Caloric Restriction Mimetics Research Articles

Calorie Restriction Mimetics: Examples and Mode of Action

The search for Calorie Restriction Mimetics (CRM) - compounds that mimic the genetic, biochemical and physical actions of calorie restriction - is not a search for a 'lazy dieters pill'. It is a quest aiming to clarify the basic mechanisms of calorie restriction and develop strategies in order to prevent, treat or alleviate age-related conditions. The development of CRM will add new and important assets in our armamentarium of anti-ageing therapies, with the ultimate result of increasing healthy human lifespan. This Special Supplement on CRM is an attempt to discuss some agents which may be used instead of calorie restriction itself. Agents such as resveratrol, metformin, carnosine and Rimonabant are mainstream oral therapies already used by millions of people for other clinical indications. New CRM such as NADH, gugulipids and certain drugs that interfere with glucose metabolism can be also used as oral therapy. Less easily available CRM such as oxaloacetic acid, naloxone, leptin, adiponectin, rapamycin and sirtuins are further examples of promising agents. In order for the therapy to be effective, a combination of these must be used. This paper summarises the actions of calorie restriction and then suggests several examples of possible CRM. Some of these examples can be used in everyday clinical setting.

The Benefits of Calorie Restriction and Calorie Restriction Mimetics as Related to the Eye

The Benefits of Calorie Restriction and Calorie Restriction Mimetics as Related to the Eye

SIRT1 and caloric restriction: an insight into possible trade-offs between robustness and frailty

This review aims to summarize the importance of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 as a critical mediator that coordinates metabolic responses to caloric restriction and the recent progress in the development of SIRT1-targeted caloric restriction mimetics. It also discusses possible trade-offs between robustness and frailty in caloric restriction and the applicability of caloric restriction or SIRT1-targeted caloric restriction mimetics to humans. Loss-of-function and gain-of-function mouse studies have provided genetic evidence that SIRT1 is a key mediator that orchestrates the physiological response to caloric restriction. SIRT1-activating compounds function as potential caloric restriction mimetics, at least in part, through the activation of SIRT1 in vivo. Increasing SIRT1 dosage/activity is effective to provide significant protection from high-fat diet-induced metabolic complications, suggesting that SIRT1 activation likely promotes robustness in the regulation of metabolism. However, caloric restriction itself and caloric restriction mimicry through systemic SIRT1 activation might also generate frailty in response to unexpected environmental stimuli, such as bacterial and viral infections. It will be of great importance to understand the principles of systemic robustness and its spatial and temporal dynamics for the regulation of aging and longevity in mammals in order to achieve an optimal balance between robustness and frailty in our complex physiological system.

Benefits of Caloric Restriction on Brain Aging and Related Pathological States: Understanding Mechanisms to Devise Novel Therapies

Long term caloric restriction is known to counteract aging and extend lifespan in several organisms from yeasts to mammals. Recent research has provided solid ground to the concept that limiting calorie intake slows down brain aging and protects from age-related neurodegenerative diseases. The present review summarizes the most relevant among these data and highlights some genetic and molecular mechanisms responsible for caloric restriction-related neuroprotection. To understand these mechanisms is important because this information makes them potential targets for therapeutic intervention aimed at reproducing the metabolic, genetic and molecular features responsible for the beneficial effect of caloric restriction. Most promising among these targets are neurotrophins, such as BDNF, transcription factors, such as FoxO and PPAR, anti-aging proteins, such as sirtuins, and caloric restriction mimetics acting on oxidative stress and energy metabolism. Notwithstanding the complexity of any therapeutic strategy aimed at reproducing the beneficial effects of caloric restriction, due to multiplicity of the cellular pathways involved in the responses, a great expansion of medicinal chemistry research in this field is expected in the next future.

Trans-Resveratrol: A Magical Elixir of Eternal Youth?

Trans-resveratrol or (E)-resveratrol [3,4',5 trihydroxy-trans-stilbene, t-RESV or (E)-RESV] is a natural component of Vitis vinifera L. (Vitaceae), abundant in the skin of grapes (but not in the flesh) and in the leaf epidermis and present in wines (especially red wines). In in vitro, ex vivo and in vivo experiments, t-RESV exhibits a number of biological activities, including anti inflammatory, antioxidant, platelet antiaggregatory and anticarcinogenic properties, and modulation of lipoprotein metabolism. Some of these activities have been implicated in the cardiovascular protective effects attributed to t-RESV and to red wine. Prior to 2002 there had been no previous studies describing the potential effects of t-RESV on the lifespan extension. However, in the last 5 years, several researchers have reported that t-RESV is a potent activator of sirtuin enzymatic activity, mimics the beneficial effects of caloric restriction (CR), retards the aging process and increases longevity in a number of organisms from different phyla such as yeasts, worms, flies and short-lived fish. In addition, t-RESV seems to be effective in delaying the onset of a variety of age-related diseases in mammals (e.g.: rodents). Therefore, this review will basically focus on the possible role of t-RESV to extend life duration and on some of the mechanisms by which t-RESV may act as an anti-aging agent.

