Caloric Restriction Mimetics Research Articles

Abstract 1577: Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized melanoma therapy. Still, the 5-year survival for advanced melanoma is only 50%. This leads to two questions: what makes some tumors less responsive to ICIs, and what can be done to increase responsiveness? Prior research suggests that hypoxia in the tumor microenvironment (TME) decreases the efficacy of ICIs, and metformin, an antihyperglycemic and caloric restriction mimetic (CRM), is able to reverse this condition. We hypothesize that other CRMs will also increase responsiveness to ICIs through hypoxia, and potentially other mechanisms. We chose three CRMs to study alongside metformin: hydroxycitrate, resveratrol, and sulforaphane. To identify pathways and understand more about CRMs effect on tumor hypoxia, we performed a proteomics experiment on B16F10 murine melanoma cells treated with all four CRMs. Proteomics analysis was done with a tandem mass tag labeling. To determine effect of caloric restriction mimetics on immunotherapy efficacy, B16F10 cells will be injected subcutaneously in immunocompetent male and female C57BL/6J mice, separated into four groups: 1) no treatment control, 2) ICI therapy only, 3) CRM therapy only, 4) ICI + CRM combination. Our preliminary data shows that, like metformin, additional CRMs decrease oxidative phosphorylation in cancer cells. This supports the hypothesis that the other CRMs may function similarly to metformin in the TME. We started testing the effect of four CRMs on tumor growth and hypoxia in an animal model. Our ultimate goal is to improve responsiveness to immune checkpoint inhibitors in patients with metastatic melanoma. Citation Format: Lauren C. Morehead, Brian S. Koss, Katherine F. Wallis, Alan J. Tackett, Isabelle Racine Miousse. Caloric restriction mimetics as adjuvant to immune checkpoint inhibitors for treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1577.

Characterization and Mechanisms of Action of Avocado Extract Enriched in Mannoheptulose as a Candidate Calorie Restriction Mimetic

Increased consumer interest in the avocado (Persea americana or Persea gratissima) has been attributed to established health benefits of this fruit associated with a wide range of ingredients. In search of effective calorie restriction mimetics (CRM), we present herein a consideration of possible health benefits of the rare sugar, mannoheptulose (MH), which acts as an intracellular glycolytic inhibitor and presents the highest concentration of this inhibitor in unripe avocados. A method for producing an extract of unripe avocado (AvX) to enrich concentrations of MH is described. Experiments using myocyte cultures demonstrated a pattern of CRM-like responses when treated with AvX. In vivo experiments confirmed that orally consumed AvX is bioavailable in both mice and dogs, as observed in urine and blood samples. Additional experiments in both these species demonstrated CRM-like improvements in glucose and insulin responses. In sum, the MH-enriched AvX exhibits promise as a CRM.

Tolerance to NADH/NAD+ imbalance anticipates aging and anti-aging interventions

SummaryRedox couples coordinate cellular function, but the consequences of their imbalances are unclear. This is somewhat associated with the limitations of their experimental quantification. Here we circumvent these difficulties by presenting an approach that characterizes fitness-based tolerance profiles to redox couple imbalances using an in silico representation of metabolism. Focusing on the NADH/NAD+ redox couple in yeast, we demonstrate that reductive disequilibria generate metabolic syndromes comparable to those observed in cancer cells. The tolerance of yeast mutants to redox disequilibrium can also explain 30% of the variability in their experimentally measured chronological lifespan. Moreover, by predicting the significance of some metabolites to help stand imbalances, we correctly identify nutrients underlying mechanisms of pathology, lifespan-protecting molecules, or caloric restriction mimetics. Tolerance to redox imbalances becomes, in this way, a sound framework to recognize properties of the aging phenotype while providing a consistent biological rationale to assess anti-aging interventions.

SGLT2 Inhibitors as Calorie Restriction Mimetics: Insights on Longevity Pathways and Age-Related Diseases.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors induce glycosuria, reduce insulin levels, and promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF1, and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favor a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signaling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms, including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors, such as PCG-1α, mitochondrial transcription factor A (TFAM), and nuclear factor E2-related factor (NRF)-2, that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared with other calorie restriction mimetics such as metformin, rapamycin, resveratrol, and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of aging-related diseases, due to their regulation of multiple longevity pathways that closely resembles that achieved by calorie restriction and their established efficacy in reducing cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-aging therapeutics.

