卡路里限制Calories Restrictions 与长寿

2009-06-20 10:10阅读：

http://blog.sina.cn/dpool/blog/u/1396292720

引文：本篇是我的一位中科院营养学博士朋友的研究心得，文章罗列了一些实验数据和结果，英文部分是参考文献资料。文章里面的名词和研究数据大家可能会看得不太明白，但他这里清晰地表达了一个观点：某种营养素（蛋白，脂肪，维生素，矿物质等）过多会导致营养不良，摄入热量相当的情况下限制蛋白的饮食有延长寿命的作用。劝谕那些认为蛋白质就是营养价值高，长期高蛋白饮食的朋友们，要建立平衡饮食观，不要迷信这种饮食能身体健康、延年益寿，单一营养素过剩一样能导致营养不良。

卡路里限制（Calories Restrictions）指的是一种饮食方式，现在认为这种方式通过限制饮食能量摄入，达到有益健康延缓衰老的效果。卡路里限制是迄今为止唯一一种被报道的可以在包括啮齿类动物，鱼类，狗，酵母的多种生物中同时延长平均寿命和最长寿命。寿命延长的程度不同，老鼠和线虫可以延长30-40% (Mattson 2005)。
卡路里限制能否延长人的寿命，现在还不确定。在已有的调查中发现，卡路里限制可以减轻超重者的体重，并且降低他们的胆固醇，饥饿时的血糖和血压。2009年的一篇报道指出卡路里限制可以改善老年人的记忆 (Witte, Fobker et al. 2009)。但是也有实验表明长期卡路里限制会导致体重过轻营养不良等多种副作用(http://www.netwellness.org/question.cfm/37350.htm) 。因此人们想寻求一种两全其美的饮食方式，既可以达到延缓衰老的目的又能使身体保持良好的状态。
很多研究者在控制摄入能量的前提下，通过改变饮食结构来寻找一种健康合理的饮食。值得一提的是这种饮食被称为饮食限制，而非卡路里限制。尽管近70年的研究表明，饮食限制导致长寿的主要原因就是由控制饮食而引起的卡路里摄入减少 (Masoro 1

990)。但是有越来越多的实验表明，至少在线虫和老鼠中，限制某种营养成分的摄入已足以延长寿命 (Mair, Piper et al. 2005; Miller, Buehner et al. 2005)。例如在线虫中，降低酵母（酵母是线虫的食物，一般认为酵母主要为线虫提供蛋白质）和糖类摄入量，尽管总的能量摄入没有改变，线虫寿命已可以有效延长 (Mair, Piper et al. 2005)。这些发现似乎为人们带来一些希望，既不需要饿肚子，又可以达到营养均衡健康长寿的目的。
所谓营养均衡是指摄入的营养与身体所需保持一致。营养不良是指两者之间没有到达平衡。一般我们都认为低蛋白质摄入饮食可以导致营养不良，现在发达国家中的调查显示某种营养素（蛋白，脂肪，维生素，矿物质等）过多都会导致营养不良。就如人们平常所说的过犹不及。营养不良包括营养不足和营养过剩，在外形上可能成瘦或者胖两种截然不同的形式。无论胖瘦，营养不良都可以引起肌肉减少，脏器偏小（例如肾脏中肾小球数目减少，胰岛中β细胞数目减少），免疫力低下。营养过剩导致的营养不良还可能形成肥胖病，高血压和某些癌症。有研究发现，在保证营养足够的条件下，卡路里和蛋白限制的饮食可以提高人的对于乙肝病毒和疟疾的抵抗能力，并且延迟或者阻止癌症或者癌细胞转移和许多与年龄相关的疾病，例如心血管疾病，糖尿病并同时延长寿命(Yu, Masoro et al. 1985; Holliday 1989; Weindruch 1996)。研究者发现低蛋白饮食（1.5%酪素）与高蛋白饮食（20%酪素）老鼠相比，不仅体重增长明显较少，脾脏和肝脏也较轻。需要提出的是，实验中高蛋白饮食和低蛋白饮食的能量是一样的。为什么蛋白含量改变会引起这么明显的变化，人们还不清楚。因为饮食中还有很多功能不详的或者未知的营养素，他们的作用也不清楚。但是这一研究起码提示，蛋白质，并非人们认为的那样，越多越好。
特别是现在人们出于爱美或者其他因素热衷于控制能量摄入，很多人为了所谓的营养，就提高饮食中蛋白的含量，降低其他营养成分摄入。这种做法显然不可取。

