, Old-CR mice show a higher percentage of IGF-1R immunoreactive cells reflecting increased hypothalamic sensitivity to IGF-1 in comparison to normally aging mice.[45]edit][46]}[44]
Researchers at New York's Mount Sinai School of Medicine reported in 2006 that compared to monkeys fed a normal diet, squirrel monkeys on a life-long calorie-restrictive diet were less likely to develop Alzheimer's-like changes in their brains. Since squirrel monkeys are relatively long-lived, definitive conclusions regarding whether or not they are aging slower are not yet available.
Moderate CR attenuates age-related

[ Rodents

Seventy years ago, McCay CM, et al., discovered that reducing the amount of calories fed to rodents nearly doubled their lifespans. The life extension was varied for each species but on average, there was a 30-40% increase in lifespan in both mice and rats. CR preserves a range of structural and functional parameters in aging rodents. For example, studies in female mice have shown that
Studies in female mice have shown that both

[ Yeast

Fungi model are very easy to manipulate and many crucial steps toward the understanding of aging has been done with it. Many studies were published in budding yeast and fission yeast to analyse the cellular mechanisms behind the increased longevity due to calorie restriction. First, calorie restriction is often called dietary restriction because the same effects on life span can be reached by only changing the nutrient quality without changing the amount of calories. The data from Dr Guarente, Dr Kennedy, Dr Jazwinski, Dr Kaeberlein, Dr Longo, Dr Shadel, Dr Nyström, Dr Piper and others showed that genetic manipulations in nutrient signaling pathways could mimic the effects of dietary restriction. In some case dietary restriction needs mitochondrial respiration to increase longevity (chronological aging) and in some other case not (replicative aging). Nutrient sensing in yeast controls stress defense, mitochondrial functions, Sir2 and others. These functions are all known to regulate aging. Genes involved in these mechanisms are: TOR, PKA, SCH9, MSN2/4, RIM15, SIR2,...^{[47][48][49][50]edit][51]edit]Caenorhabditis elegansoxidative stress to exert an ultimately increased resistance against oxidative stress, a process called (mito)hormesis.[52]edit][1]free radicals and hormesis.[53]edit]Hormesishormesis as an explanation. Southam and Ehrlich (1943) reported that a bark extract that was known to inhibit fungal growth, actually stimulated growth when given at very low concentrations. They coined the term "hormesis" to describe such beneficial actions resulting from the response of an organism to a low-intensity biological stressor. The word "hormesis" is derived from the Greek word "hormaein" which means "to excite". The (Mito)hormesis hypothesis of CR proposes that the diet imposes a low-intensity biological stress on the organism, which elicits a defense response that helps protect it against the causes of aging. In other words, CR places the organism in a defensive state so that it can survive adversity, and this results in improved health and longer life. This switch to a defensive state may be controlled by longevity genes (see below).[54]edit]Michael Ristow's group in a small worm named Caenorhabditis elegans suggests that restriction of glucose metabolism extends life span primarily by increasing oxidative stress to stimulate the organism into having an ultimately increased resistance to further oxidative stress. This is probably the first experimental evidence for [52]hormesis being the reason for extended life span following CR.[55]life span of a model organism and mitohormetically exerts life extending and health promoting effects. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction.[57][58]edit][59][60][61]Insulin#Physiological effects.insulin and substances which are related to insulin, e.g. Insulin-like growth factor 1 and Growth hormone has been shown to upregulate autophagy, the repair mechanism of the cell. A related hypothesis suggests that CR works by decreasing [62]insulin levels and thereby upregulating autophagy,[63][42]DHEA in primates, however it has not been shown to increase DHEA in post-pubescent primates.[65]edit]chromatin function. A study conducted by the [66]Salk Institute for Biological Studies and published in the journal in May 2007 determined that the Naturegene PHA-4 is responsible for the longevity behind calorie restriction in roundworms, "with similar results expected in humans".[67]edit]free radical theory and the glycation theory. With high amounts of energy available, mitochondria do not operate very efficiently and generate more superoxide. With CR, energy is conserved and there is less free radical generation. A CR organism will have less fat and require less energy to support the weight, which also means that there does not need to be as much glucose in the bloodstream. Less blood glucose means less glycation of adjacent proteins and less fat to oxidize in the bloodstream to cause sticky blocks resulting in atherosclerosis. Type II Diabetics are people with insulin insensitivity caused by long-term exposure to high blood glucose. Obesity leads to type 2 diabetes. Type 2 diabetes and uncontrolled type 1 diabetes are much like "accelerated aging", due to the above effects. There may even be a continuum between CR and the metabolic syndrome.edit]MIT biologist Leonard Guarente cautioned that "(treatment) won't be a substitute for a healthy lifestyle. You'll still need to go to the gym". Sir2 or "silent information regulator 2" is a [68]sirtuin, discovered in baker's yeast cells, which is hypothesized to suppress DNA instability. In mammals Sir2 is known as [69]SIRT1. David Sinclair at Harvard Medical School, Boston is a leading proponent of the view that the gene Sir2 may underlie the effect of calorie restriction in mammals by protecting cells from dying under stress. It is suggested a low-calorie diet that requires less [70]Nicotinamide adenine dinucleotide to metabolize may allow SIRT1 to be more active in its life-extending processes. An article in the June 2004 issue of the journal showed that SIRT1 releases fat from storage cells.Nature[71]edit]CR mimetics interventions. [72]Resveratrol has been reported to activate Sir2/SIRT1 and extend the lifespan of yeast, nematode worms, fruit flies, and mice consuming a high caloric diet. Resveratrol does not extend lifespan in normal mice.[73][74][75][76][77][78]SRT1720 and resveratrol are not direct activators of SIRT1.[79]Matt Kaeberlein and Brian Kennedy at the University of Washington Seattle believe that Sinclair's work on resveratrol is an artifact and that the Sir2 gene has no relevance to CR, they have proposed that the caloric restriction increases lifespan by decreasing the activity of the Target of Rapamycin (TOR) kinase.[81][82][81]}[80] The extent to which these findings apply to humans is still under investigation.[64] but CR affects many other health indicators and whether insulin is the main concern is still undecided. Calorie restriction has been shown to increase [62][56]