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Caloric restriction is the most effective non-genetic intervention to enhance lifespan known to date. A major research interest has been the development of therapeutic strategies capable of promoting the beneficial results of this dietary regimen. In this sense, we propose that compounds that decrease the efficiency of energy conversion, such as mitochondrial uncouplers, can be caloric restriction mimetics. Treatment of mice with low doses of the protonophore 2,4-dinitrophenol promotes enhanced tissue respiratory rates, improved serological glucose, triglyceride and insulin levels, decrease of reactive oxygen species levels and tissue DNA and protein oxidation, as well as reduced body weight. Importantly, 2,4-dinitrophenol-treated animals also presented enhanced longevity. Our results demonstrate that mild mitochondrial uncoupling is a highly effective in vivo antioxidant strategy, and describe the first therapeutic intervention capable of effectively reproducing the physiological, metabolic and lifespan effects of caloric restriction in healthy mammals.

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Tissue-specific regulation of SIRT1 by calorie restriction

Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this study, we challenge the paradigm that CR induces SIRT1 activity in all tissues by showing that activity of this sirtuin in the liver is, in fact, reduced by CR and activated by a high-caloric diet. We demonstrate this change both by assaying levels of SIRT1 and its small molecule regulators, NAD and NADH, as well as assessing phenotypes of a liver-specific SIRT1 knockout mouse on various diets. Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined.

Calorie restriction and susceptibility to intact pathogens

Long-term calorie restriction (CR) causes numerous physiological changes that ultimately increase mean and maximum lifespan of most species examined to date. One physiological change that occurs with CR is enhanced immune function, as tested using antigens and mitogens to stimulate an immune response. Fewer studies have used intact pathogen exposure to test whether the enhanced capacity of the immune response during CR actually decreases susceptibility of hosts to their pathogens. So far, studies using intact bacteria, virus, and helminth worm exposure indicate that, despite similar or enhanced immune system function, CR hosts are more susceptible to infection by intact pathogens than their fully fed counterparts. Long-term CR studies that examine susceptibility to a variety of parasite taxa will help determine if direct CR or CR mimetics will be beneficial to people living in pathogen-rich environments.

Xenohormesis: Sensing the Chemical Cues of Other Species

Many plant molecules interact with and modulate key regulators of mammalian physiology in ways that are beneficial to health, but why? We propose that heterotrophs (animals and fungi) are able to sense chemical cues synthesized by plants and other autotrophs in response to stress. These cues provide advance warning about deteriorating environmental conditions, allowing the heterotrophs to prepare for adversity while conditions are still favorable.

Understanding Pathways of Calorie Restriction: A Way To Prevent Cancer?

F or decades, researchers have been intrigued by calorie restriction, a tried and true way of extending lifespans in creatures ranging from yeast and roundworms to flies and mice. Aside from increasing the lifespan of organisms up to 80% in some studies, calorie restriction (with proper nutrition) also leads to lower insulin, glucose, and blood pressure levels, as well as increased white blood cell count. Particularly enticing is the possibility for caloric restriction to prevent, delay, and shrink a variety of tumors, a fi nding that seems to complement those of recent studies linking obesity and cancer. In animal studies, researchers reduce food intake by 10% – 60%, but because such extreme dieting would be unrealistic in humans, many researchers are now examining the biological pathways affected by caloric restriction with the aim of developing preventive agents for cancer as well as other diseases associated with aging. Together with the growing fi eld of calorie restriction mimetics — fi nding natural or synthetic compounds that mimic the effects of caloric restriction — they are fi nding these pathways to be numerous and complex. “The fi eld of [caloric restriction] seems to grow every day with new discoveries of genes, pathways, and proteins that are affected in different ways,” Julie Mattison, Ph.D., a caloric restriction researcher at the National Institute on Aging (NIA), wrote in an e-mail. In gaining information about the systems changed by caloric restriction, she said, researchers can identify targets for mimetics.