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan.

Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.

T-Cell Activation-Inhibitory Assay to Screen Caloric Restriction Mimetics Drugs for Drug Repositioning.

We previously reported a screening method for caloric restriction mimetics (CRM), a group of plant-derived compounds capable of inducing good health and longevity. In the present study, we explored the possibility of using this method to screen CRM drugs for drug repositioning. The method, T-cell activation-inhibitory assay, is based on inductive logic. Most of CRM such as resveratrol have been reported to suppress T-cell activation and have anti-inflammatory functions. Here, we assessed the activity of 12 antiallergic drugs through T-cell activation-inhibitory assay and selected four that showed the lowest IC50 values-ibudilast (IC50 0.97 µM), azelastine (IC50 7.2 µM), epinastine (IC50 16 µM), and amlexanox (IC50 33 µM)-for further investigation. Because azelastine showed high cytotoxicity, we selected only the remaining three drugs to study their biological functions. We found that all the three drugs suppressed the expression of interleukin (IL)-6, an inflammatory cytokine, in lipopolysaccharide-treated macrophage cells, with ibudilast being the strongest suppressor. Ibudilast also suppressed the secretion of another inflammatory cytokine, tumor necrosis factor (TNF)-α, and the expression of an inflammatory enzyme, cyclooxygenase-2, in the cells. These results suggest that T-cell activation-inhibitory assay can be used to screen potential CRM drugs having anti-inflammatory functions for the purpose of drug repositioning.

PI3K/AKT/MTOR and ERK1/2-MAPK signaling pathways are involved in autophagy stimulation induced by caloric restriction or caloric restriction mimetics in cortical neurons.

Caloric restriction has been shown to robustly ameliorate age-related diseases and to prolong lifespan in several model organisms, and these beneficial effects are dependent on the stimulation of autophagy. Autophagy dysfunction contributes to the accumulation of altered macromolecules, and is a key mechanism of promoting aging and age-related disorders, as neurodegenerative ones. We have previously shown that caloric restriction (CR), and CR mimetics Neuropeptide Y (NPY) and ghrelin, stimulate autophagy in rat cortical neurons, however by unknown molecular mechanisms. Overall, we show that CR, NPY, and ghrelin stimulate autophagy through PI3K/AKT/MTOR inhibition and ERK1/2-MAPK activation. The knowledge of these kinases in autophagy regulation and the contribution to the understanding of molecular mechanism facilitates the discovery of more targeted therapeutic strategies to stimulate autophagy, which is relevant in the context of age-related disorders.

Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy.

Simple SummaryReduced food intake significantly enhances healthy lifespan in both model animals and humans, and decreases the incidence of cancer and other age-related diseases. This beneficial effect is mediated by the cellular knock-on effects of reduced food intake. Interestingly, these effects differ between cancer and healthy cells because cancer cells have peculiar metabolic requirements. Some compounds called “caloric restriction mimetics” are able to recapitulate the effects of reduced food intake without impacting the nutritional status. Reduced food intake and these mimicking agents are both able to enhance responses to some chemotherapies, as well as to some regimens combining chemotherapy and immunotherapy. There are encouraging preclinical data supporting the use of reduced food intake or caloric restriction mimetics as an adjuvant to cancer chemo-immunotherapies. Clinical data are sparse, but generally favorable, and additional trials are ongoing.Caloric restriction and fasting have been known for a long time for their health- and life-span promoting effects, with coherent observations in multiple model organisms as well as epidemiological and clinical studies. This holds particularly true for cancer. The health-promoting effects of caloric restriction and fasting are mediated at least partly through their cellular effects—chiefly autophagy induction—rather than reduced calorie intake per se. Interestingly, caloric restriction has a differential impact on cancer and healthy cells, due to the atypical metabolic profile of malignant tumors. Caloric restriction mimetics are non-toxic compounds able to mimic the biochemical and physiological effects of caloric restriction including autophagy induction. Caloric restriction and its mimetics induce autophagy to improve the efficacy of some cancer treatments that induce immunogenic cell death (ICD), a type of cellular demise that eventually elicits adaptive antitumor immunity. Caloric restriction and its mimetics also enhance the therapeutic efficacy of chemo-immunotherapies combining ICD-inducing agents with immune checkpoint inhibitors targeting PD-1. Collectively, preclinical data encourage the application of caloric restriction and its mimetics as an adjuvant to immunotherapies. This recommendation is subject to confirmation in additional experimental settings and in clinical trials. In this work, we review the preclinical and clinical evidence in favor of such therapeutic interventions before listing ongoing clinical trials that will shed some light on this subject.