[ Drosophila

Research in 2003 by Mair et al. showed that calorie restriction extends the life of fruit flies of any age with instantaneous effects on death rates.

[ Caenorhabditis elegans

Recent work in has shown that restriction of glucose metabolism extends life span by primarily increasing

[ Mechanism of Action

Even though there has been research on CR for over 70 years the mechanism by which CR works is still not well understood. Some explanations included reduced cellular divisions, lower metabolism rates, reduced production of

[ Hormesis

Main article:

Research has pointed toward

[ Mitochondrial hormesis

The mitochondrial hormesis was a purely hypothetical concept until late 2007 when work by
Although aging can be conceptualized as the accumulation of damage, the more recent determination that free radicals participate in intracellular signaling has made the categorical equation of their effects with "damage" more problematic than was commonly appreciated in years past. It was previously proposed on a hypothetical basis that free radicals may induce an endogenous response culminating in more effective adaptations which protect against exogenous radicals (and possibly other toxic compounds). Recent experimental evidence strongly suggests that this is indeed the case, and that such induction of endogenous free radical production extends

[ Evolution

It has been recently argued that during years of famine, it may be evolutionarily desirable for an organism to avoid reproduction and to upregulate protective and repair enzyme mechanisms to try to ensure that it is fit for reproduction in future years. This seems to be supported by recent work studying hormones. A study in male mice has found that CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis, it concluded that CR's life-extension effects might arise partly from a shift toward a gene expression profile more typical of females. Prolonged severe CR lowers total serum and free testosterone while increasing SHBG concentrations in humans, these effects are independent of adiposity.

See also:

Lowering of the concentration of

[ Chromatin and PHA-4

Evidence suggests that the biological effects of CR are closely related to

[ Free radicals and glycation

Two very prominent proposed explanations of aging which have a bearing on calorie restriction are the
Calorie Restriction with Optimal Nutrition has not been tested in comparison to Calorie Excess with Optimal Nutrition. It may be that with extra calories, nutrition must be similarly increased to ratios comparable to that of Calorie Restriction to provide similar antiaging benefits. Stated levels of calorie needs may be biased towards sedentary individuals. Calorie restriction may be no more than adapting the diet to the body's needs.

[ Caloric restriction mimetics

Work on the mechanisms of CR has given hope to the synthesising of future drugs to increase the human lifespan by simulating the effects of calorie restriction. However,

[ Sir2/SIRT1 and resveratrol

Attempts are being made to develop
The effect of resveratrol on lifespan in C. elegans and Drosophila was re-investigated by D. Gems and L. Partridge, they concluded previously reported lifespan increases were in fact due to natural variability in C. elegans lifespans A recent study found resveratrol extends the lifespan of a vertebrate fish by 59%. In the yeast, worm, and fly studies, resveratrol did not extend lifespan if the Sir2 gene was mutated. A 2010 study concluded that

Gurarente has recently published that behavior associated with caloric restriction did not occur when Sirt1 knockout mice were put on a calorie restricted diet, the implication being that Sirt1 is necessary for mediating the effects of caloric restriction. However, the same paper also reported that the biochemical parameters thought to mediate the lifespan extending effects of calorie restriction (reduced insulin, igf1 and fasting glucose), were no different in normal mice and mice lacking Sirt1. Whether the lifespan-extending effect of CR was still evident in Sirt1 knockout mice was not reported in that study. According to Sinclair's data, Sirtuins (SirT1, Sir2, ...) are behind the putative effect of calorie restriction on longevity, however some research has cast doubt on this. A clinical trial of the resveratrol formulation SRT501 was suspended.