Enhancing Longevity: Novel Caloric Restriction Mimetics

Rejuvenation ResearchVol. 11, No. 2 Nutrient SensingEnhancing Longevity: Novel Caloric Restriction MimeticsAlexander E. MichalowAlexander E. MichalowSearch for more papers by this authorPublished Online:28 Apr 2008https://doi.org/10.1089/rej.2008.0685AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited ByThe Einsteinian Imperative30 December 2009 | Rejuvenation Research, Vol. 12, No. 6Commentary on Some Recent Theses Relevant to Combating Aging: June 200913 July 2009 | Rejuvenation Research, Vol. 12, No. 3Anticipating the anti‐ageing pill16 January 2009 | EMBO reports, Vol. 10, No. 2 Volume 11Issue 2Apr 2008 Information© 2008 Mary Ann Liebert, Inc.To cite this article:Alexander E. Michalow.Enhancing Longevity: Novel Caloric Restriction Mimetics.Rejuvenation Research.Apr 2008.473-477.http://doi.org/10.1089/rej.2008.0685Published in Volume: 11 Issue 2: April 28, 2008Online Ahead of Print:March 8, 2008PDF download

Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction

Caloric restriction (CR) is the most potent intervention known to both protect against carcinogenesis and extend lifespan in laboratory animals. A variety of anticarcinogens and CR mimetics induce and activate the NF-E2-related factor 2 (Nrf2) pathway. Nrf2, in turn, induces a number of antioxidative and carcinogen-detoxifying enzymes. Thus, Nrf2 offers a promising target for anticarcinogenesis and antiaging interventions. We used Nrf2-disrupted (KO) mice to examine its role on the biological effects of CR. Here, we show that Nrf2 is responsible for most of the anticarcinogenic effects of CR, but is dispensable for increased insulin sensitivity and lifespan extension. Nrf2-deficient mice developed tumors more readily in response to carcinogen exposure than did WT mice, and CR was ineffective in suppressing tumors in the KO mice. However, CR extended lifespan and increased insulin sensitivity similarly in KO and WT mice. These findings identify a molecular pathway that dissociates the prolongevity and anticarcinogenic effects of CR.

Introduction to clinical research sessions

The two clinical research sessions considered the status of previous trials, as examined in the Oxford Overview (Professsor Ingle) [1], as a background for the discussion of the current generation of clinical trials employing endocrine therapy and other targeted therapies (Professor Hudis) [2]. Clinical outcomes were considered within the context of the spectrum of clinical trials (Professor Cameron) [3], and the concluding presentation addressed a novel paradigm for future research (Professor Howell) [4]. Professor James Ingle [1] addressed the findings of the most recent main meeting of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) from September 2006. Updated information from this Oxford Overview addresses the value of systemic therapy (tamoxifen, ovarian oblation/suppression, polychemotherapy, anthracyclines, aromatase inhibitors, taxanes and high-dose chemotherapy) and local therapy (postmastectomy radiation therapy). All of these analyses will be the subject of reports in the near future from the EBCTCG. The Oxford Overview process was initiated in the era of relatively small and underpowered clinical trials, and the resulting meta-analyses revealed robust information that would otherwise not have been available. The meeting attendees addressed the question of the relevance of the Oxford Overview process in the era of very large clinical trials as are being conducted today. The conclusion was that the Oxford Overview remains highly relevant and is a mechanism to gain knowledge relating to end-points, such as survival and adverse events, which cannot readily be obtained from individual trials despite their large size. Professor Cliff Hudis [2] addressed the very important area of combined endocrine therapy and other targeted therapies. The primary goal of this research is to address endocrine therapy resistance in the cancer cell. The crosstalk between the oestrogen receptor pathway and growth factor pathways, such as the HER pathways, is a prime example of ongoing research. Numerous potential targets exist, including downstream signalling mediators, angiogenesis and cyclo-oxygenase-2. Of great importance and opportunity in targeted therapy research is the availability of the specific targets for interrogation in clinical trials. The acquisition of biological information in clinical research is an important goal of current and future research. Professor David Cameron [3] addressed the important questions of surrogate end-points in clinical trials. Whereas overall survival is the ultimate end-point, the case is made for utilizing other end-points according to the stage of disease and needs of the patient, for example utilizing disease-free survival as the first end-point in the adjuvant trial because of its relationship to overall survival. Important consideration in surrogate end-points is the use of biological factors that can be examined in short-term therapy studies and thus related to long-term outcome of patients. This will remain a crucial area of future research. Professor Anthony Howell considered metabolic approaches to breast cancer therapy and prevention as a paradigm for future research. This provocative discussion provided evidence of and support for targeting metabolic pathways either alone or in combination with standard therapies. Of particular interest are the data on new agents that mimic caloric restriction, called caloric restriction mimetics. This novel approach provides a new area of investigation based on our increasing understanding of metabolic pathways in tumours.

