Sci. Aging Knowl. Environ., 9 March 2005
Potential life-extending enzyme cranks up glucose synthesis
An enzyme that lengthens yeast life span helps hungry mice boost dwindling sugar supplies, new results reveal. The protein teams with another molecule to ignite glucose manufacture and quash sugar destruction. The work illuminates how the molecule tweaks metabolism in mammals.
Extra amounts of the protein Sir2p help yeast cells survive to a ripe old age (see Kaeberlein Perspective). Some studies suggest that the molecule also enables the fungi to reap the life-extending benefits of reduced calorie intake, a treatment that also extends rodents' lives. Researchers don't know if the mammalian edition of the protein, known as SIRT1, increases longevity. But a 2004 study by molecular biologist Leonard Guarente of the Massachusetts Institute of Technology in Cambridge and colleagues showed that SIRT1 spurs famished mice to burn fat, and losing ounces can boost the animals' survival (see "Counterattack"). Molecular biologist Pere Puigserver of Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues wanted to further investigate SIRT1's role in calorie restriction.
The researchers starved mice for 24 hours, a regimen that prompts many of the same metabolic changes that calorie restriction prompts. Amounts of SIRT1 in the animals' livers jumped, the team found. Going hungry also boosted quantities of NAD--a compound that helps capture energy from food and that hikes SIRT1 activity--and of PGC-1. This protein responds to an empty stomach by inciting the liver to fashion glucose from amino acids and other molecules. That supplies of SIRT1 and PGC-1 rise together suggests that the two molecules team up. To test the idea, the scientists used antibodies to fish SIRT1 molecules from liver-cell contents and found that they also hooked PGC-1, indicating that the molecules intertwine.
To determine if PGC-1 and SIRT1 collaborate, the researchers dosed cultured liver cells with pyruvate, a compound that amasses during fasting. The researchers found that pyruvate hiked the activity of genes that prod the liver to manufacture glucose. However, adding snippets of RNA that squelch production of PGC-1 or SIRT1 slashed the output of these genes. Pyruvate hampered genes that encode glucose-splitting enzymes, and the anti-SIRT1 RNA restored their activity. Together, the results suggest that nutrient scarcity prods SIRT1 to collaborate with PGC-1 in the liver, shutting off glucose breakdown and encouraging its production. The connection between SIRT1 and glucose control in response to reduced diets jibes with the idea that the protein influences mouse longevity, says Puigserver.
"It's a really nice insight into how metabolism and life span may be linked together," says molecular biologist Toren Finkel of the National Heart, Lung, and Blood Institute in Bethesda, Maryland. The work "helps define the central regulators of caloric restriction," says Guarente. However, he notes that the findings contradict his group's work, which indicated that SIRT1 suppressed one of the glucose-building genes. To resolve that conflict and understand SIRT1's effects on the metabolism of the entire body, researchers now need to pin down how the protein operates in different tissues, says cell biologist Shin-Ichiro Imai of Washington University in St. Louis, Missouri. Further experiments might reveal whether SIRT1's effect on longevity is sweet.
March 9, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150