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Caloric restriction (CR) is one of the most important strategies for improving health and increasing lifespan. Restricting calories does not only lengthen lifespan, but also healthspan (the period of healthy living before the onset of age-related diseases, such as diabetes, cardiovascular disease, and some cancers).

CR has been shown to improve heart function, reduce markers of inflammation, and reduce risk factors for cardiovascular disease and diabetes.

However, CR has been shown to increase risk of diminishing muscle strength, aerobic capacity, and bone mineral density; therefore, proper exercise in addition to a CR diet is crucial.

What are Caloric Restriction Mimetics?

Maintaining long-term CR can be very difficult and demanding. Therefore, calorie restriction mimetics (CRMs), or compounds that mimic the effects of CR, are desirable. CRMs mimic the metabolic, hormonal, or physiological effects of CR without reducing long-term food intake, while stimulating maintenance and repair processes, and producing CR-like effects on longevity and reduction of age-related disease.

Here are a few examples of these CRM's:

  • Curcumin and green tea polyphenols have both demonstrated increases in average and maximum lifespan.

  • Resveratrol has anti-inflammatory activity, as well as CR-mimicking activity, in several species

  • It has been suggested that several plant-derived polyphenols, including quercetin, exerted health benefits via CR-like modulations of stress-response pathways.

  • Hesperidin, a plant flavonoid, has demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity. Evidence suggests hesperidin may help prevent and treat several age-related chronic diseases.

  • Fish oil, while not a CRM, appeared to work synergistically with CR to reduce oxidative damage.

Caloric restriction (CR) is a general strategy for improving wellbeing and lifespan. It is more than a simple limitation of calories for maintenance of body weight; CR is the dramatic reduction of caloric intake to levels that may be significantly (up to 50% in some cases) below that for maximum growth and fertility, but nutritionally sufficient for maintaining overall health (“undernutrition without malnutrition”).

It remains one of the most researched and successful approaches to increasing lifespan in laboratory settings. Although the effects of CR on health are diverse, its mechanisms are not fully understood, and are thought to involve the activation of survival mechanisms that have been evolutionarily conserved to protect organisms from stress.

Caloric Restriction in Humans and Increased Lifespan

Assessing the effects of dietary interventions on human lifespan is a difficult endeavor; with average life expectancies of 75 and 80 years for men and women, respectively. Human aging studies must rely on surrogate measures (biomarkers) of aging. Reduced body temperature and lowered fasting insulin levels are robust markers of CR.

Dehydroepiandrosterone sulfate (DHEA-S), which declines in both rhesus monkeys and humans during normal aging, may be important in health maintenance and may serve as another potential longevity marker. DHEA-S, a product of the adrenal glands and the most abundant circulating steroid hormone, serves as the precursor to the sex steroids (androgens and estrogens). Increased DHEA-S levels in monkeys on CR are associated with survival. Similarly, data from the Baltimore Longitudinal Study of Aging (BLSA) suggest long-lived humans exhibit some of the same physiological and biochemical changes that accompany CR in animals. In the study, human survival rates were highest in those with low body temperatures, low levels of circulating insulin; and high DHEA-S levels.

One study revealed that 60 healthy seniors, receiving an average of 1,500 kcal/day for a period of three years, had significantly lowered rates of hospital admissions and a numerically lowered death rate than an equal number of control volunteers.

Caloric Restriction in Humans Mitigates Disease Risk

There is a growing body of evidence suggesting that CR may reduce disease risk factors, which may have a direct influence on healthspan (and indirectly increase lifespan). Several observational studies have tracked the effects of CR on lean, healthy individuals, and have demonstrated that moderate CR (22‒30% decreases in caloric intake from normal levels) improves heart function, reduces markers of inflammation (C-reactive protein, tumor necrosis factor [TNF]), reduces risk factors for cardiovascular disease (elevated LDL cholesterol, triglycerides, blood pressure) and reduces diabetes risk factors (fasting blood glucose and insulin levels). CR in healthy individuals has also been associated with reductions in circulating insulin-like growth factor-1 (IGF-1), and cyclooxygenase II (COX-2), all of which may be indicative of a decreased risk of certain cancers. Epidemiological data shows an association between higher plasma IGF-1 concentrations and a greater risk of breast, prostate, and colon cancers. COX-2, in addition to its role in inflammation, can promote the growth and spread of tumors.

Preliminary results from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study have been promising. The National Institute on Aging (NIA) is sponsoring a multi-site randomized human clinical study to assess the safety and efficacy of two years of CR in non-obese but overweight healthy individuals. Researchers of the Pennington CALERIE group have followed 48 overweight (average body mass index [BMI] 27.5) middle-aged (average age 37) individuals for six months adopting one of four protocols: 1) 25% caloric restriction (CR group); 2) 12.5% CR with an additional 12.5% caloric expenditure from exercise (CREX group); 3) very low calorie diet (890 kcal/day) until 15% weight reduction, followed by a diet of sufficient calories to maintain this weight (VLCD group); or 4) control.

Not surprisingly, all three intervention groups demonstrated reduced body weight, visceral (abdominal) fat, and fat cell size, as well as reduced liver fat deposits. All three intervention groups also demonstrated reductions in DNA damage. Only the CR and CREX groups, however, were able to improve two markers of longevity (reduced body temperature and reduced fasting plasma insulin), as well as reduce cardiovascular risk factors (LDL-C, triglycerides, and blood pressure).

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.

The free-radical theory of aging proposes that cumulative oxidative damage during the course of normal metabolism compromises cellular function and causes aging. The observation that CR inhibits oxidative damage to lipids, DNA, and protein supports a role of antioxidation as a CR mechanism. 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. CR also stimulates DNA repair.

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.

Autophagy is a major repair process for cellular damage, one which has been associated with positive effects on longevity. 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. 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.

Practicing Caloric Restriction with Optimum Nutrition

Although CR has in the past been defined as a 30‒40% reduction in calorie intake (as determined by daily energy expenditure) there is no “official” definition of caloric restriction, 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.

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. 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 four popular, published diet plans that limited calories to 1,100‒1,700 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.

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 study) and consumption of “fast” proteins, like whey, that are rapidly absorbed and quickly signal satiety.

What You Need to Know About Caloric Restriction

Caloric restriction (CR), a significant, sustained reduction of caloric intake from baseline levels, is the most thoroughly and successfully researched method for lifespan and healthspan extension in a broad range of animals and non-human primates.

In many cases, the reduction of caloric intake by 30‒40% in animal models resulted in longevity increases by 40% or more.

Although there is not yet direct human evidence of lifespan extension in humans from CR, results of the NIA-funded CALERIE study have shown significant reductions in risk factors for disease (cardiovascular disease, diabetes, some cancers), from moderate CR.

CR in humans reduces fasting insulin levels and lowers resting body temperature, which are two biomarkers for aging reversal. Although CR has classically been defined as a long-term 30‒40% reduction in calories, some CR health benefits in humans have been observed at less-restrictive caloric reductions (16‒25%) over short time periods (weeks to months).

CR may work by reducing oxidative damage, increasing cellular repair, lowering production of inflammatory cytokines, or by hormesis, a mild stress that may stimulate cellular protection. Several compounds may mimic the effects of CR without requiring a reduction in calories; these include resveratrol, metformin, green tea polyphenols, aspirin, PQQ, and branched-chain amino acids.


Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional.



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