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 to 40 percent 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
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
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 caloric restriction123 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 mice124 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 ,126, 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
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 SIRT1132, a central activity of CR. In vitro, fisetin, like CR, reduced mTOR signaling133, Nf-kB activation and COX-2 gene expression134, and activated antioxidative and detoxifying gene pathways (Nrf2).135 Fisetin has also been shown to increase lifespan in Saccharomyces 136 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 cells141, 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
The glucoregulatory agent metformin can produce many of the gene expression changes found in mice on long-term caloric restriction, 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 percent and their maximum life span by up to 26 percent in multiple studies (reviewed in145) 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
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 caloric restriction.35,104,166
Trans-tiliroside is an extract obtained from rose hips that has been used for nearly a century to treat a variety of conditions, including cardiovascular disease, diabetes, and inflammatory diseases.167 Trans-tiliroside’s effects appear to be due in part to its ability to activate AMPK.168 Caloric restriction and exercise are both efficient activators of AMPK, as this enzyme pathway is stimulated when energy demand exceeds supply.161,169,170
In a clinical trial, rose hip extract supplementation in 32 overweight individuals resulted in significantly less total abdominal fat, abdominal visceral fat, body weight, and body mass index by the end of the 12-week trial compared with those who received placebo.171 Numerous preclinical trials have shown that trans-tiliroside and its derivatives boost AMPK signaling.168,172,173 In a mouse study, administration of a rose hips extract significantly reduced dangerous after-meal glucose spikes and inhibited weight gain, particularly abdominal fat deposition.174
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 mice153, 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 enzyme155) 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 to 40 percent in animal models has resulted in longevity increases by 40 percent 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 to 40 percent reduction in calories, some CR health benefits in humans have been observed at less-restrictive caloric reductions (16 to 25 percent) 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, pyrroloquinoline quinone (PQQ), and branched-chain amino acids.