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Life Extension Magazine February 2010

Calorie Restriction

Dietary strategies for improving post-prandial glucose, lipids, inflammation, and cardiovascular health.

The highly processed, calorie-dense, nutrient-depleted diet favored in the current American culture frequently leads to exaggerated supraphysiological post-prandial spikes in blood glucose and lipids. This state, called post-prandial dysmetabolism, induces immediate oxidant stress, which increases in direct proportion to the increases in glucose and triglycerides after a meal. The transient increase in free radicals acutely triggers atherogenic changes including inflammation, endothelial dysfunction, hypercoagulability, and sympathetic hyperactivity. Post-prandial dysmetabolism is an independent predictor of future cardiovascular events even in nondiabetic individuals. Improvements in diet exert profound and immediate favorable changes in the post-prandial dysmetabolism. Specifically, a diet high in minimally processed, high-fiber, plant-based foods such as vegetables and fruits, whole grains, legumes, and nuts will markedly blunt the post-meal increase in glucose, triglycerides, and inflammation. Additionally, lean protein, vinegar, fish oil, tea, cinnamon, calorie restriction, weight loss, exercise, and low-dose to moderate-dose alcohol each positively impact post-prandial dysmetabolism. Experimental and epidemiological studies indicate that eating patterns, such as the traditional Mediterranean or Okinawan diets, that incorporate these types of foods and beverages reduce inflammation and cardiovascular risk. This anti-inflammatory diet should be considered for the primary and secondary prevention of coronary artery disease and diabetes.

J Am Coll Cardiol. 2008 Jan 22;51(3):249-55

Resveratrol: biologic and therapeutic implications.

Resveratrol (3,4’,5 trihydroxystilbene), a naturally-occurring molecule known as a phytoalexin, is synthesized by plants in response to attacks by fungi, bacteria, or other injurious substances; it is also known to possess an array of cardioprotective effects. Recently, studies have shown resveratrol to protect against the metabolic changes associated with hypercaloric diets in mice with induced insulin resistance, hyperglycemia, and dyslipidemia. Despite impressive gains in diagnosis and treatment, cardiovascular disease (CVD) remains a serious clinical problem and threat to public health. The metabolic syndrome, which identifies persons at higher risk for diabetes mellitus and CVD, is approaching a prevalence of nearly 25% of the western world. If the metabolic syndrome can be considered a polar opposite to caloric restriction, then agents that mimic caloric restriction may offer a new therapeutic approach to preventing CVD. The authors discuss the cardioprotective effects of resveratrol and highlight its role in glucose homeostasis and lipid metabolism in mice. Armed with the ability to prevent the deleterious effects of excess caloric intake and prevent detrimental cardiovascular events, resveratrol merits proper clinical investigations for its efficacy in treating metabolic diseases and CVD.

J Cardiometab Syndr. 2009 Spring;4(2):102-6

Life extension by calorie restriction in humans.

Long-term reduction in energy intake in the diet (calorie restriction [CR]) extends the life of the laboratory rat by about 25%. However, in humans there are no life-long studies of CR, but only short-term trials which indicate that 20% CR acting over periods of 2-6 years is associated with reduced body weight, blood pressure, blood cholesterol, and blood glucose--risk factors for the major killer diseases of cardiovascular disease and diabetes. In addition, recent research has shown that CR for 6 months is able to improve biomarkers for longevity (deep body temperature and plasma insulin) and thus should increase life expectancy. The magnitude of the life-extension effect of CR in humans can only be estimated. The Okinawans, the longest-lived people on earth, consume 40% fewer calories than the Americans and live only 4 years longer. Similarly, women in United States consume 25% fewer calories than men and live 5 years longer. From the survival studies of overweight and obese people, it is estimated that long-term CR to prevent excessive weight gain could add only 3-13 years to life expectancy. Thus the effects of CR on human life extension are probably much smaller than those achieved by medical and public health interventions, which have extended life by about 30 years in developed countries in the 20th century, by greatly reducing deaths from infections, accidents, and cardiovascular disease.

Ann N Y Acad Sci. 2007 Oct;1114:428-33

Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial.

CONTEXT: Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans. OBJECTIVE: To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La. INTERVENTION: Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). MAIN OUTCOME MEASURES: Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature. RESULTS: Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/d]), calorie restriction with exercise (-117 kcal/d [52 kcal/d]), and very low-calorie diet (-125 kcal/d [35 kcal/d]) groups (all P<.008). These “metabolic adaptations” (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005). CONCLUSIONS: Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans. TRIAL REGISTRATION: Identifier: NCT00099151.

