healthy bowl of vegetables to maintain Caloric Restriction

Caloric Restriction

Caloric Restriction

Last Section Update: 02/2011

Contributor(s): Maureen Williams, ND; Debra Gordon, MS; Shayna Sandhaus, PhD

Table of Contents

  1. Overview
  2. Introduction
  3. Caloric Restriction in Animals and Non-human Primates
  4. Caloric Restriction in Humans and Increased Lifespan
  5. Caloric Restriction in Humans Mitigates Disease Risk
  6. Mechanisms of Caloric Restriction
  7. Practicing Caloric Restriction with Optimum Nutrition
  8. Caloric Restriction Mimetics
  9. Update History
  10. References

1 Overview

Summary and Quick Facts for Caloric Restriction

  • McCay’s work in the 1930s first demonstrated that reducing calories below the level required for maximum fertility, while avoiding malnutrition, could extend the mean and maximum lifespan of laboratory rats by 40 percent or more. In the years following that seminal work, the health and longevity effects of caloric restriction (CR) have been observed in a wide range of organisms, ranging from single-celled Saccharomyces, to primates and man.
  • 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.
  • Although controlled longevity data is unavailable for humans, one could imagine that, based on human observational data and the wealth of animal studies, life extension through CR requires a lifetime commitment. However, several compounds may mimic the effects of CR without requiring a reduction in calories; these include resveratrol, metformin, green tea polyphenols, aspirin, and pyrroloquinoline quinone (PQQ).

What are the Potential Benefits of Caloric Restriction?

Caloric restriction (CR), the significant decrease in calorie intake, is a strategy for improving health and increasing lifespan. Increased lifespan has been observed in many types of calorie-restricted animals, including rhesus monkeys. Significantly, 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).

Lifespan studies in humans are difficult; however, CR studies in humans can measure biomarkers of aging (eg, dehydroepiandrosterone sulfate [DHEA-S], the levels of which decrease with age).

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

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. Never attempt a drastic change in diet or exercise regimen without consulting a doctor.

What are Caloric Restriction Mimetics?

Maintaining a long-term CR diet 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.

  • Tetrahydrocurcumin and green tea polyphenols have both demonstrated increases in average and maximum lifespan in mice.
  • Ginkgo biloba significantly increased the lifespan of male Fischer rats.
  • Rapamycin and aspirin were both identified as having CR mimetic activity in rodents.
  • 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.
  • Nicotinamide riboside is a source of vitamin B3 and a precursor for nicotinamide adenine dinucleotide (NAD+). Nicotinamide riboside supplementation had CR-like positive effects on health in yeast and mice.
  • Metformin, generally used as a diabetes drug, extended the lifespan of mice and decreased the incidence of certain tumors. Metformin can also activate adenosine monophosphate-activated protein kinase (AMPK), an enzyme that affects glucose metabolism and fat storage.
  • Gynostemma pentaphyllum (G. pentaphyllum) can also activate AMPK. G. pentaphyllum supplementation in humans has been shown to exert effects seen in CR, such as improved glucose metabolism and reduced body weight.
  • 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.
  • Pyrroloquinoline quinone (PQQ) increased mitochondrial DNA content and stimulated oxygen respiration (both indicative of biogenesis) in mouse hepatoma cells.
  • Fish oil, while not a CRM, appeared to work synergistically with CR to reduce oxidative damage.

2 Introduction

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”).1 It remains one of the most researched and successful approaches to life extension 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.

The idea of extending healthspan (the period of healthy living before the onset of age-related disease) and lifespan by lowering food intake is not a new one. Louis Caranaro’s 16th century best-selling anti-aging book suggested that longevity would come to those who ate only enough to sustain life; Benjamin Franklin supported the concept of abstinence as a defense against disease two centuries later.2 But it was the work of McCay in the 1930’s that first demonstrated that reducing calories below the level required for maximum fertility, while avoiding malnutrition, could extend the mean and maximum lifespan of laboratory rats by 40% or more.3 In the years following that seminal work, the health and longevity effects of CR have been observed in a wide range of organisms, ranging from single-celled Saccharomyces, to primates and man.

The practical challenge of long-term or lifetime CR has recently generated interest in caloric restriction mimetics (CRMs), an alternative to CR which may provide the pro-longevity benefits without an actual reduction in caloric intake.4 CRMs are a broad class of compounds and interventions that may promote life- and health-span by a diversity of mechanisms, ranging from induction of genes that protect against stress, to antioxidation and anti-inflammation.

3 Caloric Restriction in Animals and Non-human Primates

Seventy-five years of research have determined that the longevity and health effects of CR are a broad biological phenomenon that has been observed in species from three kingdoms of life (Animalia, Fungi, and Protoctista).5 Both the mean and maximum life spans of yeast (Saccharomyces cerevisiae), rotifers, nematodes (Caenorhabditis elegans), fruit flies (Drosophila melanogaster) and medflies, spiders, fish (guppies, zebrafish), rodents (hamsters, rats, mice), and dogs have been extended significantly by decreasing normal caloric consumption by 30‒40%.6 Recently, the effects of CR on lifespan have been observed in non-human primates. The rhesus monkey (Macaca mulatta) is an excellent model for the study of human aging, exhibiting many physiological and biochemical similarities to humans.7 Unlike other animal aging models, the rhesus monkey also allows the study of brain atrophy, a characteristic of human aging that does not occur in smaller mammals.8 With an average lifespan of about 27 years in captivity,9 the rhesus also is suitable for determining the effects of CR on maximal lifespan.

Studies of the effects of CR on three separate rhesus colonies are currently underway; results from two have been published. A 20-year study conducted at the Wisconsin National Primate Research Center suggests that CR of baseline diet by 30% may slow aging in the rhesus, as gauged by two indicators of aging retardation: delays in mortality, and in the onset of age-associated diseases (particularly diabetes, cancer, cardiovascular disease, and neurological impairment; the most prevalent age-related diseases in humans).10 At study entry, the animals (46 males and 30 females) were at adult age (7‒14 years); at the time the study was published (twenty years later), nearly three times as many control monkeys had died of age-related causes than CR monkeys (37% vs. 13%). The CR monkeys appeared to be biologically younger than their normal-fed counterparts, and not surprisingly, had lower body and fat mass. Sarcopenia (age-related muscle loss) was attenuated in the CR group. CR monkeys were also free of diabetes (compared to 5/38 of control animals) or glucose intolerance (compared to 11/38 of control animals). Incidence of cardiovascular disease, all cancers, and adenocarcinoma of the GI tract (the most common cancer in rhesus monkeys)11 was reduced by half in the CR group. Calorie restriction resulted in preservation of brain volume in the caudate, putamen and insula, areas that are classically involved in regulation of motor and executive function. The effects of CR on maximum lifespan have yet to be determined for this colony, as animals in both groups are still living.

