Mouse Neoplasia and Immunity: Effects of Radiation, Hyperthermia, 2-deoxy-&lt;i&gt;D&lt;/i&gt;-glucose, and &lt;i&gt;Corynebacterium parvum&lt;/i&gt;

Gridley, Daila S.; Nutter, Robert L.; Kettering, James D.; Mantik, David W.; Slater, James M.

doi:10.1159/000226070

Cited by 18 publications

(5 citation statements)

References 5 publications

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“…As an initial approach,16 rats and mice were fed a diet containing 2‐deoxy‐d‐glucose (2DG), which inhibits the enzyme, phosphohexose isomerase, and thus reduces glycolytic processing. Previous studies revealed that 2DG injections could inhibit tumor growth42 and produce torpor43 and increase glucocorticoids,44 all of which paralleled effects of CR.…”

Section: ‐Deoxyglucosementioning

confidence: 95%

Development of Calorie Restriction Mimetics as a Prolongevity Strategy

Ingram

Anson

Cabo

et al. 2004

Annals of the New York Academy of Sciences

178

118

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By applying calorie restriction (CR) at 30-50% below ad libitum levels, studies in numerous species have reported increased life span, reduced incidence and delayed onset of age-related diseases, improved stress resistance, and decelerated functional decline. Whether this nutritional intervention is relevant to human aging remains to be determined; however, evidence emerging from CR studies in nonhuman primates suggests that response to CR in primates parallels that observed in rodents. To evaluate CR effects in humans, clinical trials have been initiated. Even if evidence could substantiate CR as an effective antiaging strategy for humans, application of this intervention would be problematic due to the degree and length of restriction required. To meet this challenge for potential application of CR, new research to create "caloric restriction mimetics" has emerged. This strategy focuses on identifying compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. Microarray studies show that gene expression profiles of key enzymes in glucose (energy) handling pathways are modified by CR. Drugs that inhibit glycolysis (2-deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicity, enhanced dopamine action, and upregulated brain-derived neurotrophic factor. Further life span analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic, but this strategy now appears to offer a very promising and expanding research field.

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Section: ‐Deoxyglucosementioning

confidence: 95%

Development of Calorie Restriction Mimetics as a Prolongevity Strategy

Ingram

Anson

Cabo

et al. 2004

Annals of the New York Academy of Sciences

178

118

View full text Add to dashboard Cite

show abstract

“…For this initial study, the compound selected was 2‐deoxy‐D‐glucose (2DG), which inhibits the enzyme phosphohexose isomerase and thus reduces glycolytic processing. Results of previous rodent studies had shown that injections of 2DG could inhibit tumor growth (Gridley et al ., 1985), produce torpor (Dark et al ., 1994) and increase glucocorticoids (Weidenfeld et al ., 1994), all indicative of a CRM. In the initial evaluation of 2DG as a CRM, young male Fischer‐344 (F344) rats were fed diets supplemented (by weight) with 0.2%, 0.4%, or 0.6% 2DG, approximating doses of 100–150, 250–300, or 400–450 mg kg −1 , respectively.…”

Section: Glycolytic Inhibitionmentioning

confidence: 99%

Calorie restriction mimetics: an emerging research field

et al. 2006

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SummaryWhen considering all possible aging interventions evaluated to date, it is clear that calorie restriction (CR) remains the most robust. Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet can increase lifespan, reduce the incidence and delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline. A current major focus of this research area is whether this nutritional intervention is relevant to human aging. Evidence emerging from studies in rhesus monkeys suggests that their response to CR parallels that observed in rodents. To assess CR effects in humans, clinical trials have been initiated. However, even if results from these studies could eventually substantiate CR as an effective pro-longevity strategy for humans, the utility of this intervention would be hampered because of the degree and length of restriction required. As an alternative strategy, new research has focused on the development of 'CR mimetics'. The objective of this strategy is to identify compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. For example, drugs that inhibit glycolysis (2-deoxyglucose), enhance insulin action (metformin), or affect stress signaling pathways (resveratrol), are being assessed as CR mimetics (CRM). Promising results have emerged from initial studies regarding physiological responses which resemble those observed in CR (e.g. reduced body temperature and plasma insulin) as well as protection against neurotoxicity (e.g. enhanced dopamine action and up-regulated neurotrophic factors). Ultimately, lifespan analyses in addition to expanded toxicity studies must be accomplished to fully assess the potential of any CRM. Nonetheless, this strategy clearly offers a very promising and expanding research endeavor.

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“…Supporting data for this hypothesis include studies where 2DG has been shown to recapitulate key hallmarks of CR such as reduced body temperature (Ingram et al, 2006), increased torpor (Dark et al, 1994), reduced heart rate (Wan et al, 2003), and reduced circulating levels of glucose and insulin (Lane et al, 1998; Wan et al, 2003; Wan et al, 2004). 2DG has also been shown to confer functional benefits that parallel those seen with CR including inhibition of tumor growth (Gridley et al, 1985; Zhu et al, 2005) and increased stress resistance to neurotoxins and cold shock (Duan and Mattson, 1999; Yu and Mattson, 1999; Guo and Mattson 2000; Wan et al, 2004). 2DG has also shown potential benefits in the treatment of seizures in rodents (Stafstrom et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Chronic ingestion of 2-deoxy-d-glucose induces cardiac vacuolization and increases mortality in rats

Minor

Smith

Sossong

et al. 2010

Toxicology and Applied Pharmacology

118

101

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Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway rats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound.

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Mouse Neoplasia and Immunity: Effects of Radiation, Hyperthermia, 2-deoxy-<i>D</i>-glucose, and <i>Corynebacterium parvum</i>

Cited by 18 publications

References 5 publications

Development of Calorie Restriction Mimetics as a Prolongevity Strategy

Development of Calorie Restriction Mimetics as a Prolongevity Strategy

Calorie restriction mimetics: an emerging research field

Chronic ingestion of 2-deoxy-d-glucose induces cardiac vacuolization and increases mortality in rats

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