These investigators demonstrate that in the adult fruit fly, Drosophila melanogaster, heterozygous inactivating mutations in a newly identified gene Indy (for I’m not dead yet from the film “Monty Python and the Holy Grail”) double the active, fertile, and fecund life span of this insect. Indy encodes a 572 amino acid sodium dicarboxylate cotransporter, a membrane protein that shepherds the uptake and re-uptake of di- and tricarboxylic acid intermediate metabolites (e.g., succinate, citrate) of the Krebs cycle across cell membranes of organs responsible for metabolism and storage of fat, glycogen, and protein (e.g., the liver in mammals).  The investigators suggest that heterozygous loss-of-function mutations in Indy decrease the rate of absorption and utilization of metabolites, thus acting functionally to extend life span in a manner similar to that of partial caloric restriction.

Editor’s Comment: Energy restriction has been demonstrated to extend life span in worms, mammals, and insects, but the mechanism(s) by which decreased calories does (do) so have not been identified.  It may be that caloric restriction down regulates the expression of sodium dicarboxylate cotransporter(s) genes thus decreasing the rate of intracellular metabolism and consequently increasing cellular life.  These observations suggest that perhaps some obese subjects possibly have gain-of-function mutations in one or another sodium dicarboxylate cotransporter that enhance intracellular intermediary metabolism leading to accumulation of fat, while other individuals (who can “eat a tone and never gain an ounce”) may have a variant that impedes metabolism.  The data also suggest that it may be possible to modify the activity of these cotransporter molecules chemically - opening a portal for treatment of a group of obese subjects.

Pennisi E.  Old files may hold secrets of aging.  Science 290:2048, 2000.

Allen Root, MD

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