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 by activating sirtuins (SIRT1 is the human homolog), and has been shown to increase lifespan in fungi, nematodes, flies, fish, and mice.124 SIRT1 also suppresses NF-kB (and the inflammatory cytokines and enzymes NF-kB activates), lending resveratrol 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 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, 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.
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 treatments 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.
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