A smaller study at the University of Maryland tracked eight CR rhesus monkeys and 109 ad-libitum (free-fed) controls over a period of 25 years, and produced many of the same observations.12,13 Ad libitum fed animals died at 25 years of age compared to a median survival of 32 years in the CR group. Calorie restriction also reduced hyperinsulinemia (elevated circulating insulin) and the frequency of age-associated diseases.

Although the available data is limited, these two studies do implicate that the healthspan and lifespan benefits of CR that have been observed in rodents and lower animals may also extend to primates and possibly man.

4 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,14 any prospective study would likely necessitate several generations of researchers to carry out. Therefore, human aging studies must rely on surrogate measures (biomarkers) of aging. Reduced body temperature and lowered fasting insulin levels are robust markers of CR and slowed aging in rodents and rhesus monkeys.15

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.16 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.17 Similarly, data from the Baltimore Longitudinal Study of Aging (BLSA)18 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.19

While there is yet no direct evidence of human lifespan extension by CR, there has been limited observational and clinical data that suggests a connection. In the 1970s, the Japanese island of Okinawa was reported to contain up to 40 times as many centenarians as other Japanese communities, which was suggested to result from CR (The caloric intake of adults and children in Okinawa was 20% and 40% lower than their mainland counterparts, respectively).20 Two decades earlier, a small 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.21

5 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).22-25 CR in healthy individuals has also been associated with reductions in circulating insulin-like growth factor-1 (IGF-1), and cyclooxygenase II (COX-2),26 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,27 prostate,28 and colon cancers.29 COX-2, in addition to its role in inflammation, can promote the growth and spread of tumors.30-32

Preliminary results from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE)33 are reproducing many of the metabolic and physiologic responses to CR observed in rodents and monkeys.34 To better elucidate the effects of CR in humans, 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 size35,36 as well as reduced liver fat deposits.37 Fat loss was not significantly different between the CR and CREX groups (24% total fat, 27% visceral fat).38 All three intervention groups also demonstrated reductions in DNA damage.39 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). C-reactive protein was reduced only in the CREX group.40 Circulating thyroid hormone (T3) concentrations were lower in the CR and CREX groups.41 Under conditions of CR, reduction in circulating thyroid hormone and body temperature suggests the normal adaptation of the body to lower energy intake and expenditure; similar reductions in T3 and metabolic rate have been observed in other human and animal CR studies.42 The CR groups also exhibited increases in the amount of mitochondria (the cellular sites of energy production), and increased expression of two genes (TFAM and PGC-1α) that are indicative of mitochondrial biogenesis, the formation of new mitochondria.43 Mitochondrial loss and dysfunction may be responsible for some of the most potent effects of the aging process.44

Similar results have been observed from the CALERIE studies at Washington University on a separate group of 50‒60-year-old non-obese overweight (average BMI 27) volunteers after one year of either CR (three months of 16% CR followed by nine months of 20% CR) or exercise training of equivalent energy expenditure (ie, expending 20% of daily caloric intake).45 CR improved cardiovascular parameters (left ventricular diastolic function, diastolic and systolic blood pressure),46 lowered C-reactive protein and insulin resistance,47 and lowered circulating thyroid hormone T348 and fasting plasma insulin.49

CR in this second, older volunteer population was not without some negative consequences: Compared to the exercise-only group, CR demonstrated decreases in muscle mass, strength, and aerobic capacity.50,51 The CR group also demonstrated significantly more loss of bone mineral density (BMD) at the spine, hip, and femur (intertrochanter) than either the exercise-only or control groups, which was observable by month three of the study.52 It should be noted that in the younger CALERIE study group, there was no significant differences in BMD in any of the groups at month six.53 The potential of losses in aerobic capacity and BMD stress the importance of exercise in CR protocols.

The CALERIE group at the Jean Mayer-USDA Human Nutrition Center on Aging at Tufts University compared the effects of CR diet composition (high glycemic vs. low glycemic load) in 29 healthy overweight adults provided with 30% calorie restricted meals for six months, followed by self-monitored restriction for an additional six months. Clinical indicators (fasting serum triglycerides, cholesterol, insulin) were significantly reduced in both groups at six and 12 months, but were not different between groups.54 There was no significant difference in weight loss or energy expenditure between the high glycemic (HG; 60% of calories from carbohydrates) and low glycemic (LG; 40% of calories from carbohydrates) groups, but the LG group lost significantly more fat mass, and retained more fat-free mass.55 The LG group also demonstrated greater declines in CRP during the first six months of the CR protocol.56 While these data indicate that the overall reduction in energy intake, and not diet composition, may be a more important determinant of weight loss and its associated CR health benefits, it does suggest additional benefits of LG diets. By their very nature, LG diets can limit postprandial (“post-meal”) elevations in blood glucose; aiding in the maintenance of the target 2-hour post-meal level of <140 mg/dL, which the International Diabetes Federation suggests may lower the risk of several diseases, including cancer, cognitive impairment, cardiovascular disease, and retinopathy.57

A randomized clinical trial examined the effects of two years of calorie restriction on metabolism and oxidative stress. The 53 participants who completed the trial were healthy and either normal-weight or slightly overweight at the time of enrollment; 34 were in a calorie restriction group, given detailed instructions and support to help them achieve a 25% reduction in daily caloric intake while maintaining adequate nutritional intake; 19 were in a control group, instructed not to substantially change their diet.

At the end of two years, the calorie restriction group had achieved an average calorie reduction of 14.8% and sustained an average weight loss of 19.1 pounds, mostly due to loss of fat. In addition, a significant drop in resting energy output, particularly during sleep, was measured in tests done after one and two years of calorie restriction. While some of this reduction could be attributed to loss of metabolically active tissue due to weight loss, most of it—equivalent to 80–120 calories per day—exceeded this expected outcome. This phenomenon of decreased energy output in excess of what could be accounted for by weight loss alone has been noted in previous weight loss studies and is known as metabolic adaptation. Metabolic adaptation is thought to represent a shift toward more efficient energy use.