Is Sirt1 a miracle bullet for longevity?

The Sir2 (silent information regulator 2) family of nicotinamide adenine dinucleotide-dependent deacetylases has been implicated in the regulation of aging and longevity across a wide variety of organisms. Although controversial, Sir2 proteins have also been implicated as key mediators for the beneficial effects of caloric restriction (CR) on aging and longevity. In this issue, Bordone et al. report that transgenic mice in which the mammalian Sir2 ortholog Sirt1 is overexpressed mimic the physiological changes in response to CR. These findings have important implications for the development of CR mimetics and perhaps also for lifespan extension.

Do We Age on Sirt1 Expression?

Aging leads to a progressive decline in multiple organ systems, including the heart. Heart failure in response to cellular aging and chronic or acute cellular stresses represents one of the major burdens of the western civilization. Over the last 15 years, the interest in the therapeutic use of caloric restriction to prevent aging has emerged. However, it is difficult to determine whether caloric restriction influences longevity in humans because no validated biomarker exists, which can serve as a surrogate marker of aging and it is impossible to conduct a randomized, diet-controlled longterm survival study in humans. Nevertheless, caloric restriction has been shown in several studies to lower fasting plasma glucose concentration and serum low-density lipoprotein cholesterol, to decrease insulin resistance, visceral fat mass and the levels of inflammatory markers. Most of these markers are known to be risk factors for coronary heart disease. Thus, even it is not known whether caloric restriction does prolong maximum life-span, it could increase life expectancy and the quality of late life by reducing the burden of chronic diseases. However, the precise biological and cellular mechanisms responsible for aging and the antiaging effects of caloric restriction are not known. Moreover, even if caloric restriction would result in an increase in maximum life span in humans, it will be difficult to maintain long-term caloric restriction in modern society. Therefore, one major interest is to develop caloric restriction mimetics to provide all of the “healthy” physiological, metabolic and hormonal effects of caloric restriction without the need to reduce food intake. Based on these ideas, it has been proposed, that resveratrol increases lifespan in several different organisms, mimicking the effects of caloric restriction.1 Recent reports indicate, that resveratrol can even restore the health and lifespan of mice on a high calorie diet to levels seen in mice on a normal diet, rising the hope of “guilt-free gluttony” when adding resveratrol as a dietary supplement.1,2 But how does resveratrol induce these caloric restriction-like effects on the molecular level? An in vitro screen for activators of the sirtuin/Sir2 family of NAD-dependent deacetylases identified resveratrol as the most potent of 18 inducers of Sir2 deacetylase activity. 3 Subsequent work has shown that resveratrol extends the lifespans of S. cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, but only if the gene that encodes Sir2 is present in these organisms, providing further evidence that the observed effects of resveratrol are because of an activation of Sir2. 3,4 Sirtuins are a conserved family of NAD-dependent deacetylases (class III histone deacetylases) that were named after the founding member, the Saccharomyces cerevisiae silent information regulator 2 (Sir2) protein. 5 In yeast, worms and flies, overexpression of the genes that encode sirtuins are reported to extend lifespan,6–8 suggesting that sirtuins are evolutionarily conserved mediators of longevity. Moreover, sirtuins are suggested to play a role in lifespan extension

Increased mitochondrial H2O2 production promotes endothelial NF-κB activation in aged rat arteries

Previous studies have shown that the aging vascular system undergoes pro-atherogenic phenotypic changes, including increased oxidative stress and a pro-inflammatory shift in endothelial gene expression profile. To elucidate the link between increased oxidative stress and vascular inflammation in aging, we compared the carotid arteries and aortas of young and aged (24 mo old) Fisher 344 rats. In aged vessels there was an increased NF-kappaB activity (assessed by luciferase reporter gene assay and NF-kappaB binding assay), which was attenuated by scavenging H(2)O(2). Aging did not alter the vascular mRNA and protein expression of p65 and p50 subunits of NF-kappaB. In endothelial cells of aged vessels there was an increased production of H(2)O(2) (assessed by 5,6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate-acetyl ester fluorescence), which was attenuated by the mitochondrial uncoupler FCCP. In young arteries and cultured endothelial cells, antimycin A plus succinate significantly increased FCCP-sensitive mitochondrial H(2)O(2) generation, which was associated with activation of NF-kappaB. In aged vessels inhibition of NF-kappaB (by pyrrolidenedithiocarbamate, resveratrol) significantly attenuated inflammatory gene expression and inhibited monocyte adhesiveness. Thus increased mitochondrial oxidative stress contributes to endothelial NF-kappaB activation, which contributes to the pro-inflammatory phenotypic alterations in the aged vaculature. Our model predicts that by reducing mitochondrial H(2)O(2) production and/or directly inhibiting NF-kappaB novel anti-aging pharmacological treatments (e.g., calorie restriction mimetics) will exert significant anti-inflammatory and vasoprotective effects.

