Calorie restriction increases muscle mitochondrial biogenesis in healthy humans.
Calorie restriction increases muscle mitochondrial biogenesis in healthy humans.
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DOI：
10.1371/journal.pmed.0040076
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发表时间：
2007-03
期刊：
影响因子：
15.8
通讯作者：
CALERIE Pennington Team
中科院分区：
文献类型：
--
作者：
Civitarese AE;Carling S;Heilbronn LK;Hulver MH;Ukropcova B;Deutsch WA;Smith SR;Ravussin E;CALERIE Pennington Team
在不出现营养不良的情况下限制热量可以延长包括昆虫和哺乳动物在内的一系列生物体的寿命，并降低线粒体产生的自由基。然而，人们对这种适应机制知之甚少。目前的研究旨在检查肌肉线粒体生物能量学对单独热量限制或结合运动的反应，对 36 名年轻（36.8 ± 1.0 岁）超重（体重指数，27.8 ± 0.7 kg/m2）个体随机分为三组之一，进行 6 个月的干预：对照组，100% 的能量需求； CR，25%热量限制； CREX，运动热量限制 (CREX)，12.5% CR + 12.5% 能量消耗增加 (EE)。在对照组中，24 小时 EE 没有变化，但在 CR 和 CREX 中，即使在调整代谢量损失后，24 小时 EE 仍较基线显着降低（CR，-135 ± 42 kcal/d，p = 0.002 和 CREX，-117 ± 52 kcal/d，p = 0.008）。 CR 和 CREX 组的参与者编码参与线粒体功能的蛋白质的基因表达增加，例如 PPARGC1A、TFAM、eNOS、SIRT1 和 PARL（全部，p < 0.05）。与此同时，CR 组的线粒体 DNA 含量增加了 35% ± 5% (p = 0.005)，CREX 组的线粒体 DNA 含量增加了 21% ± 4% (p < 0.004)，而对照组则没有变化 (2% ± 2%)。然而，TCA（三羧酸）循环（柠檬酸合成酶）、β-氧化（β-羟酰基辅酶A脱氢酶）和电子传递链（细胞色素C氧化酶II）的关键线粒体酶的活性没有变化。 CR（-0.56 ± 0.11 任意单位，p = 0.003）和 CREX（-0.45 ± 0.12 任意单位，p = 0.011）中 DNA 损伤较基线有所减少，但对照组则没有。在人肌管的原代培养物中，一氧化氮供体（模仿 eNOS 信号传导）诱导线粒体生物发生，但未能诱导 SIRT1 蛋白表达，表明其他因素可能在 CR 期间调节 SIRT1 含量。观察到的肌肉线粒体 DNA 的增加与全身耗氧量和 DNA 损伤的减少相关，表明热量限制可以改善年轻非肥胖成年人的线粒体功能。 Anthony Civitarese 及其同事观察到，在接受热量限制的健康成年人中，肌肉中的线粒体 DNA 增加，全身耗氧量减少。 20 世纪，大多数国家的预期寿命（平均寿命）大大增加，这主要归功于卫生、营养和医疗保健的改善。进一步延长人类寿命的一种可能方法是“热量限制”。热量限制饮食提供健康生活所需的所有营养，但最大限度地减少饮食中提供的能量（热量）。这种饮食可以延长小鼠的寿命，并延缓心脏病和中风等与年龄相关的慢性疾病的发生。还有迹象表明，限制热量饮食的人可能比暴饮暴食的人寿命更长。生活在日本冲绳的人们比其他日本人摄入的能量要低，而且寿命极长。此外，热量限制饮食有益于影响衰老的多种生物标志物，包括胰岛素敏感性降低（糖尿病的先兆）。但热量限制如何延缓衰老呢？与年龄相关的身体机能衰退的一个主要因素是体内蛋白质、脂肪和DNA中“氧化损伤”的积累。当食物通过称为线粒体的细胞结构转化为能量时，就会产生氧化剂，特别是称为“自由基”的化学物质。关于热量限制如何延缓衰老的一种理论是，它通过诱导有效线粒体的形成来降低自由基的产生。尽管有迹象表明热量限制可能对人类产生与啮齿类动物相似的效果，但很少有关于优质低热量饮食对健康人的影响的良好对照研究。尚不清楚在吃相同量的食物的情况下增加体力活动所产生的能量不足是否与热量限制具有相同的效果。最后，目前还不清楚热量限制如何改变线粒体功能。减少能量摄入长期影响综合评估 (CALERIE) 组织正在研究热量限制干预措施对生理、身体成分和年龄相关疾病危险因素的影响。在这项研究中，研究人员测试了这样的假设：短期热量不足（有或没有运动）会增加人体肌肉中线粒体的效率。研究人员招募了 36 名健康超重但不肥胖的年轻人参加他们的研究。其中三分之一的人从饮食中获得了 100% 的能量需求；热量限制 (CR) 组的热量摄入量减少了 25%；热量限制加运动（CREX）组的热量摄入减少了12.5%，能量消耗增加了12.5%。研究人员发现，通过单独饮食或通过饮食加运动实现六个月25%的热量赤字，可以减少24小时全身能量消耗（即身体功能燃烧的总热量），这表明线粒体功能得到改善。他们对参与线粒体形成的基因的分析表明，CR 和 CREX 都增加了骨骼肌中线粒体的数量。这两种干预措施还减少了参与者肌肉中 DNA 损伤的数量（氧化应激的标志）。这些结果表明，短期热量赤字，无论是通过饮食还是通过饮食加运动来实现，都会像啮齿动物一样诱导人类“高效线粒体”的形成。这些有效线粒体的诱导反过来又减少了骨骼肌的氧化损伤。因此，这种对热量限制的适应性反应可能有可能像其他动物一样减缓人类的衰老并延长人类的寿命。然而，这项为期六个月的研究显然没有为此提供直接证据，并且通过与啮齿类动物的研究进行类比，延长寿命可能需要终生限制热量。这里的结果表明，即使是短期的热量限制也可以产生有益的生理变化，但在明确是否应该向健康个体推荐热量限制之前，还需要进行更多的研究。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0040076。 CALERIE（减少能量摄入的长期影响的综合评估）网站包含有关该研究以及如何参与的信息 美国老龄化研究联合会包含有关衰老的信息以及有关衰老生物学和热量限制的页面 冲绳百岁老人研究是一项针对日本冲绳长寿老人的人口研究 美国政府有关营养的信息 MedlinePlus 百科全书有关饮食和卡路里的页面 卡路里限制协会，一个提供有关寿命和卡路里限制信息的非营利组织有关卡路里限制和线粒体的维基百科页面（注：维基百科是任何人都可以编辑的在线百科全书）
Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 ± 1.0 y), overweight (body mass index, 27.8 ± 0.7 kg/m2) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, −135 ± 42 kcal/d, p = 0.002 and CREX, −117 ± 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% ± 5% in the CR group (p = 0.005) and 21% ± 4% in the CREX group (p < 0.004), with no change in the control group (2% ± 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (−0.56 ± 0.11 arbitrary units, p = 0.003) and CREX (−0.45 ± 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults. Anthony Civitarese and colleagues observed an increase in mitochondrial DNA in muscle and a decrease in whole body oxygen consumption in healthy adults who underwent caloric restriction. Life expectancy (the average life span) greatly increased during the 20th century in most countries, largely due to improved hygiene, nutrition, and health care. One possible approach to further increase human life span is “caloric restriction.” A calorie-restricted diet provides all the nutrients necessary for a healthy life but minimizes the energy (calories) supplied in the diet. This type of diet increases the life span of mice and delays the onset of age-related chronic diseases such as heart disease and stroke. There are also hints that people who eat a calorie-restricted diet might live longer than those who overeat. People living in