Importantly, measures of oxidative stress were improved in the calorie restriction group. This effect was noted after one year and was sustained at two years. The drop in oxidative stress correlated with the degree of calorie restriction and metabolic adaptation attained. It has been proposed that reduced production of harmful free radicals resulting from more efficient metabolic activity is the link between calorie restriction and extended lifespan. This theory is supported by the current findings.185

6 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).

7 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,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 (six 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 six 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 six times per day to three 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 one 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 four 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 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.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 study)108 and consumption of “fast” proteins, like whey, that are rapidly absorbed and quickly signal satiety.109,110

8 Caloric Restriction Mimetics

Maintaining a dramatically reduced caloric intake over the long-term can be very demanding. Few people are willing to reduce their caloric consumption by the 30‒40% to meet the classic CR definition,111 and even the less restrictive protocols (16‒25%) used in human interventions have not been met with full compliance.112 The search for an alternative or complement to CR has involved the identification or development of compounds that mimic some of the physiological or gene-expression changes associated with CR, without the requirement of lowered caloric intake or loss of body weight. While many compounds can be broadly interpreted as CRMs, a more focused definition of CRM would be a compound or intervention that mimics 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.113

Curcumin, Green Tea, and Ginkgo Biloba

Several compounds have been investigated as CRMs, with encouraging preliminary results in animal models. Tetrahydrocurcumin (a curcumin metabolite) and green tea polyphenols have both demonstrated increases in average and maximum lifespans in mice.114 The effects were observed when the mice received treatments by month 13 (if given later in life, the treatments had no effect on lifespan), and in the case of green tea extract, the treatment had no effect on body weight. An investigation of ginkgo biloba on cognitive behavior in male Fischer rats revealed an unexpected, statistically significant increase in average lifespan when compared to controls (26.4 vs. 31.0 months).115 The NIA Aging Intervention Testing program,116,117 a multi-center study on longevity-enhancing compounds, has already identified life-extending or CR mimetic activities in rapamycin118,119 and aspirin120 in rodents, and is currently testing other potential compounds including medium chain triglycerides, caffeic acid esters, and curcumin.121

Resveratrol and Pterostilbene

Stress-induced plant compounds can stimulate stress responses in other species, this cross-species hormesis is called xenohormesis.122 Xenohormesis may have evolved as an early warning in animals about impending changes in the environment (such as scarcities in the food supply), allowing them to adapt accordingly. The most familiar of these stress-inducing compounds is resveratrol, well-known for its presence in grape skin, but present at detectable levels in several plant species. Resveratrol simulates CR123 in the absence of actual nutrient deficiency and has been shown to increase lifespan in fungi, nematodes, flies, fish, and mice.124 Resveratrol has also shown anti-inflammatory activity in cell culture and animal models.125-127 High-dose resveratrol reduced IGF-1 levels in healthy human volunteers, a chemopreventative activity that is also associated with CR.128 Pterostilbene, a methylated analogue of resveratrol from blueberries, similarly attenuates inflammation in a CR-like manner, reducing NF-kB signaling and COX-2 activities in cell culture.129,130

Fisetin, Quercetin, and Theaflavins

Other plant-derived polyphenolic compounds (such as catechins, curcumin, or flavonoids) may also have xenohormesis activities as well; it has been suggested that the majority of health benefits from plant phytochemical consumption might not be from their antioxidant properties, but rather by a CR-like modulation of stress-response pathways.131 Fisetin, quercetin, proanthocyanidins, and theaflavins are examples of compounds that have inherent chain-breaking antioxidant chemistries, but appear to exert profound health effects unrelated to their ability to quench free radicals. Fisetin and quercetin have both been shown to stimulate SIRT1,132 a central activity of CR. In vitro, fisetin, like CR, reduced mTOR signaling,133 Nf-kB activation and COX-2 gene expression,134 and activated antioxidative and detoxifying gene pathways (Nrf2).135 Fisetin has also been shown to increase lifespan in Saccharomyces136 and Drosophila.137 Quercetin, in addition to proanthocyanidins from grape seed, have also been shown to reduce the production of inflammatory cytokines, and the expression of vascular endothelial growth factor (VEGF),138 which may prevent tumors from recruiting blood vessels. This same chemoprotective activity has been observed in rats under CR.139 Theaflavins are flavan-3-ols from black tea that are produced during the oxidation (fermentation) of tea leaves. Aside from their suppression of NF-kB and inflammatory cytokines in vitro and in mice140 and their induction of apoptosis in cancer cells,141 theaflavins also stimulate the longevity factor Forkhead box 1 (FOXO1) in invertebrate and mammalian cells.142

Nicotinamide Riboside

Nicotinamide riboside is another naturally-occurring compound that may act as a CRM. It is a source of vitamin B3 and a precursor for nicotinamide adenine dinucleotide (NAD+), a molecule involved in a wide array of biological processes. NAD+, one of the important biologically active forms of NAD, is necessary for the activation of proteins called sirtuins, including SIRT1, that regulate cellular metabolism and DNA transcription.175-177 NAD+ levels are known to decrease with age, resulting in lower sirtuin activity. This may contribute to dysfunction in cell nuclei and mitochondria, and to a range of age-related disorders.177,178 Like calorie restriction and exercise, nicotinamide riboside can increase NAD+ levels and SIRT1 activation, and may be able to prevent or reverse age-related mitochondrial and metabolic dysfunction and disease.177-180 In cultured yeast cells, nicotinamide riboside supplementation raised NAD+ levels and increased lifespan without calorie restriction.181 Even in mice on a high-fat diet, nicotinamide riboside supplementation was found to raise NAD+ levels and SIRT1 activity, and was associated with positive metabolic effects, including less weight gain, improved exercise performance, and decreased liver fat.179