Glucosamine Displays a Potent Caloric Restriction Mimetic Effect in Senescent Rats by Activating Mitohormosis.

Aging is strongly correlated with several noncommunicable disorders such as diabetes, obesity, cardiovascular disease, and neurodegenerative conditions. Glucosamine (2-amino-2-deoxy-d-glucose, GlcN) is a naturally occurring amino sugar and is reported to act as a caloric restriction mimetic (CRM). In young and d-galactose-induced accelerated rat aging models, we tested a persistent oral dietary dose of GlcN and evaluated various aging biomarkers in erythrocytes and plasma. A significant increase in the reactive oxygen species (ROS) was observed in GlcN-treated young and accelerated senescent rat model. Increased value of ferric reducing ability of plasma (FRAP), superoxide dismutase, catalase, and plasma membrane redox system (PMRS) was observed. We suggest that GlcN induces a mitohormetic impact by a transient increase in ROS. Our findings indicate that GlcN may be a successful CRM.

Mass spectrometric investigations of caloric restriction mimetics.

Caloric restriction (CR) is an innovative therapy used in tumor tissue and tumor model studies to promote cell death and decrease cell viability. Caloric restriction mimetics (CRMs) are a class of drugs that induce CR and starvation conditions within a cell. When used simultaneously with other chemotherapy agents, the effects are synergistic and effective at promoting tumor cell death. In this review, we discuss CRMs and their potential as cancer therapeutics. Firstly, we establish an overview of CR and its impacts on healthy and tumor cells. CR and CRM drugs have shown to decrease age-related diseases and can act as an anti-cancer agent. As it can be challenging for an individual to diligently stick to a diet that would induce CR, CRMs are even more desirable. Then, we discuss the drug class by highlighting three CRMs: resveratrol, (-)-hydroxycitric acid, and rapamycin. These CRMs are commonly known for their dietary effects, but the underlying mechanisms that drive cellular metabolic and proteomic changes show promise as a cancer therapeutic. Lastly, we highlight the use of mass spectrometry and proteomic techniques on experiments utilizing CRM drugs to understand the cellular pathways impacted by this drug class, leading to a better understanding of the anti-cancer properties and potentials of CRM.

Recent advances in the field of caloric restriction mimetics and anti-aging molecules

Caloric restriction (CR) mimetics are molecules that produce beneficial effects on health and longevity in model organisms and humans, without the challenges of maintaining a CR diet. Conventional CR mimetics such as metformin, rapamycin and spermidine activate autophagy, leading to recycling of cellular components and improvement of physiological function. We review here novel CR mimetics and anti-aging compounds, such as 4,4′-dimethoxychalcone, fungal polysaccharides, inorganic nitrate, and trientine, highlighting their possible molecular targets and mechanisms of action. The activity of these compounds can be understood within the context of hormesis, a biphasic dose response that involves beneficial effects at low or moderate doses and toxic effects at high doses. The concept of hormesis has widespread implications for the identification of CR mimetics in experimental assays, testing in clinical trials, and use in healthy humans. We also discuss the promises and limitations of CR mimetics and anti-aging molecules for delaying aging and treating chronic diseases.

Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control.

Cellular senescence, a stable cell division arrest caused by severe damage and stress, is a hallmark of aging in vertebrates including humans. With progressing age, senescent cells accumulate in a variety of mammalian tissues, where they contribute to tissue aging, identifying cellular senescence as a major target to delay or prevent aging. There is an increasing demand for the discovery of new classes of small molecules that would either avoid or postpone cellular senescence by selectively eliminating senescent cells from the body (i.e., 'senolytics') or inactivating/switching damage-inducing properties of senescent cells (i.e., 'senostatics/senomorphics'), such as the senescence-associated secretory phenotype. Whereas compounds with senolytic or senostatic activity have already been described, their efficacy and specificity has not been fully established for clinical use yet. Here, we review mechanisms of senescence that are related to mitochondria and their interorganelle communication, and the involvement of proteostasis networks and metabolic control in the senescent phenotype. These cellular functions are associated with cellular senescence in invitro and invivo models but have not been fully exploited for the search of new compounds to counteract senescence yet. Therefore, we explore possibilities to target these mechanisms as new opportunities to selectively eliminate and/or disable senescent cells with the aim of tissue rejuvenation. We assume that this research will provide new compounds from the chemical space which act as mimetics of caloric restriction, modulators of calcium signaling and mitochondrial physiology, or as proteostasis optimizers, bearing the potential to counteract cellular senescence, thereby allowing healthy aging.

