Elsevier

Experimental Gerontology

Volume 46, Issues 2–3, February–March 2011, Pages 148-154
Experimental Gerontology

Review
Glycolytic inhibition as a strategy for developing calorie restriction mimetics

https://doi.org/10.1016/j.exger.2010.12.001Get rights and content

Abstract

Calorie restriction (CR) remains the most robust environmental intervention for altering aging processes and increasing healthspan and lifespan. Emerging from progress made in many nonhuman models, current research has expanded to formal, controlled human studies of CR. Since long-term CR requires a major commitment of will power and long-term negative consequences remain to be determined, the concept of a calorie restriction mimetic (CRM) has become a new area of investigation within gerontology. We have proposed that a CRM is a compound that mimics metabolic, hormonal, and physiological effects of CR, activates stress response pathways observed in CR and enhances stress protection, produces CR-like effects on longevity, reduces age-related disease, and maintains more youthful function, all without significantly reducing food intake. Over 12 years ago, we introduced the concept of glycolytic inhibition as a strategy for developing mimetics of CR. We have argued that inhibiting energy utilization as far upstream as possible might offer a broader range of CR-like effects as opposed to targeting a singular molecular target downstream. As the first candidate CRM, 2-deoxyglucose, a known anti-glycolytic, provided a remarkable phenotype of CR, but turned out to produce cardiotoxicity in rats. Since the introduction of 2DG as a candidate CRM, many different targets for development have now been proposed at more downstream sites, including insulin receptor sensitizers, sirtuin activators, and inhibitors of mTOR. This review discusses these various strategies to assess their current status and future potential for this emerging research field.

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

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