Metformin and Cinnamon

The glucoregulatory agent metformin can produce many of the gene expression changes found in mice on long-term CR, in particular, it can decrease the expression of chaperones; a set of proteins which, in addition to their other functions, can reduce apoptosis (self-destruction of damaged or malignant cells) and promote tumorgenesis.143 Metformin has increased mean lifespan in the worm C elegans.144 Along with the related anti-diabetic biguanide drugs phenformin and buformin, metformin extended the mean life span of mice by up to 37.9% and their maximum life span by up to 26% in multiple studies145 while significantly decreasing the incidence and size of mammary tumors.146 These effects on spontaneous tumor incidence, however, were limited to female animals.147 Metformin’s CR-like effects are possibly due to influence on insulin or IGF-1 signaling. This mechanism may also explain the lifespan extension properties of the glucoregulatory herb Cinnamomum cassia (cinnamon bark) in the C. elegans.148

Gynostemma pentaphyllum and Hesperidin

Numerous studies have found that metformin, which can induce a calorie restriction-like state, activates a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK). This enzyme, which affects glucose metabolism and fat storage, has been called a “metabolic master switch” because it controls numerous pathways related to extracting energy from food and storing and distributing that energy throughout the body.144,157-162

Gynostemma pentaphyllum (G. pentaphyllum) is used in Asian medicine to promote longevity.163 Its longevity effects appear to be due, in part, to its ability to activate AMPK.161 Studies of G. pentaphyllum supplementation in humans demonstrate effects also found in calorie restriction, such as improved glucose metabolism, and reduced body weight, abdominal fat, and overall fat.112,162,164,165 Other studies found that G. pentaphyllum significantly improves insulin sensitivity, a mechanism also observed in studies of CR.35,104,166

Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels.167,168 Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity.169,170 Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway.171-173 Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging.169

Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury.174 Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level.182

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker high-sensitivity C-reactive protein (hs-CRP), as well as significant decreases in levels of total cholesterol, apolipoprotein B (ApoB), and markers of vascular inflammation, relative to placebo.172 In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation.183 Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism.184

Fish Oil

Fish oil, while not a CRM, appears to increase the efficacy of CR at preventing free radical damage; fish oil feeding with 40% CR in mice demonstrated synergistic reductions in thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation), and was more effective at reducing inflammatory markers (COX-2 and iNOS expression) that CR or fish oil alone.149

The branched-chain amino acids (leucine, isoleucine, and valine) exhibit several CR-like properties, particularly related to mitochondrial biogenesis. Leucine increased mitochondrial mass in cultured human myocytes (muscle cells), and activated genes associated with CR (PGC-1α and SIRT-1).150 Elevations in CR gene expression were observed in mouse cardiomyocytes using a mixture of all three BCAAs.151 The BCAAs have also extended lifespan in Saccharomyces152 as well as in mice,153 when supplied above normal dietary levels. Similarly, pyrroloquinoline quinone (PQQ), a bacterial electron carrier154 and cofactor for several bacterial enzymes (and at least one mammalian enzyme)155 increased mitochondrial DNA content and stimulated oxygen respiration (both indicative of biogenesis) in cultured mouse hepatoma cells through the activation of the CR gene PGC-1α.156

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.

2011

  • Feb: Comprehensive update & review

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. 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. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