Still Living Better through Chemistry: An Update on Caloric Restriction and Caloric Restriction Mimetics as Tools to Promote Health and Lifespan.

Caloric restriction (CR), the reduction of caloric intake without inducing malnutrition, is the most reproducible method of extending health and lifespan across numerous organisms, including humans. However, with nearly one-third of the world’s population overweight, it is obvious that caloric restriction approaches are difficult for individuals to achieve. Therefore, identifying compounds that mimic CR is desirable to promote longer, healthier lifespans without the rigors of restricting diet. Many compounds, such as rapamycin (and its derivatives), metformin, or other naturally occurring products in our diets (nutraceuticals), induce CR-like states in laboratory models. An alternative to CR is the removal of specific elements (such as individual amino acids) from the diet. Despite our increasing knowledge of the multitude of CR approaches and CR mimetics, the extent to which these strategies overlap mechanistically remains unclear. Here we provide an update of CR and CR mimetic research, summarizing mechanisms by which these strategies influence genome function required to treat age-related pathologies and identify the molecular fountain of youth.

Effects of caloric restriction on immunosurveillance, microbiota and cancer cell phenotype: Possible implications for cancer treatment.

Fasting, caloric restriction and foods or compounds mimicking the biological effects of caloric restriction, known as caloric restriction mimetics, have been associated with a lower risk of age-related diseases, including cardiovascular diseases, cancer and cognitive decline, and a longer lifespan. Reduced calorie intake has been shown to stimulate cancer immunosurveillance, reducing the migration of immunosuppressive regulatory T cells towards the tumor bulk. Autophagy stimulation via reduction of lysine acetylation, increased sensitivity to chemo- and immunotherapy, along with a reduction of insulin-like growth factor 1 and reactive oxygen species have been described as some of the major effects triggered by caloric restriction. Fasting and caloric restriction have also been shown to beneficially influence gut microbiota composition, modify host metabolism, reduce total cholesterol and triglyceride levels, lower diastolic blood pressure and elevate morning cortisol level, with beneficial modulatory effects on cardiopulmonary fitness, body fat and weight, fatigue and weakness, and general quality of life. Moreover, caloric restriction may reduce the carcinogenic and metastatic potential of cancer stem cells, which are generally considered responsible of tumor formation and relapse. Here, we reviewed in vitro and in vivo studies describing the effects of fasting, caloric restriction and some caloric restriction mimetics on immunosurveillance, gut microbiota, metabolism, and cancer stem cell growth, highlighting the molecular and cellular mechanisms underlying these effects. Additionally, studies on caloric restriction interventions in cancer patients or cancer risk subjects are discussed. Considering the promising effects associated with caloric restriction and caloric restriction mimetics, we think that controlled-randomized large clinical trials are warranted to evaluate the inclusion of these non-pharmacological approaches in clinical practice.

Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics.

Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and D-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied.

Caloric restriction mimetics for the treatment of cardiovascular diseases.

Caloric restriction mimetics (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis, or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy. Previous evidence demonstrated the ability of CRMs to ameliorate cardiac function and reduce cardiac hypertrophy and maladaptive remodelling in animal models of ageing, mechanical overload, chronic myocardial ischaemia, and in genetic and metabolic cardiomyopathies. In addition, CRMs were found to reduce acute ischaemia-reperfusion injury. In many cases, these beneficial effects of CRMs appeared to be mediated by autophagy activation. In the present review, we discuss the relevant literature about the role of different CRMs in animal models of cardiac diseases, emphasizing the molecular mechanisms underlying the beneficial effects of these compounds and their potential future clinical application.

Diabetes medications as potential calorie restriction mimetics-a focus on the alpha-glucosidase inhibitor acarbose.

