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Health Protocols

Caloric Restriction

Mechanisms of Caloric Restriction

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 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 the course of normal metabolism compromises cellular function and causes aging.59,60 The observation that CR inhibits oxidative damage to lipids, DNA, and protein supports a role of antioxidation as a CR mechanism.61-64 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.65-67 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).69 CR has reduced the activity of the inflammatory enzyme COX-2 in rats70 and humans,71 and has suppressed COX-derived free-radical production in rats.72

Autophagy is a major repair process for cellular damage,73 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 (upregulates) 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 activity,83 improve glucose tolerance,84 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 cancers,86 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, TNF-alpha, 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 CR (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 CR, 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).