  1. Lane M, Black A and Ingram D. Calorie restriction in nonhuman primates: implications for age-related disease risk. Journal of Anti-Aging 1998;
  2. Morley JE, Chahla E and Alkaade S. Antiaging, longevity and calorie restriction. Current Opinion in Clinical Nutrition and Metabolic Care. 2010;13(1):40-45
  3. McCay CM, Crowell MF and Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. Nutrition. 1935;10(1):63-79
  4. Lane MA, Ingram DK. and Roth, GS. 2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction. Journal of Anti-Aging Medicine, 1998;1(4):327-337
  5. Spindler SR. Caloric restriction: from soup to nuts. Ageing Res Rev. 2010;9(3):324-353
  6. Masoro EJ. Dietary restriction-induced life extension: a broadly based biological phenomenon. Biogerontology. 2006;7(3):153-155
  7. Bodkin NL, Alexander TM, Ortmeyer HK, Johnson E and Hansen BC. Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. J Gerontol A Biol Sci Med Sci. 2003;58(3):212-219
  8. Yankner BA, Lu T and Loerch P. The aging brain. Annu Rev Pathol. 2008;3(41-66
  9. Colman RJ, Anderson RM, Johnson SC, et al. Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys. Science. 2009;325(5937):201-204
  10. Colman RJ, Anderson RM, Johnson SC, et al. Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys. Science. 2009;325(5937):201-204
  11. Rodriguez NA, Garcia KD, Fortman JD, Hewett TA, Bunte RM and Bennett BT. Clinical and histopathological evaluation of 13. cases of adenocarcinoma in aged rhesus macaques (Macaca mulatta). J Med Primatol. 2002;31(2):74-83
  12.  Bodkin NL, Alexander TM, Ortmeyer HK, Johnson E and Hansen BC. Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. J Gerontol A Biol Sci Med Sci. 2003;58(3):212-219
  13. Bodkin NL, Ortmeyer HK and Hansen BC. A comment on the comment: relevance of nonhuman primate dietary restriction to aging in humans. J Gerontol A Biol Sci Med Sci. 2005;60(8):951-952
  14. Oeppen, Vaupel. Demography. Broken limits to life expectancy. Science.2002;296(5570):1029-1031
  15. Lane M, Black A and Ingram D. Calorie restriction in nonhuman primates: implications for age-related disease risk. Journal of Anti-Aging 1998;
  16. Kalimi M, Regelson W, eds. Dehydroepiandrosterone (DHEA): Biochemical, Physiological and Clinical Aspects. New York , NY : Walter de Gruyter; 1999.
  17. Lane MA, Ingram DK, Ball SS and Roth GS. Dehydroepiandrosterone sulfate: a biomarker of primate aging slowed by calorie restriction. J Clin Endocrinol Metab. 1997;82(7):2093-2096
  18. N. W. Shock et al., Eds., Normal Human Aging: The Baltimore Longitudinal Study on Aging (U.S. Government Printing Office, Washington, DC, 1984).
  19. Roth GS, Lane MA, Ingram DK, et al. Biomarkers of caloric restriction may predict longevity in humans. Science. 2002;297(5582):811
  20. Kagawa Y. Impact of Westernization on the nutrition of Japanese: changes in physique, cancer, longevity and centenarians. Prev Med. 1978;7(2):205-217
  21. Vallejo EA. Hunger diet on alternate days in the nutrition of the aged. Prensa Med Argent. 1957; 44(2):119-120
  22. Walford RL, Mock D, Verdery R and MacCallum T. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol A Biol Sci Med Sci. 2002;57(6):B211-224
  23. Fontana L, Meyer TE, Klein S and Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA. 2004;101(17):6659-6663
  24. Fontana L, Klein S, Holloszy JO and Premachandra BN. Effect of long-term calorie restriction with adequate protein and micronutrients on thyroid hormones. J Clin Endocrinol Metab. 2006;91(8):3232-3235
  25. Meyer TE, Kovács SJ, Ehsani AA, Klein S, Holloszy JO and Fontana L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol. 2006;47(2):398-402
  26. Civitarese AE, Carling S, Heilbronn LK, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007;4(3):e76
  27. Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998;351(9113):1393-1396
  28. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279(5350):563-566
  29. Kaaks R, Toniolo P, Akhmedkhanov A, et al. Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst. 2000;92(19):1592-1600
  30. Chang S-H, Liu CH, Conway R, et al. Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci USA. 2004;101(2):591-596
  31. Cianchi F, Cortesini C, Fantappiè O, et al. Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer. Clin Cancer Res. 2004;10(8):2694-2704
  32. Fosslien E. Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci. 2000;37(5):431-502
  33. About CALERIE. http://calerie.dcri.duke.edu/about/index.html
  34. Smith DL, Nagy TR and Allison DB. Calorie restriction: what recent results suggest for the future of ageing research. Eur J Clin Invest. 2010;40(5):440-450
  35. Larson-Meyer DE, Heilbronn LK, Redman LM, et al. Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care. 2006;29(6):1337-1344
  36. Redman LM, Heilbronn LK, Martin CK, et al. Effect of calorie restriction with or without exercise on body composition and fat distribution. J Clin Endocrinol Metab. 2007;92(3):865-872
  37. Larson-Meyer DE, Newcomer BR, Heilbronn LK, et al. Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function. Obesity (Silver Spring). 2008;16(6):1355-1362
  38. Redman LM, Heilbronn LK, Martin CK, et al. Effect of calorie restriction with or without exercise on body composition and fat distribution. J Clin Endocrinol Metab. 2007;92(3):865-872
  39. Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006;295(13):1539-1548
  40. Lefevre M, Redman LM, Heilbronn LK, et al. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis. 2009;203(1):206-213
  41. Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006;295(13):1539-1548
  42. DeLany JP, Hansen BC, Bodkin NL, et a. Long-term calorie restriction reduces energy expenditure in aging monkeys. J Gerontol A Biol Sci Med Sci. 1999;54(1):B5-11
  43. Civitarese AE, Carling S, Heilbronn LK, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007;4(3):e76
  44. López-Lluch G, Irusta PM, Navas P, de Cabo R. Mitochondrial biogenesis and healthy aging. Experimental Gerontology. 2008; 43(9): 813-9.
  45. Weiss EP, Racette SB, Villareal DT, et al. Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. Am J Clin Nutr. 2006;84(5):1033-1042
  46. Riordan MM, Weiss EP, Meyer TE, et al. The effects of caloric restriction- and exercise-induced weight loss on left ventricular diastolic function. Am J Physiol Heart Circ Physiol. 2008;294(3):H1174-1182
  47. Fontana L, Villareal DT, Weiss EP, et al. Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial. Am J Physiol Endocrinol Metab. 2007;293(1):E197-202
  48. Weiss EP, Villareal DT, Racette SB, et al. Caloric restriction but not exercise-induced reductions in fat mass decrease plasma triiodothyronine concentrations: a randomized controlled trial. Rejuvenation Research. 2008;11(3):605-609
