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Mannoheptulose: glycolytic inhibitor and novel caloric restriction mimetic
Author(s) -
Roth George,
Hayek Mike,
Massimino Stefan,
Davenport Gary,
Arking Robert,
Bartke Andrzej,
Bonkowski Michael,
Ingram Don
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.553.1
Subject(s) - glycolysis , caloric theory , hexokinase , prediabetes , chemistry , insulin , medicine , glucose 6 phosphate isomerase , endocrinology , metabolism , biochemistry , biology , enzyme , diabetes mellitus , type 2 diabetes
Caloric restriction (CR) is the most robust and reproducible strategy for retarding aging. Benefits of CR have been demonstrated in multiple species, but application to human or companion animal aging represents a challenge. In 1998 the concept of CR "mimetic" (CRM) was introduced as a method to obtain "anti‐aging" and health‐promoting benefits of CR without reducing food intake. We hypothesized that an effective CRM would best mimic the effects of CR if it impeded initial stages of energy metabolism. We focused initially on glycolytic inhibition using 2‐deoxyglucose (2DG). Upon entry into cells, this glucose analog is phosphorylated and becomes a strong competitive inhibitor of phosphohexose isomerase. 2DG effectively induces a CR‐like state in rats based on metabolic effects such as reduced plasma glucose, insulin, body temperature, pulse, heart rate and inhibiting tumor growth. Results show 2DG has a narrow window between efficacy and toxicity so recently we shifted our focus to mannoheptulose (MH), a seven‐carbon sugar that reduces glycolysis via hexokinase inhibition. MH appears non‐toxic with negligible effects on food intake and BW, and increased insulin tolerance by 25% in mice. MH extends median and maximal lifespan (~15%) in D. melanogaster and median lifespan (~30%) in C3H/HeJ mice. These findings, coupled with simple extraction from avocados, suggest that MH may be a practical, highly effective CRM.