Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats.
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 vacuolization 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.
Minor
Robin K
RK
Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Smith
Daniel L
DL
Sossong
Alex M
AM
Kaushik
Susmita
S
Poosala
Suresh
S
Spangler
Edward L
EL
Roth
George S
GS
Lane
Mark
M
Allison
David B
DB
de Cabo
Rafael
R
Ingram
Donald K
DK
Mattison
Julie A
JA
D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology* / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D016019:Survival Analysis; D014617:Vacuoles / Q000187:drug effects* / Q000648:ultrastructure
D007328:Insulin; D006003:Glycogen; D003847:Deoxyglucose; D005947:Glucose