  49. Weiss EP, Racette SB, Villareal DT, et al. Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. Am J Clin Nutr. 2006;84(5):1033-1042
  50. Weiss EP, Racette SB, Villareal DT, et al. Lower extremity muscle size and strength and aerobic capacity decrease with caloric restriction but not with exercise-induced weight loss. J Appl Physiol. 2007;102(2):634-640
  51. Weiss EP, Racette SB, Villareal DT, et al. Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. Am J Clin Nutr. 2006;84(5):1033-1042
  52. Villareal DT, Fontana L, Weiss EP, et al. Bone mineral density response to caloric restriction-induced weight loss or exercise-induced weight loss: a randomized controlled trial. Arch Intern Med. 2006;166(22):2502-2510
  53. Redman LM, Rood J, Anton SD, et al. Calorie restriction and bone health in young, overweight individuals. Arch Intern Med. 2008;168(17):1859-1866
  54. Das SK, Gilhooly CH, Golden JK et al. Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial. Am J Clin Nutr. 2007;85(4):1023-30
  55. Das SK, Gilhooly CH, Golden JK et al. Long Term Effects of Energy-Restricted Diets Differing in Glycemic Load on Metabolic Adaptation and Body Composition. Open Nutr J. 2007;85(4):1023-1030
  56. Pittas AG, Roberst SB, Das SK et al. et al. The effects of the dietary glycemic load on type 2 diabetes risk factors during weight loss. Obesity 2006;14(12):2200-2209
  57. International Diabetes Federation. Guideline For Management of Postmeal Glucose. 2007. Available at: http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf . Accessed Feb 15, 2011
  58. Masoro EJ. Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms. BBA - General Subjects. 2009;1790(10):1040-1048
  59. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11(3):298-300
  60. Harman D. Extending functional life span. Experimental Gerontology. 1998;33(1-2):95-112
  61. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273(5271):59-63
  62. Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006;295(13):1539-1548
  63. Yu BP. Aging and oxidative stress: modulation by dietary restriction. Free Radic Biol Med. 1996;21(5):651-668
  64. Lass A, Sohal BH, Weindruch R, Forster MJ and Sohal RS. Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free Radic Biol Med. 1998;25(9):1089-1097
  65. Armeni T, Pieri C, Marra M, Saccucci F and Principato G. Studies on the life prolonging effect of food restriction: glutathione levels and glyoxalase enzymes in rat liver. Mech Ageing Dev. 1998;101(1-2):101-110
  66. Kim JD, McCarter RJ and Yu BP. Influence of age, exercise, and dietary restriction on oxidative stress in rats. Aging (Milano). 1996;8(2):123-129
  67. Van Remmen H, Ward WF, et al. Gene expression and protein degradation. In: Masoro EJ, ed. Handbook of Physiology. Oxford , England : Oxford University Press; 1995:171-234.
  68. Heydari AR, Unnikrishnan A, Lucente LV and Richardson A. Caloric restriction and genomic stability. Nucleic Acids Res. 2007;35(22):7485-7496
  69. Chung HY, Kim HJ, Kim KW, et al. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc Res Tech. 2002;59(4):264-272
  70. Jung KJ, Lee EK, Kim JY, et al. Effect of short term calorie restriction on pro-inflammatory NF-kB and AP-1 in aged rat kidney. Inflamm. Res. 2009;58(3):143-150
  71. Civitarese AE, Carling S, Heilbronn LK, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007;4(3):e76
  72. Chung, HY, Kim HJ, Shim KH, and Kim KW. Dietary modulation of prostanoid synthesis in the aging process: role of cyclooxygenase-2. Mech Ageing Dev. 1999;111(2-3):97-106
  73. Rabinowitz JD and White E. Autophagy and metabolism. Science. 2010;330(6009):1344-1348
  74. Weber TA and Reichert AS. Impaired quality control of mitochondria: aging from a new perspective. Experimental Gerontology. 2010;45(7-8):503-511
  75. Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 2005;120(2):237-248
  76. Wohlgemuth SE, Seo AY, Marzetti E, Lees HA and Leeuwenburgh C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Experimental Gerontology. 2010;45(2):138-148
  77. Donati A, Recchia G, Cavallini G and Bergamini E. Effect of aging and anti-aging caloric restriction on the endocrine regulation of rat liver autophagy. J Gerontol A Biol Sci Med Sci. 2008;63(6):550-555
  78. López-Lluch G, Hunt N, Jones B, et al. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA. 2006;103(6):1768-1773
  79. Hagopian K, Harper M-E, Ram JJ, Humble SJ, Weindruch R and Ramsey JJ. Long-term calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria. Am J Physiol Endocrinol Metab. 2005;288(4):E674-684
  80. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008 Apr; 88(2): 611-38.
  81. Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR. Peroxisome Proliferator-activated Receptor Co-activator 1 (PGC-1 ) and Sirtuin 1 (SIRT1) Reside in Mitochondria: POSSIBLE DIRECT FUNCTION IN MITOCHONDRIAL BIOGENESIS. Journal of Biological Chemistry. 2010; 285(28): 21590-9.
  82. Ekstrand MI, Falkenberg M, Rantanen A, et al. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet. 2004 May 1; 13(9): 935-44.
  83. Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010 Sep 20; Epub ahead of print
  84. Banks AS, Kon N, Knight C, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008 Oct; 8(4): 333-41.
  85. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11; 425(6954): 191-6.
  86. Morley JE, Chahla E and Alkaade S. Antiaging, longevity and calorie restriction. Current Opinion in Clinical Nutrition and Metabolic Care. 2010;13(1):40-45
  87. Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-395
  88. Cao SX, Dhahbi JM, Mote PL and Spindler SR. Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc Natl Acad Sci USA. 2001;98(19):10630-10635
  89. Chung HY, Kim HJ, Kim KW, et al. Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc Res Tech. 2002;59(4):264-272
  90. Chung HY, Kim HJ, Kim JW, and Yu BP. The inflammation hypothesis of aging: molecular modulation by calorie restriction. Ann N Y Acad Sci. 2001;928:327-35
  91. Masoro EJ. Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms. BBA - General Subjects. 2009;1790(10):1040-1048
  92. Calabrese EJ and Baldwin LA. Hormesis as a biological hypothesis. Environ Health Perspect. 1998;106 Suppl 1(357-362
  93. Rattan SIS. Aging, anti-aging, and hormesis. Mech Ageing Dev. 2004;125(4):285-289
  94. Morley JE, Chahla E and Alkaade S. Antiaging, longevity and calorie restriction. Current Opinion in Clinical Nutrition and Metabolic Care. 2010;13(1):40-45
  95. Viljanen APM, Karmi A, Borra R, et al. Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults. Am J Cardiol. 2009;103(12):1721-1726
  96. Viljanen APM, Iozzo P, Borra R, et al. Effect of weight loss on liver free fatty acid uptake and hepatic insulin resistance. J Clin Endocrinol Metab. 2009;94(1):50-55
  97. Keys A, Brozek J, Henschels A, Mickelsen O, Taylor H. The Biology of Human Starvation. Vol 2. Minneapolis: University of Minnesota Press; 1950:1133.
