Gut adaptation to chronic calorie restriction in aged mice.

Chronic calorie restriction (CR) increases lifespan of mice. Body and organ weights decrease sharply, but the gut is surprisingly spared and intestinal sugar and amino acid absorption rates increase. How does the small intestine adapt to the chronically low nutrient intake? 9 mo old CR (n = 7) mice were fed since 2 mo of age 30% less food each week than control (n = 7) (AL) mice. Uptake of glucose but not that of its nonmetabolizable analog 3‐O‐methyl‐glucose increased with CR. Uptake of glutamine, a major source of energy for intestinal metabolism, also increased with CR. Using the Affymetrix mouse genome 430 2.0 array, we found the expression of 84 genes to increase and of 204 to decrease by > 2‐fold (P < 0.05) with CR. CR had no effect on mRNA levels of most sugar and amino acid transporters, but dramatically reduced that of NaPi2b, the intestinal phosphate transporter known to respond to energy levels in the enterocytes. CR down‐regulated intestinal genes involved in glycolysis, anion and lipid transport, proteo‐ and peptido‐lysis, cell growth and immune processes. It also up‐regulated genes involved in transcription modulation, glutathione synthesis and metabolism, thyroid hormone binding and protein/amino acid glycosylation as well as phosphorylation. Hence, the gut spares itself during CR probably by increases in sugar and amino acid uptake rates linked not to changes in transporter mRNA abundance but to extensive, CR‐adaptive alterations in intestinal cell metabolism. (NSF‐IBN 0235011; USDA 2004‐35206‐14154, 2003‐35202‐13520)