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Caloric Restriction

Mechanisms of CR

The mechanism(s) of CR has not been definitively determined, although theories abound. Possible mechanisms include protection from oxidative damage, increased cellular repair, reduction in the production of catabolic cytokines, such as the inflammatory molecules tumor necrosis factor (TNF) and interleukin-6 (IL-6), and increases in energy (ATP) production.58

The free-radical theory of aging proposes that cumulative oxidative damage during to the course of normal metabolism compromise cellular function and cause aging59,60 the observation that CR inhibits oxidative damage to lipids, DNA, and protein supports a role of antioxidation as a CR mechanism.61,62,63,64 Levels of endogenous antioxidants (glutathione) and antioxidant enzymes (superoxide dismutase, catalase, glutathione-S-transferase) are also protected by CR from age-related decline in animal models. 65,66,67 CR also stimulates DNA repair.68

While inflammation is a complex, well-orchestrated process that is designed to limit injury and promote repair, uncontrolled or chronic inflammation can have the opposite effect; chronic inflammation has been implicated in a range of age-related diseases. Age-related increases in the production of pro-inflammatory enzymes, cytokines, and adhesion molecules may also accelerate aging through the increase in reactive oxygen and nitrogen species (ROS and RNS) and subsequent oxidative damage. In cell culture and animal models, CR has been shown to attenuate the inflammatory response by suppressing the production of pro-inflammatory proteins (interleukins 1B, 6 and, TNF) and prostaglandins (E2, I2) (reviewed in 69). CR has reduced the activity of the inflammatory enzyme COX-2 in rats70 and humans71, and has suppressed COX-derived free-radical production in rats.72

Autophagy is a major repair process for cellular damage73, one which has been associated with positive effects on longevity.74 During autophagy, intracellular components such as damaged or unnecessary cellular machinery or aggregated proteins are engulfed by organelles called autophagosomes and degraded within lysosomes (organelles that digest cellular wastes). Autophagy also represents an important mechanism for cell survival during nutrient deprivation.75 Recent studies have revealed that age-related reductions in autophagy in rats are slowed by CR.76,77

CR has been shown to increase efficiency of the mitochondrial energy production while decreasing the generation of reactive oxygen species, the undesirable by-product of this process.78,79

At the genetic level, CR has been shown to stimulate the production of several factors that are involved in nutrient sensing and insulin signaling, notably the proteins PGC-1α and SIRT1. PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) is often described as the master regulator of mitochondrial biogenesis. Amongst its many functions, PGC-1α turns up (up-regulates) the expression of genes in the cell nucleus that encode mitochondrial enzymes.80 Additionally, PGC-1α stimulates the replication of mitochondrial DNA, a necessary step in mitochondrial biogenesis.81,82 The enzyme SIRT1, the founding member of the sirtuin gene family, has been of considerable interest in the last decade: acting as a “metabolic sensor”, SIRT1 may increase mitochondrial activity83, improve glucose tolerance84, and extend lifespan in experimental models.85 CR also reduces the production of mTOR (mammalian target of rapamycin), an enzyme that responds to levels of insulin and IGF-1, to control cell growth and division. mTOR is abnormally elevated in many cancers86, and its inhibition has been found to slow aging in yeast, nematodes, and mice.87

CR may attenuate some of the detrimental changes in gene expression that accompany the aging process. Aging in rats is accompanied by changes in expression of genes associated with increased inflammation and stress, and decreased apoptosis and DNA replication; CR reversed many of these changes.88 CR reduces the expression of nuclear factor kappa beta (NF-kB), a key mediator of inflammation. NF-kB senses cellular threats (such as free radicals or pathogens) and responds by activating other inflammatory genes. NF-kB activity is enhanced in many tissues during the aging process.89 By reducing NF-kB, CR in turn reduces the expression of other pro-inflammatory genes, including IL-1B, IL-6, TNFa, COX-2, and inducible nitric oxide synthase (iNOS).90

An attempt to resolve the seemingly disparate mechanisms of CR on life extension and health promotion has suggested a unified process, called hormesis, may also be at work.91 Hormesis is classically described as a phenomenon in which the response to a chemical or physical agent is different depending in the degree of its intensity92; for example, a cell might respond positively to caloric restriction (low intensity) but negatively to frank starvation (high intensity). In the context of aging, hormesis is characterized by the beneficial effects of cellular responses to the mild stress of caloric restriction, which stimulates maintenance and repair processes.93 In this manner, a significant, sustained reduction of calories below a certain threshold may activate several genes that sense the nutrient deprivation (such as sirtuins, PGC-1α, or mTOR), which turn off cell growth, and switch on processes that protect or repair the cell (which, in turn, may increase antioxidant capacity and attenuate inflammation).