Okinawa, Japan, have a lower energy intake than the rest of the Japanese population and an extremely long life span. In addition, calorie-restricted diets beneficially affect several biomarkers of aging, including decreased insulin sensitivity (a precursor to diabetes). But how might caloric restriction slow aging? A major factor in the age-related decline of bodily functions is the accumulation of “oxidative damage” in the body's proteins, fats, and DNA. Oxidants—in particular, chemicals called “free radicals”—are produced when food is converted to energy by cellular structures called mitochondria. One theory for how caloric restriction slows aging is that it lowers free-radical production by inducing the formation of efficient mitochondria. Despite hints that caloric restriction might have similar effects in people as in rodents, there have been few well-controlled studies on the effect of good quality calorie-reduced diets in healthy people. It is also unknown whether an energy deficit produced by increasing physical activity while eating the same amount of food has the same effects as caloric restriction. Finally, it is unclear how caloric restriction alters mitochondrial function. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) organization is investigating the effect of caloric restriction interventions on physiology, body composition, and risk factors for age-related diseases. In this study, the researchers have tested the hypothesis that short-term caloric deficit (with or without exercise) increases the efficiency of mitochondria in human muscle. The researchers enrolled 36 healthy overweight but non-obese young people into their study. One-third of them received 100% of their energy requirements in their diet; the caloric restriction (CR) group had their calorie intake reduced by 25%; and the caloric restriction plus exercise (CREX) group had their calorie intake reduced by 12.5% and their energy expenditure increased by 12.5%. The researchers found that a 25% caloric deficit for six months, achieved by diet alone or by diet plus exercise, decreased 24-hour whole body energy expenditure (i.e., overall calories burned for body function), which suggests improved mitochondrial function. Their analysis of genes involved in mitochondria formation indicated that CR and CREX both increased the number of mitochondria in skeletal muscle. Both interventions also reduced the amount of DNA damage—a marker of oxidative stress—in the participants' muscles. These results indicate that a short-term caloric deficit, whether achieved by diet or by diet plus exercise, induces the formation of “efficient mitochondria” in people just as in rodents. The induction of these efficient mitochondria in turn reduces oxidative damage in skeletal muscles. Consequently, this adaptive response to caloric restriction might have the potential to slow aging and increase longevity in humans as in other animals. However, this six-month study obviously provides no direct evidence for this, and, by analogy with studies in rodents, an increase in longevity might require lifelong caloric restriction. The results here suggest that even short-term caloric restriction can produce beneficial physiological changes, but more research is necessary before it becomes clear whether caloric restriction should be recommended to healthy individuals. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040076. The CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) Web site contains information on the study and how to participate American Federation for Aging Research includes information on aging with pages on the biology of aging and on caloric restriction The Okinawa Centenarian Study is a population-based study on long-lived elderly people in Okinawa, Japan US Government information on nutrition MedlinePlus encyclopedia pages on diet and calories The Calorie Restriction Society, a nonprofit organization that provides information on life span and caloric restriction Wikipedia pages on calorie restriction and on mitochondria (note: Wikipedia is an online encyclopedia that anyone can edit)
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DOI：
10.1016/0925-4439(95)00024-x
发表时间：
1995-05-24
影响因子：
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