  98. Racette SB, Weiss EP, Villareal DT, et al. One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue. J Gerontol A Biol Sci Med Sci. 2006;61(9):943-950
  99. Cheney KE, Liu RK, Smith GS, Meredith PJ, Mickey MR and Walford RL. The effect of dietary restriction of varying duration on survival, tumor patterns, immune function, and body temperature in B10C3F1 female mice. J Gerontol. 1983;38(4):420-430
  100. Nelson W and Halberg F. Meal-timing, circadian rhythms and life span of mice. J Nutr. 1986;116(11):2244-2253
  101. Varady KA and Hellerstein MK. Alternate-day fasting and chronic disease prevention: a review of human and animal trials. Am J Clin Nutr. 2007;86(1):7-13
  102. Stote KS, Baer DJ, Spears K, et al. A controlled trial of reduced meal frequency without caloric restriction in healthy, normal-weight, middle-aged adults. Am J Clin Nutr. 2007;85(4):981-988
  103. Heilbronn LK, Smith SR, Martin CK, Anton SD and Ravussin E. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr. 2005;81(1):69-73
  104. Bloomer RJ, Kabir MM, Canale RE, et al. Effect of a 21 day Daniel Fast on metabolic and cardiovascular disease risk factors in men and women. Lipids Health Dis. 2010;9:94
  105. Trepanowski JF and Bloomer RJ. The impact of religious fasting on human health. Nutr J. 2010;9:57
  106. Cao SX, Dhahbi JM, Mote PL and Spindler SR. Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc Natl Acad Sci USA. 2001;98(19):10630-10635
  107. Calton JB. Prevalence of micronutrient deficiency in popular diet plans. J Int Soc Sports Nutr. 2010;7:24
  108. Gilhooly CH, Das SK, Golden JK et al. Use of cereal fiber to facilitate adherence to a human caloric restriction program. Aging Clin Exp Res. 2008;20(6):513-520
  109. Veldhorst MA, Nieuwenhuizen AG, Hochstenbach-Waelen A, et al. Dose-dependent satiating effect of whey relative to casein or soy. Physiol Behav. 2009 Mar 23; 96(4-5): 675-82.
  110. Hall WL, Millward DJ, Long SJ, Morgan LM. Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr. 2003 Feb; 89(2): 239-48.
  111. Lane MA, Roth GS and Ingram DK. Caloric restriction mimetics: a novel approach for biogerontology. Methods Mol Biol. 2007;371(143-149
  112. Racette SB, Weiss EP, Villareal DT, et al. One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue. J Gerontol A Biol Sci Med Sci. 2006;61(9):943-950
  113. Ingram DK, Zhu M, Mamczarz J, et al. Calorie restriction mimetics: an emerging research field. Aging Cell. 2006;5(2):97-108
  114. Kitani K, Osawa T and Yokozawa T. The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice. Biogerontology. 2007;8(5):567-573
  115. Winter JC. The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiol Behav. 1998;63(3):425-433
  116. Nadon NL, Strong R, Miller RA, et al. Design of aging intervention studies: the NIA interventions testing program. Age (Dordr). 2008;30(4):187-199
  117. Miller RA, Harrison DE, Astle CM, et al. An Aging Interventions Testing Program: study design and interim report. Aging Cell. 2007;6(4):565-575
  118. Miller RA, Harrison DE, Astle CM, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011;66(2):191-201
  119. Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-395
  120. Strong R, Miller RA, Astle CM, et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell. 2008;7(5):641-650
  121. National Institute on Aging. Compounds in Testing. http://www.nia.nih.gov/ResearchInformation/ScientificResources/CompoundsInTesting.htm
  122. Howitz KT and Sinclair DA. Xenohormesis: sensing the chemical cues of other species. Cell. 2008;133(3):387-391
  123. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191-196
  124. Westphal CH, Dipp MA and Guarente L. A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci. 2007;32(12):555-560
  125. Lee JH, Song MY, Song, EK et al. Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes 2009;58(2):344-351
  126. Kubota S, Kurihara T, Mochimaru H et al. Prevention of ocular inflammation in endotoxin-induced uveitis with resveratrol by inhibiting oxidative damage and nuclear factor-kappaB activation. Invest Ophthalmol Vis Sci 2009;50(7): 3512-3519
  127. Hofseth LJ, Singh UP, Singh NP, Nagarkatti M, Nagarkatti PS. Taming the beast within: resveratrol suppresses colitis and prevents colon cancer. Aging 2010;2(4):183-184
  128. Brown VA, Patel KR, Viskaduraki M, et al. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 2010;70(22):9003-11
  129. Pan MH, Chiou YS, Chen WJ, Wang JM, Badmaev V, Ho CT. Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Carcinogenesis 2009;30(7):1234-1242
  130. Hougee S, Faber J, Sanders A et al. Selective COX-2 Inhibition by a Pterocarpus marsupiumExtract Characterized by Pterostilbene, and its Activity in Healthy Human Volunteers. Planta Med 2005;71(5):387-392
  131. Howitz KT and Sinclair DA. Xenohormesis: sensing the chemical cues of other species. Cell. 2008;133(3):387-391
  132. Howitz KT, Bitterman,KJ, Cohen HY et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425(6954):191-196
  133. Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 2010;31(8): 1424-1433
  134. Sung B, Pandey MK, Aggarwal BB. Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol 2007;71(6):1703-1714
  135. Hanneken A, Lin FF, Johnson J, Maher P. Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci 2006;47(7):3164-77
  136. Howitz KT, Bitterman,KJ, Cohen HY et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425(6954):191-196
  137. Wood JG, Rogina B, Lavu S et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004;430(7000):686-689
  138. Wen W, Lu J, Zhang K, Chen S. Grape seed extract inhibits angiogenesis via suppression of the vascular endothelial growth factor receptor signaling pathway. Cancer Prev Res. 2008;1(7):554-61.
  139. Powolny AA, Wang S, Carlton PS, Hoot DR, Clinton SK. Interrelationships between dietary restriction, the IGF-I axis, and expression of vascular endothelial growth factor by prostate adenocarcinoma in rats. Mol Carcinog 2008;47(6):458-65
  140. Gosslau A, En Jao D, Huang M et al. Effects of the black tea polyphenol theaflavin-2 on apoptotic and inflammatory pathways in vitro and in vivo. Mol. Nutr. Food Res. 2011;55:198-208
  141. Lu, J., Ho, C., Ghai, G., Chen, K., Differential effects of theaflavin monogallates on cell growth, apoptosis, and Cox-2 gene expression in cancerous versus normal cells. Cancer Res. 2000;60:6465–6471.
  142. Cameron AR, Anton S, Melville L et al. Black tea polyphenols mimic insulin/insulin-like growth factor-1 signalling to the longevity factor FOXO1a. Aging Cell 2008;7(1):69-77
  143. Dhahbi JM, Mote PL, Fahy GM and Spindler SR. Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics. 2005;23(3):343-350
  144. Onken B and Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS ONE. 2010;5(1):e8758