JAMA. 2006 Apr 5;295(13):1539-48

Caloric restriction in humans.

Studies on mice and rats have demonstrated that calorie restriction (CR) slows primary aging, has a protective effect against secondary aging, and markedly decreases the incidence of malignancies. However, the only way to determine whether CR “works” in humans is to conduct studies on people. Such studies are difficult to perform in free-living people. While research on CR in humans is still at an early stage, a modest amount of information has accumulated. Because it is not feasible to conduct studies of the effects of CR on longevity in humans, surrogate measures have to be used. Preliminary information obtained using this approach provides evidence that CR provides a powerful protective effect against secondary aging in humans. This evidence consists of the finding that risk factors for atherosclerosis and diabetes are markedly reduced in humans on CR. Humans on CR also show some of the same adaptations that are thought to be involved in slowing primary aging in rats and mice. These include a very low level of inflammation as evidenced by low circulating levels of C-reactive protein and TNFalpha, serum triiodothyronine levels at the low end of the normal range, and a more elastic “younger” left ventricle (LV), as evaluated by echo-doppler measures of LV stiffness.

Exp Gerontol. 2007 Aug;42(8):709-12

Calorie restriction increases muscle mitochondrial biogenesis in healthy humans.

BACKGROUND: 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. METHODS AND FINDINGS: 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/m(2)) 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. CONCLUSIONS: 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.

PLoS Med. 2007 Mar;4(3):e76

Caloric restriction in primates.

Caloric restriction (CR) remains the only nongenetic intervention that reproducibly extends mean and maximal life span in short-lived mammalian species. This nutritional intervention also delays the onset, or slows the progression, of many age-related disease processes. The diverse effects of CR have been demonstrated many hundreds of times in laboratory rodents and other short-lived species, such as rotifers, water fleas, fish, spiders, and hamsters. Until recently, the effects of CR in longer-lived species, more closely related to humans, remained unknown. Long-term studies of aging in nonhuman primates undergoing CR have been underway at the National Institute on Aging (NIA) and the University of Wisconsin-Madison (UW) for over a decade. A number of reports from the NIA and UW colonies have shown that monkeys on CR exhibit nearly identical physiological responses as reported in laboratory rodents. Studies of various markers related to age-related diseases suggest that CR will prevent or delay the onset of cardiovascular disease, diabetes, and perhaps cancer, and preliminary data indicate that mortality due to these and other age-associated diseases may also be reduced in monkeys on CR, compared to controls. Conclusive evidence showing that CR extends life span in primates is not presently available; however, the emerging data from the ongoing primate studies strengthens the possibility that the diverse beneficial effects of CR on aging in rodents will also apply to nonhuman primates and perhaps ultimately to humans.

Ann N Y Acad Sci. 2001 Apr;928:287-95

Caloric restriction in primates and relevance to humans.

Dietary caloric restriction (CR) is the only intervention conclusively and reproducibly shown to slow aging and maintain health and vitality in mammals. Although this paradigm has been known for over 60 years, its precise biological mechanisms and applicability to humans remain unknown. We began addressing the latter question in 1987 with the first controlled study of CR in primates (rhesus and squirrel monkeys, which are evolutionarily much closer to humans than the rodents most frequently employed in CR studies). To date, our results strongly suggest that the same beneficial “antiaging” and/or “antidisease” effects observed in CR rodents also occur in primates. These include lower plasma insulin levels and greater sensitivity; lower body temperatures; reduced cholesterol, triglycerides, blood pressure, and arterial stiffness; elevated HDL; and slower age-related decline in circulating levels of DHEAS. Collectively, these biomarkers suggest that CR primates will be less likely to incur diabetes, cardiovascular problems, and other age-related diseases and may in fact be aging more slowly than fully fed counterparts. Despite these very encouraging results, it is unlikely that most humans would be willing to maintain a 30% reduced diet for the bulk of their adult life span, even if it meant more healthy years. For this reason, we have begun to explore CR mimetics, agents that might elicit the same beneficial effects as CR, without the necessity of dieting. Our initial studies have focused on 2-deoxyglucose (2DG), a sugar analogue with a limited metabolism that actually reduces glucose/energy flux without decreasing food intake in rats. In a six-month pilot study, 2DG lowered plasma insulin and body temperature in a manner analagous to that of CR. Thus, metabolic effects that mediate the CR mechanism can be attained pharmacologically. Doses were titrated to eliminate toxicity; a long-term longevity study is now under way. In addition, data from other laboratories suggest that at least some of the same physiological/metabolic end points that are associated with the beneficial effects of underfeeding may be obtained from other potential CR mimetic agents, some naturally occurring in food products. Much work remains to be done, but taken together, our successful results with CR in primates and 2DG administration to rats suggest that it may indeed be possible to obtain the health- and longevity-promoting effects of the former intervention without actually decreasing food intake.