Holliday, R. (1989). 'Food, reproduction and longevity: is the extended lifespan of calorie-restricted animals an evolutionary adaptation?' Bioessays 10(4): 125-7.
Calorie restriction results in an increased lifespan and reduced fecundity of rodents. In a natural environment the availability of food will vary greatly. It is suggested that Darwinian fitness will be increased if animals cease breeding during periods of food deprivation and invest saved resources in maintenance of the adult body, or soma. This would increase the probability of producing viable offspring during an extended lifespan. The diversion of limited energy resources from breeding to maintenance of the soma is seen as an evolutionary adaptation, fully compatible with the 'disposable soma' theory of the evolution of ageing.

http://www.netwellness.org/question.cfm/37350.htm.

Mair, W., M. D. Piper, et al. (2005). 'Calories do not explain extension of life span by dietary restriction in Drosophila.' PLoS Biol 3(7): e223.
Dietary restriction (DR) extends life span in diverse organisms, including mammals, and common mechanisms may be at work. DR is often known as calorie restriction, because it has been suggested that reduction of calories, rather than of particular nutrients in the diet, mediates extension of life span in rodents. We here demonstrate that extension of life span by DR in Drosophila is not attributable to the reduction in calorie intake. Reduction of either dietary yeast or sugar can reduce mortality and extend life span, but by an amount that is unrelated to the calorie content of the food, and with yeast having a much greater effect per calorie than does sugar. Calorie intake is therefore not the key factor in the reduction of mortality rate by DR in this species.

Masoro, E. J. (1990). 'Assessment of nutritional components in prolongation of life and health by diet.' Proc Soc Exp Biol Med 193(1): 31-4.
Restricting the food intake of rodents extends the median length of life and the maximum life-span. It also retards most age-associated physiologic change and age-associated diseases. Our research indicates that the ability to retard disease processes is not the major reason for the extension of life-span or for the retardation of age change in most physiologic systems. Rather, it appears that most of the actions of food restriction are due to its ability to slow the primary aging processes. We found this action to relate to the restriction of calories rather than specific nutrients (e.g., protein or fat or minerals). Our findings point to the reduction in caloric intake per rat rather than per gram lean body mass as the basis of the retardation of aging processes by food restriction. The challenge is to learn how caloric intake per rat is coupled to the aging processes. We are currently focusing on the possibility that neural and endocrine mechanisms are involved. Our preliminary findings point to the likelihood of an involvement of the insulin-glucose system.

Mattson, M. P. (2005). 'Energy intake, meal frequency, and health: a neurobiological perspective.' Annu Rev Nutr 25: 237-60.
The size and frequency of meals are fundamental aspects of nutrition that can have profound effects on the health and longevity of laboratory animals. In humans, excessive energy intake is associated with increased incidence of cardiovascular disease, diabetes, and certain cancers and is a major cause of disability and death in industrialized countries. On the other hand, the influence of meal frequency on human health and longevity is unclear. Both caloric (energy) restriction (CR) and reduced meal frequency/intermittent fasting can suppress the development of various diseases and can increase life span in rodents by mechanisms involving reduced oxidative damage and increased stress resistance. Many of the beneficial effects of CR and fasting appear to be mediated by the nervous system. For example, intermittent fasting results in increased production of brain-derived neurotrophic factor (BDNF), which increases the resistance of neurons in the brain to dysfunction and degeneration in animal models of neurodegenerative disorders; BDNF signaling may also mediate beneficial effects of intermittent fasting on glucose regulation and cardiovascular function. A better understanding of the neurobiological mechanisms by which meal size and frequency affect human health may lead to novel approaches for disease prevention and treatment.

