Sci. Aging Knowl. Environ., 7 April 2004
More Without TOR
Inhibiting nutrient sensor extends life span in fruit flies
Scarfing pizzas wouldn't shorten a person's life if the body didn't notice the extra intake. Similarly, flies can eat rich food and not die early if a nutrient-sensing gadget is turned down, according to a new study. Quelling a protein that detects an abundance of food delays fly death, the work shows. The result suggests a potential mechanistic connection between decreased insulin-like signaling and calorie restriction, two manipulations that increase life span.
A protein called TOR senses amino acids to determine nutrient availability in species ranging from bacteria to mammals. If TOR finds an abundance of amino acids, cells are allowed to grow. If not, they prepare for starvation. Last December, researchers found that worms with reduced amounts of TOR live about twice as long as normal. Additional genetic experiments suggest that insulin-like signaling, the dampening of which prolongs life in many species (see "One for All"), controls the TOR nutrient-sensing pathway. Some researchers think that insulin-like signaling extends life span by reducing oxidative damage (see "Turning a Daf Ear to Stress" and Johnson Review). The experiments in worms revealed that TOR operates in a separate branch of the insulin-signaling pathway from the one that protects against oxidative damage.
To find out whether TOR's influence on life span extends beyond worms, biogerontologist Pankaj Kapahi and colleagues at the California Institute of Technology in Pasadena investigated whether TOR controls longevity in flies. They overproduced two proteins--Tsc1 and Tsc2--that foil TOR's activity. Flies that churned out either of these molecules lived 14% and 12% longer than normal, respectively. The team then overproduced Tsc2 in different tissues to determine which were responsible for life extension and found that deluging fat alone increased longevity by 22% to 31%.
Because of TOR's role in nutrient sensing, the researchers wondered whether the protein's longevity effects depend on what flies eat. Unaltered insects that consumed food packed with protein lived about one-third as long as those that consumed the usual fare, but flies producing supplemental Tsc2 could indulge themselves and live about two-thirds as long as Tsc2-supplemented flies fed normally. This result suggests that inhibiting TOR protects the insects from the ravages of gluttony, says Kapahi, perhaps by mimicking some molecular aspects of calorie restriction (see Masoro Review and "Common Ingredients").
The work doesn't distinguish whether diminished TOR makes flies eat less or tricks their well-fed bodies into behaving as if that's what's happening (see "Dietary Drawbacks"). But it suggests that the ability to detect nutrients influences life span, and it strengthens an alternative to the notion that insulin-like signaling acts through oxidative damage to adjust longevity, says geneticist Bruce Edgar of the Fred Hutchinson Cancer Research Center in Seattle, Washington. Molecular geneticist Leonard Guarente of Massachusetts Institute of Technology in Cambridge points out that the experiments don't directly address the connection between nutrient sensing and calorie restriction. But Guarente says he's excited that the fly work and the earlier worm study bring a new pathway into the longevity puzzle. Perhaps this pathway will help lead researchers to new slices of life-extending insights.
April 7, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150