Practicing Caloric Restriction with Optimum Nutrition (CRON)

Although CR has in the past been defined as a 30 to 40 percent reduction in calorie intake (as determined by daily energy expenditure) there is no “official” definition of caloric restriction,94 and newer investigations have revealed CR benefits can still occur at less-restrictive caloric intakes. Based on our current knowledge of CR, its definition may someday be not simply based on a restriction “value”, but rather a combination of anticipated gene expression patterns and physiological changes. As demonstrated in the examples above, CR protocols that have demonstrated significant results over a range of caloric intakes and durations, with and without the inclusion of exercise. Extremely low caloric intakes (only 550 kcal/day) have been used for very short durations (6 weeks) with dramatic results in obese individuals, insulin sensitivity increased by 35%; CRP decreased by half, and liver triglycerides decreased by 60%.95,96 However, maintenance of extreme CR for longer periods of time, for instance 45% CR for 6 months has resulted in several negative side effects including anemia, muscle wasting, neurologic deficits, edema.97 Although the comprehensive CALERIE studies were designed for CR of 16-25% and have demonstrated short-term success; when compliance is considered, the actual degree of CR in the groups may have been closer to 11.5%98

The frequency of meals is not important for CR, at least in animal models. Lifespan extensions in rodents have been observed at meal frequencies ranging from 6 times per day to 3 times per week.99,100 “Every-other-day-feeding” (EOD), which was initially thought to be distinct from CR, may actually function as a mild CR , and demonstrate a lower incidence of diabetes, lower fasting blood glucose and insulin concentrations.101 It is unclear whether meal frequency affects the benefits of CR in humans. While reduced meal frequency to 1 meal per day consuming sufficient calories to maintain body weight in healthy, normal-weight, middle-aged adults demonstrated significant increases in blood pressure and LDL-C 102, this effect was not observed in non-obese overweight individuals following an EOD approach to CR. 103

The duration of a CR plan depends on its anticipated outcomes. Although controlled longevity data is unavailable for humans, one could imagine that, based on human observational data and the wealth of animal studies, that life extension through CR requires a lifetime commitment. However, reduction in body fat mass, cardiovascular disease and diabetes risks are observable even within the abbreviated timescales of the CALERIE studies (6-12 months), as are certain markers of slowed aging, such as mitochondrial biogenesis and reduced DNA oxidative damage. Even short (21-48 day) periods of fasting or caloric/dietary restriction (such as religious fasts) can have favorable effects on blood lipids, insulin sensitivity, and biomarkers of oxidative stress.104,105 Short term CR has also been validated by gene expression data, in which alterations in the expression of age-related genes including those involved in inflammation, apoptosis, and DNA expression could be observed after only 4 weeks of CR in mice.106

While there is no defined composition of the CR diet, the potentially significant reduction in caloric intake necessitates the consumption of nutrient-dense foods, and the avoidance of “empty” calories from foods such as white flour and refined sugar. It is also imperative that the intake of essential micronutrients, such as vitamins, minerals, essential fatty acids and essential amino acids, are carefully monitored, and added back to the diet if necessary. Even a carefully chosen CR diet may not be nutritionally complete; in studies of 4 popular, published diet plans that limited calories to 1100-1700 per day including the NIH and American Heart Association-recommended “DASH diet”, all were found to be on average only 43.5% sufficient in RDIs for 27 essential micronutrients values, and deficient in 15 of them.107 While hunger cannot realistically be eliminated during a dedicated CR diet, there are dietary strategies to reduce hunger such as sufficient fiber consumption (increasing fiber intake to 35 grams/day had a significant effect on satiation and adherence to the CR protocol in the CALERIE study108) and consumption of “fast” proteins, like whey, that are rapidly absorbed and quickly signal satiety.109,110