Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics
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ORIGINAL ARTICLE
Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics Donald K. Ingram & George S. Roth
Received: 28 July 2020 / Accepted: 5 November 2020 # American Aging Association 2020
Abstract 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, 3bromopyruvate, 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.
D. K. Ingram (*) Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70809, USA e-mail: [email protected] G. S. Roth GeroScience, Inc., 1124 Ridge Road, Pylesville, MD 21132, USA e-mail: [email protected]
Keywords Aging . Longevity . Glucose . Insulin . Glycolysis
Over 20 years ago, we proposed a new class of antiaging interventions to be labeled “calorie restriction mimetics” (CRM) [1]. The long-term objective of this new strategy was to identify and develop therapeutics that mimicked the myriad of anti-aging effects of CR without requiring stringent dieting. The following were the initial criteria applied to define CRM: (1) mimics the metabolic, hormonal, and physiological effects of calorie restriction (CR); (2) activates stress response pathways observed in CR and enhances stress protection; (3) produces CR-like effects on longevity, reduces agerelated disease, and maintains more youthful function; and (4) does not significantly reduce food intake, at least over the short term. This field has expanded greatly since its introduction with many candidate CRMs emerging with several different target mechanisms. As presented in our past reviews of this subject [2–5], the leading candidate targets are as follows: (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 companies have been formed to promote their approac
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