ReviewGlycolytic inhibition as a strategy for developing calorie restriction mimetics
Research Highlights
► Research and development of candidate calorie restriction mimetics is a growing field within gerontology. ► Many targets exist for development including upstream and downstream targeting. ► Among downstream targeting, several approaches have yielded positive results, including SIRT1 activation, mTOR inhibition, and increased insulin receptor sensitivity; however, to date no candidates focused on these targets have provided the complete phenotype of a calorie restriction mimetic. ► We have argued that upstream targeting would likely have a broader array of effects to mimic calorie restriction. ► Specifically, we have suggested that glycolytic inhibition was a logical strategy for such approaches.
Section snippets
Sirtuins
The best example of a downstream target would be represented as the great flurry of activity surrounding research in manipulation of sirtuins as a strategy for developing CRM (Baur, 2010, Baur et al., 2006, Chen and Guarente, 2007, Howitz et al., 2003, Kaeberlein, 2010, Kume et al., 2010, Milne et al., 2007, Pearson et al., 2008, Wood et al., 2004). One company that has taken the lead in developing this strategy is Sirtris Pharmaceutical, who lists on the home page of their website the
mTOR signaling
As another major example of downstream targeting to create a candidate CRM, mTOR has taken center stage recently (Blagosklonny, 2010, Kapahi et al., 2010, Stanfel et al., 2009). Interest in this target emerged out of the debate over the centrality of SIRT1 in mediating the anti-aging effects of CR as well as the growing interest in autophagy (Blagosklonny, 2010, Hands et al., 2009, Kapahi et al., 2010, Salminen and Kaarniranta, 2009, Stanfel et al., 2009). mTOR is a serine/threonine protein
Insulin signaling
Turning attention to a more upstream target than mTOR and SIRT1, the search for effective CRM can logically focus on insulin signaling (Anisimov, 2003, Bartke, 2008, Ingram et al., 2006, Tatar et al., 2003). Using invertebrate models, genetic manipulation of the daf-2 pathway in a variety of targets demonstrated that reduced signaling could increase lifespan (Anisimov, 2003, Bartke, 2008, Tatar et al., 2003). A major biomarker of reduced insulin signaling is reduced plasma levels of insulin,
Glycolytic inhibition
We first proposed glycolytic inhibition as a logical upstream target for developing CRM (Lane et al., 1998). The main contention was that reducing cellular energy processing would stimulate the cell to induce responses similar to that induced by actual CR. Other upstream targets can be identified, such as blocking glucose absorption in the intestine or glucose transport into the cell; however, we felt that by manipulating an intracellular target, we might be most effective in triggering a
Summary
Many other targets exist for developing CRM beyond glycolytic inhibition. We covered a few candidates in this review, but have not mentioned several others that mimic mechanisms of CR, including, antioxidants, mitochondrial biogenerators, autophagy stimulators, and inhibitors of insulin signaling. We focused on targets for glycolytic inhibition in this review because it is our contention that such interventions would most directly mimic the metabolic actions of CR, that is, triggering cellular
References (112)
Insulin/IGF-1 signaling pathway driving aging and cancer as a target for pharmacological intervention
Exp. Gerontol.
(2003)- et al.
Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice
Exp. Gerontol.
(2005) - et al.
Rapamycin extends maximal lifespan in cancer-prone mice
Am. J. Pathol.
(2010) - et al.
Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans
Mech. Ageing Dev.
(2007) Resveratrol, sirtuins, and the promise of a DR mimetic
Mech. Ageing Dev.
(2010)- et al.
Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments
J. Biol. Chem.
(2010) Hormesis: From marginalization to mainstream: a case for hormesis as the default dose–response model in risk assessment
Toxicol. Appl. Pharmacol.
(2004)- et al.
Local toxicity of hepatic arterial infusion of hexokinase II inhibitor, 3-bromopyruvate: in vivo investigation in normal rabbit model
Acad. Radiol.
(2007) - et al.
Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity
Free Radic. Biol. Med.
(2008) - et al.
SIR2: a potential target for calorie restriction mimetics
Trends Mol. Med.
(2007)
SIRT1 activation by small molecules—kinetic and biophysical evidence for direct interaction of enzyme and activator
J. Biol. Chem.
Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation
Cell Metab.
Holeboard maze-learning deficits and brain monoaminergic neurotransmitter concentrations in rats after intracerebroventricular injection of 3-bromopyruvate
Pharmacol. Biochem. Behav.
In vivo 2-deoxyglucose administration preserves glucose and glutamate transport and mitochondrial function in cortical synaptic terminals after exposure to amyloid β-peptide and iron: evidence for a stress response
Exp. Neurol.
Protective effect of trans-resveratrol against kainic acid-induced seizures and oxidative stress in rats
Pharmacol. Biochem. Behav.
2-Deoxyglucose: an anticancer and antiviral therapeutic, but not any more a low glucose mimetic
Life Sci.
With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging
Cell Metab.
Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease
Neurochem. Int.
Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson's disease
Brain Res.
Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase
Cancer Lett.
Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP
Biochem. Biophys. Res. Commun.
Dietary factors, hormesis health
Ageing Res. Rev.
Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span
Mech. Ageing Dev.
Chronic ingestion of 2-deoxy-d-glucose induces cardiac vacuolization and increases mortality in rats
Toxicol. Appl. Pharmacol.
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1
J. Biol. Chem.
Resveratrol Delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span
Cell Metab.
Hormesis in aging
Ageing Res. Rev.
Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1
Exp. Neurol.
Regulation of the aging process by autophagy
Trends Mol. Med.
Redox regulation of the nutrient-sensitive raptor–mTOR pathway and complex
J. Biol. Chem.
Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress
Cell Metab.
Toward a unified theory of caloric restriction and longevity regulation
Mech. Ageing Dev.
The TOR pathway comes of age
Biochim. Biophys. Acta
Role of mTOR in physiology and pathology of the nervous system
Biochim. Biophys. Acta
mTOR integrates amino acid- and energy-sensing pathways
Biochem. Biophys. Res. Commun.
Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate
Curr. Biol.
Sirtuin-targeting drugs: mechanisms of action and potential therapeutic applications
Curr. Opin. Investig. Drugs
Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice
Bull. Exp. Biol. Med.
Metformin slows down aging and extends life span of female SHR mice
Cell Cycle
Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo
Cell Cycle
Metformin
N. Engl. J. Med.
A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice
PLoS ONE
Insulin and aging
Cell Cycle
Resveratrol improves health and survival of mice on a high-calorie diet
Nature
Metformin in cancer therapy: a new perspective for an old antidiabetic drug?
Mol. Cancer Ther.
Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans)
Cell Cycle
The mTOR pathway: a new target in cancer therapy
Curr. Cancer Drug Targets
Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle
Am. J. Physiol. Endocrinol. Metab.
Reduced glucose availability induces torpor in Siberian hamsters
Am. J. Physiol.
Resveratrol and red wine, healthy heart and longevity
Heart Fail. Rev.
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