Ann N Y Acad Sci. 2001 Apr;928:305-15

Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury.

The life-prolonging effects of calorie restriction (CR) may be due to reduced damage from cumulative oxidative stress. Our goal was to determine the long-term effects of moderate dietary CR on the myocardial response to reperfusion after a single episode of sublethal ischemia. Male Fisher 344 rats were fed either an ad libitum (AL) or CR (40% less calories) diet. At age 12 mo the animals were anaesthetized and subjected to thoracotomy and a 15-min left-anterior descending coronary artery occlusion. The hearts were reperfused for various periods. GSH and GSSG levels, nuclear factor-kappaB (NF-kappaB) DNA binding activity, cytokine, and antioxidant enzyme expression were assessed in the ischemic zones. Sham-operated animals served as controls. Compared with the AL diet, chronic CR limited oxidative stress as seen by rapid recovery in GSH levels in previously ischemic myocardium. CR reduced DNA binding activity of NF-kappaB. The kappaB-responsive cytokines interleukin-1beta and tumor necrosis factor-alpha were transiently expressed in the CR group but persisted longer in the AL group. Furthermore, expression of manganese superoxide dismutase, a key antioxidant enzyme, was significantly delayed in the AL group. Collectively these data indicate that CR significantly attenuates myocardial oxidative stress and the postischemic inflammatory response.

Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2094-102

Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction.

Accumulating evidence strongly suggests that oxidative stress underlies aging processes. Research provides consistent evidence that calorie restriction (CR) reduces age-related oxidative stress and has anti-inflammatory properties. However, information is lacking on the molecular mechanism that would better define the interrelation of reactive oxygen species and nitrogen species and the pro-inflammatory states of the aging process. In this review, the biochemical and molecular bases of the inflammatory process in the aging process are analyzed to delineate the molecular inflammation hypothesis of aging. The key players involved in the proposed hypothesis are the age-related upregulation of NF-kappa B, IL-1 beta, IL-6, TNFalpha, cyclooxygenase-2, and inducible NO synthase, all of which are attenuated by CR. Furthermore, age-related NF kappa B activation is associated with phosphorylation by I kappa B kinase/NIK and MAPKs, while CR blocked these activation processes. The modulation of these factors provides molecular insights of the anti-inflammatory action of CR in relation to the aging process. Based on available finding and our recent supporting evidence, we prefer to use “molecular inflammation” to emphasize the importance of the molecular reaction mechanisms and their aberrance, predisposing to fully expressed chronic inflammatory phenomena. It was further proposed that CR’s major force of the regulation of redox-sensitive inflammation may well be its life-prolonging action.

Microsc Res Tech. 2002 Nov 15;59(4):264-72

The inflammation hypothesis of aging: molecular modulation by calorie restriction.

Current evidence strongly indicates that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are widely implicated in the inflammatory process. However, mechanistic information is not readily available on the extent to which ROS/RNS contributes to the proinflammatory states of the aging process. The involvement of the underlying inflammation during the aging process and the molecular delineation of anti-inflammatory action of calorie restriction (CR) is described. Age-related upregulations of NF-kappaB, IL-beta, IL-6, TNFalpha, cyclooxygenase-2, and inducible NO synthase are all attenuated by CR. The suppression of the NF-kappaB activation was accomplished by blocking the dissociation of inhibitory IkappaBalpha and IkappaBbeta by CR. These findings provide underlying molecular insights into the anti-inflammatory action of CR in relation to the aging process. Based on these and other available data, it is suggested that the “Inflammation Hypothesis of Aging” supports the molecular basis of the inflammatory process as a plausible cause of the aging process.

Ann N Y Acad Sci. 2001 Apr;928:327-35

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