Gene expression profiling of long-lived dwarf mice: longevity-associated genes and relationships with diet, gender and aging

BackgroundLong-lived strains of dwarf mice carry mutations that suppress growth hormone (GH) and insulin-like growth factor I (IGF-I) signaling. The downstream effects of these endocrine abnormalities, however, are not well understood and it is unclear how these processes interact with aging mechanisms. This study presents a comparative analysis of microarray experiments that have measured hepatic gene expression levels in long-lived strains carrying one of four mutations (Prop1df/df, Pit1dw/dw, Ghrhrlit/lit, GHR-KO) and describes how the effects of these mutations relate to one another at the transcriptional level. Points of overlap with the effects of calorie restriction (CR), CR mimetic compounds, low fat diets, gender dimorphism and aging were also examined.ResultsAll dwarf mutations had larger and more consistent effects on IGF-I expression than dietary treatments. In comparison to dwarf mutations, however, the transcriptional effects of CR (and some CR mimetics) overlapped more strongly with those of aging. Surprisingly, the Ghrhrlit/lit mutation had much larger effects on gene expression than the GHR-KO mutation, even though both mutations affect the same endocrine pathway. Several genes potentially regulated or co-regulated with the IGF-I transcript in liver tissue were identified, including a DNA repair gene (Snm1) that is upregulated in proportion to IGF-I inhibition. A total of 13 genes exhibiting parallel differential expression patterns among all four strains of long-lived dwarf mice were identified, in addition to 30 genes with matching differential expression patterns in multiple long-lived dwarf strains and under CR.ConclusionComparative analysis of microarray datasets can identify patterns and consistencies not discernable from any one dataset individually. This study implements new analytical approaches to provide a detailed comparison among the effects of life-extending mutations, dietary treatments, gender and aging. This comparison provides insight into a broad range of issues relevant to the study of mammalian aging. In this context, 43 longevity-associated genes are identified and individual genes with the highest level of support among all microarray experiments are highlighted. These results provide promising targets for future experimental investigation as well as potential clues for understanding the functional basis of lifespan extension in mammalian systems.

Sirtuins as potential targets for metabolic syndrome

Metabolic syndrome threatens health gains made during the past century. Physiological processes degraded by this syndrome are often oppositely affected by calorie restriction, which extends lifespan and prevents disease in rodents. Recent research in the field of ageing has begun to identify important mediators of calorie restriction, offering the hope of new drugs to improve healthspan. Moreover, if metabolic syndrome and calorie restriction are opposite extremes of the same metabolic spectrum, calorie restriction mimetics might provide another therapeutic approach to metabolic syndrome. Sirtuins and other important metabolic pathways that affect calorie restriction may serve as entry points for drugs to treat metabolic syndrome.

How Evolutionary Thinking Affects People's Ideas About Aging Interventions

Evolutionary theory has guided the development of antiaging interventions in some conscious and some unconscious ways. It is a standard assumption that the body's health has been optimized by natural selection, and that the most benign and promising medical strategies should support the body's efforts to maintain itself. The very concept of natural healing is a reflection of evolutionary thinking about health. Meanwhile, a developing body of experimental evidence points to the startling hypothesis that aging is a metabolic program, under genetic control we are programmed for death. Evolution has provided that the aging program can be abated in times of stress, e.g., caloric restriction. CR mimetics are already recognized as a promising avenue for antiaging research. Beyond this, there are two ancient mechanisms of programmed death in protists that have survived half a billion years of evolution, and still figure in the aging of vertebrates today. These are apoptosis and replicative senescence via telomere truncation. Most researchers have been wary of modifying these mechanisms because they are known to play a stopgap role in cancer prevention. But intriguing evidence suggests that, despite some counter-carcinogenic function, the net result of both these mechanisms may be to shorten lifespan. Thus, interventions that suppress apoptosis and that preserve telomeres may be promising avenues for life extension research. A third element of the body's self-destruction program co-opts the inflammation response. Epidemiological evidence suggests that NSAIDs including aspirin protect against atherosclerosis, arthritis, and some forms of cancer. It may be that aging engages an autoimmune response that can be modified by drugs acting more narrowly on this same pathway. The existence of an evolutionary program that controls aging from the top down supports a new optimism concerning the types of antiaging interventions that are possible, and the likelihood that simple strategies may have dramatic results without dramatic side-effects.