Miller, R. A., G. Buehner, et al. (2005). 'Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance.' Aging Cell 4(3): 119-25.
A diet deficient in the amino acid methionine has previously been shown to extend lifespan in several stocks of inbred rats. We report here that a methionine-deficient (Meth-R) diet also increases maximal lifespan in (BALB/cJ x C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have significantly lower levels of serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have higher levels of liver mRNA for MIF (macrophage migration inhibition factor), known to be higher in several other mouse models of extended longevity. Meth-R mice are significantly slower to develop lens turbidity and to show age-related changes in T-cell subsets. They are also dramatically more resistant to oxidative liver cell injury induced by injection of toxic doses of acetaminophen. The spectrum of terminal illnesses in the Meth-R group is similar to that seen in control mice. Studies of the cellular and molecular biology of methionine-deprived mice may, in parallel to studies of calorie-restricted mice, provide insights into the way in which nutritional factors modulate longevity and late-life illnesses.

Weindruch, R. (1996). 'The retardation of aging by caloric restriction: studies in rodents and primates.' Toxicol Pathol 24(6): 742-5.
Caloric restriction (CR), which has been investigated by gerontologists for more than 60 yr, provides the only intervention tested to date in mammals (typically mice and rats) that repeatedly and strongly increases maximum life span while retarding the appearance of age-associated pathologic and biologic changes. Although the large majority of rodent studies have initiated CR early in life (1-3 mo of age), CR started in midadulthood (at 12 mo) also extends maximum life span in mice. Two main questions now face gerontologists investigating CR. By what mechanisms does CR retard aging and disease processes in rodents? There is evidence to suggest that age-associated increases in oxidative damage may represent a primary aging process that is attenuated by CR. Will CR exert similar actions in primates? Studies in rhesus monkeys subjected to CR and limited human epidemiological data support the notion of human translatability. However, no matter what the answers are to these questions, the prolongation of the health span and life span of rodents by CR has major implications for many disciplines, including toxicologic pathology, and raises important questions about the desirability of ad libitum feeding.

Witte, A. V., M. Fobker, et al. (2009). 'Caloric restriction improves memory in elderly humans.' Proc Natl Acad Sci U S A 106(4): 1255-60.
Animal studies suggest that diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age. Here, we tested in a prospective interventional design whether the same effects can be induced in humans. Fifty healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m(2)) were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed under standardized conditions. We found a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet (all r values < -0.8; all P values <0.05). Levels of brain-derived neurotrophic factor remained unchanged. No significant memory changes were observed in the other 2 groups. This interventional trial demonstrates beneficial effects of caloric restriction on memory performance in healthy elderly subjects. Mechanisms underlying this improvement might include higher synaptic plasticity and stimulation of neurofacilitatory pathways in the brain because of improved insulin sensitivity and reduced inflammatory activity. Our study may help to generate novel prevention strategies to maintain cognitive functions into old age.

Yu, B. P., E. J. Masoro, et al. (1985). 'Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics.' J Gerontol 40(6): 657-70.
The aims of this research were (a) to compare food restriction initiated in adult life of male Fischer 344 rats with that limited to early life or involving most of the life span on physical, metabolic, and longevity characteristics and (b) to study a similar level of protein restriction without caloric restriction on these characteristics. Food restriction (60% of the ad libitum intake) initiated at 6 months of age markedly increased life span as did a similar restriction started at 6 weeks of age, but food restriction limited to early life (6 weeks to 6 months of age) and protein restriction caused only a small increase in longevity. Food restriction does not act by reducing the intake of calories or other nutrient per gram of body mass, a finding not in accord with classic views. A progressive decrease in spontaneous locomotive activity with age occurred in ad libitum fed but not restricted rats.

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