Objections

[ No benefit to houseflies, overfed model organisms

One set of experiments shows that CR has no benefits in the
Another related theory says that some of the calorie-restriction effects are artifacts, because the laboratory model organisms are kept at non-physiological high calorie diets. This would mean that calorie restriction simply means mimicking a natural environment energy supply.

[ Physical activity testing biases

While some tests of calorie restriction have shown increased muscle tissue in the calorie-restricted test subjects, how this has occurred is unknown.^[] Muscle tissue grows when stimulated, so it is possible that the calorie-restricted test animals exercised more than their companions on higher calories. The reasons behind this may be that animals enter a foraging state during calorie restriction. In order to control this variable, such tests would need to be monitored to make sure that levels of physical activity are equal between groups.

[ Insufficient calories and amino acids for exercise

Exercise has also been shown to increase health and lifespan and lower the incidence of several diseases. Calorie restriction comes into conflict with the high calorie needs of

[ Does Calorie Restriction only benefit the young?

There is some evidence to suggest that the benefit of CR in rats might only be reaped in early years. A study on rats which were gradually introduced to a CR lifestyle at 18 months showed no improvement over the average lifespan of the

[ Midlife Onset of Calorie Restriction as a Means of Prolonging Lifespan

This is a highly controversial topic of if and how to start such in Midlife in humans. See the books by lifetime calorie restriction researcher Roy Walford which offer inconclusive but supportive evidence for this thesis.

[ Possible contraindications

Both animal and human research suggest BUD CR may be contraindicated for people with
Previously, Pedersen and Mattson also found that in the ALS mouse model, CR "accelerates the clinical course" of the disease and had no benefits. Suggesting that a calorically dense diet may slow ALS, a

[ Negligible effect on larger organisms

Another objection to CR as an advisable lifestyle for humans is the claim that the physiological mechanisms that determine longevity are very complex, and that the effect would be small to negligible in our species.

[ Intermittent fasting as an alternative approach

Main article:

Studies by Mark P. Mattson, Ph. D., chief of the
Another NIA study found that intermittent fasting and calorie restriction delays the onset of Huntington's disease-like symptoms in mice and prolongs their lives. Huntington's disease (HD), a
This NIA study compared adult HD mice who ate as much as they wanted with HD mice who were kept on an intermittent fasting diet during adulthood. HD mice possess the abnormal human gene huntingtin and exhibit clinical signs of the disease, including abnormal metabolism and neurodegeneration in the striatum. The mice on the fasting program developed clinical signs of the disease about 12 days later and lived 10 to 15% longer than the free-fed mice. The brains of the fasting mice also showed less degeneration. Those on the fasting program also regulated their glucose levels better and did not lose weight as quickly as the other mice. Researchers found that fasting mice had higher
Another NIA study compared intermittent fasting with cutting calorie intake. Researchers let a control group of mice eat freely (ad libitum). Another group was fed 60% of the calories that the control group consumed. A third group was fasted for 24 hours, then permitted to free-feed. The fasting mice didn't cut total calories at the beginning and the end of the observation period, and only slightly cut calories in between. A fourth group was fed the average daily intake of the fasting mice every day. Both the fasting mice and those on a restricted diet had significantly lower blood sugar and insulin levels than the free-fed controls.
Another Mattson study in which overweight adult asthmatics followed alternate day calorie restriction (ADCR) for eight weeks showed marked improvement in oxidative stress, inflammation, and severity of the disease. Evidence from the medical literature suggests that ADCR in the absence of weight loss prolongs lifespan in humans.
Intermittent fasting has also been shown to increase the resistance of
pus

Another Mattson study^[101] in which overweight adult asthmatics followed alternate day calorie restriction (ADCR) for eight weeks showed marked improvement in oxidative stress, inflammation, and severity of the disease. Evidence from the medical literature suggests that ADCR in the absence of weight loss prolongs lifespan in humans.^[102]

Intermittent fasting has also been shown to increase the resistance of neurons in the brain to excitotoxic stress.^[99]