  145. Anisimov VN. Metformin for aging and cancer prevention. Aging. 2010;2(11):760-774
  146. Anisimov VN, Berstein LM, Egormin PA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Experimental Gerontology. 2005;40(8-9):685-693
  147. Anisimov VN, Piskunova TS, Popovich IG, et al. Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice. Aging (Albany NY). 2010 Dec;2(12):945-58.
  148. Yu Y-B, Dosanjh L, Lao L, Tan M, Shim BS and Luo Y. Cinnamomum cassia Bark in Two Herbal Formulas Increases Life Span in Caenorhabditis elegans via Insulin Signaling and Stress Response Pathways. PLoS ONE. 2010;5(2):e9339
  149. Kim YJ, Kim H, No JK, Chung H, Fernandes G. Anti-inflammatory action of dietary fish oil and calorie restriction. Life Sci 2006:78(21):2523-32
  150. Sun X, Zemel MB. Leucine modulation of mitochondrial mass and oxygen consumption in skeletal muscle cells and adipocytes. Nutr Metab (Lond). 2009; 6: 26.
  151. D'Antona G, Ragni M, Cardile A, et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. 2010 Oct 6; 12(4): 362-72.
  152. D'Antona G, Ragni M, Cardile A, et al. Branched-Chain Amino Acid Supplementation Promotes Survival and Supports Cardiac and Skeletal Muscle Mitochondrial Biogenesis in Middle-Aged Mice. Cell Metabolism. 2010; 12(4): 362-72.
  153. Alvers AL, Fishwick LK, Wood MS, et al. Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell. 2009 Aug; 8(4): 353-69.
  154. Hauge J. Glucose dehydrogenase of Bacterium anitratum: an enzyme with a novel prosthetic group. J Biol Chem. 1964;239:3630-3639
  155. Kasahara T and Kato T. Nutritional biochemistry: A new redox-cofactor vitamin for mammals. Nature 2003;422(6934):832
  156. Chowanadisai W, Bauerly KA, Tchaparian E et al. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1αlpha expression. J Biol Chem. 2010;285(1):142-152.
  157. McCarty MF. AMPK activation--protean potential for boosting healthspan. Age (Dordrecht, Netherlands). Apr 2014;36(2):641-663.
  158. Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. The Biochemical journal. Nov 1 2015;471(3):307-322.
  159. Chung MM, Chen YL, Pei D, Cheng YC, Sun B, Nicol CJ, . . . Chiang MC. The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent. Biochimica et biophysica acta. May 2015;1852(5):720-731.
  160. Grahame Hardie D. AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J Intern Med. Dec 2014;276(6):543-559.
  161. Winder WW, Ukropcova B, Deutsch WA, et al. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol. 1999 Jul;277(1 Pt 1):E1-10.
  162. Park SH, Huh TL, Kim SY, Oh MR, Tirupathi Pichiah PB, Chae SW, Cha YS. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): A randomized, double-blind, placebo-controlled trial. Obesity. 2014;22(1):63-71.
  163. Li XL, Wang ZH, Zhao YX, Luo SJ, Zhang DW, Xiao SX, et al. Isolation and antitumor activities of acidic polysaccharide from Gynostemma pentaphyllum Makino. Carbohydr Polym. 2012 Jul 1;89(3):942-7.
  164. Huyen VT, Phan DV, Thang P, Hoa NK, Ostenson CG. Antidiabetic effect of Gynostemma pentaphyllum tea in randomly assigned type 2 diabetic patients. Horm Metab Res. 2010 May;42(5):353-7.
  165. Ravussin E, Redman LM, Rochon J, et al. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci. 2015;70(9):1097-104. 
  166. Huyen VT, Phan DV, Thang P, Hoa NK, Ostenson CG. Gynostemma pentaphyllum tea improves insulin sensitivity in type 2 diabetic patients. J Nutr Metab. 2013;2013:765383.
  167. Umeno A, Horie M, Murotomi K, Nakajima Y, Yoshida Y. Antioxidative and Antidiabetic Effects of Natural Polyphenols and Isoflavones. Molecules. May 30 2016;21(6).
  168. Devi KP, Rajavel T, Nabavi SF, Setzer WN, Ahmadi A, Mansouri K, Nabavi SM. Hesperidin: A promising anticancer agent from nature. Industrial Crops and Products. 2015;76:582-589.
  169. Li C, Schluesener H. Health-promoting effects of the citrus flavanone hesperidin. Critical reviews in food science and nutrition. Feb 11 2017;57(3):613-631.
  170. Roohbakhsh A, Parhiz H, Soltani F, Rezaee R, Iranshahi M. Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin--a mini-review. Life sciences. Sep 15 2014;113(1-2):1-6.
  171. Jia S, Hu Y, Zhang W, Zhao X, Chen Y, Sun C, . . . Chen K. Hypoglycemic and hypolipidemic effects of neohesperidin derived from Citrus aurantium L. in diabetic KK-A(y) mice. Food Funct. Mar 2015;6(3):878-886.
  172. Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, . . . Quon MJ. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. The Journal of clinical endocrinology and metabolism. May 2011;96(5):E782-792.
  173. Zhang J, Sun C, Yan Y, Chen Q, Luo F, Zhu X, . . . Chen K. Purification of naringin and neohesperidin from Huyou (Citrus changshanensis) fruit and their effects on glucose consumption in human HepG2 cells. Food chemistry. Dec 01 2012;135(3):1471-1478.
  174. Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Hesperidin Supplementation Alleviates Oxidative DNA Damage and Lipid Peroxidation in Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Clinical Trial. Phytotherapy research : PTR. Aug 14 2017.
  175. Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev.Apr 2010;31(2):194-223.
  176. Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection. Current opinion in clinical nutrition and metabolic care.Nov 2013;16(6):657-661.
  177. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol.Aug 2014;24(8):464-471.
  178. Srivastava S. Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders. Clinical and translational medicine.Dec 2016;5(1):25.
  179. Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab.Jun 6 2012;15(6):838-847.
  180. Handschin C. Caloric restriction and exercise "mimetics'': Ready for prime time? Pharmacological research: the official journal of the Italian Pharmacological Society.Jan 2016;103:158-166.
  181. Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell.May 4 2007;129(3):473-484.
  182. Sun Q, Wedick NM, Tworoger SS, Pan A, Townsend MK, Cassidy A, . . . van Dam RM. Urinary Excretion of Select Dietary Polyphenol Metabolites Is Associated with a Lower Risk of Type 2 Diabetes in Proximate but Not Remote Follow-Up in a Prospective Investigation in 2 Cohorts of US Women. The Journal of nutrition. Jun 2015;145(6):1280-1288.
  183. Salden BN, Troost FJ, de Groot E, Stevens YR, Garces-Rimon M, Possemiers S, . . . Masclee AA. Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals. The American journal of clinical nutrition. Dec 2016;104(6):1523-1533.
  184. Haidari F, Heybar H, Jalali MT, Ahmadi Engali K, Helli B, Shirbeigi E. Hesperidin supplementation modulates inflammatory responses following myocardial infarction. Journal of the American College of Nutrition. 2015;34(3):205-211.
  185. Redman LM, Smith SR, Burton JH, et al. Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging. Cell Metab. 2018;27(4):805-815.

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