The field of aging research has grown rapidly over the last half-century, with advancement of scientific technologies to interrogate mechanisms underlying the benefit of life-extending interventions like calorie restriction (CR). Coincident with this increase in knowledge has been the rise of obesity and type 2 diabetes (T2D), both associated with increased morbidity and mortality. Given the difficulty in practicing long-term CR, a search for compounds (CR mimetics) which could recapitulate the health and longevity benefits without requiring food intake reductions was proposed. Alpha-glucosidase inhibitors (AGIs) are compounds that function predominantly within the gastrointestinal tract to inhibit α-glucosidase and α-amylase enzymatic digestion of complex carbohydrates, delaying and decreasing monosaccharide uptake from the gut in the treatment of T2D. Acarbose, an AGI, has been shown in pre-clinical models to increase lifespan (greater longevity benefits in males), with decreased body weight gain independent of calorie intake reduction. The CR mimetic benefits of acarbose are further supported by clinical findings beyond T2D including the risk for other age-related diseases (e.g., cancer, cardiovascular). Open questions remain regarding the exclusivity of acarbose relative to other AGIs, potential off-target effects, and combination with other therapies for healthy aging and longevity extension. Given the promising results in pre-clinical models (even in the absence of T2D), a unique mechanism of action and multiple age-related reduced disease risks that have been reported with acarbose, support for clinical trials with acarbose focusing on aging-related outcomes and incorporating biological sex, age at treatment initiation, and T2D-dependence within the design is warranted.

Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and D-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging.

Spermidine (SPD) is a natural polyamine present in all living organisms and is involved in the maintenance of cellular homeostasis by inducing autophagy in different model organisms. Its role as a caloric restriction mimetic (CRM) is still being investigated. We have undertaken this study to investigate whether SPD, acting as a CRM, can confer neuroprotection in D-galactose induced accelerated senescence model rat and naturally aged rats through modulation of autophagy and inflammation. Young male rats (4months), D-gal induced (500mg/kg b.w., subcutaneously) aging and naturally aged (22months) male rats were supplemented with SPD (10mg/kg b.w., orally) for 6weeks. Standard protocols were employed to measure prooxidants, antioxidants, apoptotic cell death and electron transport chain complexes in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy and inflammatory marker genes. Our data demonstrate that SPD significantly (p ≤ 0.05) decreased the level of pro-oxidants and increased the level of antioxidants. SPD supplementation also augmented the activities of electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. RT-PCR data revealed that SPD up-regulated the expression of autophagy genes (ATG-3, Beclin-1, ULK-1 and LC3B) and down-regulated the expression of the inflammatory gene (IL-6) in aging brain. Our results provide first line of evidence that SPD provides neuroprotection against aging-induced oxidative stress by regulating autophagy, antioxidants level and also reduces neuroinflammation. These results suggest that SPD may be beneficial for neuroprotection during aging and age-related disorders.

Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow.

Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the rapid screening of non-toxic substances causing such a de-energization of cells. We looked for chemicals allowing the growth of yeast lacking trehalose phosphate synthase on a non-fermentable carbon source in the presence of glucose. Under such conditions, the cells cannot grow because the cellular phosphate is mostly being used to phosphorylate the sugars in upper glycolysis, while the biosynthesis of bisphosphoglycerate is blocked. We reasoned that by decreasing the ATP/ADP ratio, one might prevent the phosphorylation of the sugars and also boost bisphosphoglycerate synthesis by providing the substrate, i.e., inorganic phosphate. We confirmed that a complete inhibition of oxidative phosphorylation alleviates the block. As our system includes a non-fermentable carbon source, only the chemicals that did not cause a complete block of mitochondrial ATP synthesis allowed the initial depletion of glucose followed by respiratory growth. Using this system, we found two novel compounds, dodecylmethyl diphenylamine (FS1) and diethyl (tetradecyl) phenyl ammonium bromide (Kor105), which possess a mild membrane-depolarizing activity.

Human antiaging research: a viewpoint from food science on calorie restriction mimetics

Calorie restriction (CR) is to reduce food intake without malnutrition and is sometimes adopted intentionally to reduce body weight for improving health. CR has been known to prolong the lifespan in several animal models such as nematodes, flies, and mice. While it is not feasible to implement long term CR in humans, the intake of specific food substances that produce the same effect as CR can result in significant health benefits to humans. This paper highlights the need for promoting research on such calorie restriction mimetics (CRMs). This scientific opinion suggests that the promotion of research on CRMs derived from foods and food resources has the potential to enhance health and prolong life span. Collaboration between researchers from the fields of food science and those working on CRMs has the potential to promote good health and enhance human longevity in the aging society.