Sci. Aging Knowl. Environ., 11 December 2002
Long Life Starts Early
Worms gain time by cutting energy production as larvae
Key Words: electron transport ATP synthase cyc-1 nuo-2 dcr-1 pumping rate
Children know that drinking milk boosts bone strength decades later, and worm youngsters might consider thinking ahead as well. During larval development, but not adulthood, disrupting the pathway that converts food into useable energy prolongs a nematode's life, according to new work. The results extend preliminary work (see "Youthful Restraint") by suggesting that this life-extending process acts independently of a well-studied hormonal system that also governs worm longevity.
Numerous studies have identified worm genes involved in aging, but technological limitations have prevented researchers from screening large numbers of genes. A new method allows researchers to create a collection of nematodes, each with a reduced amount of a specific protein, and identify unusually long-lived worms. In this RNA interference (RNAi) procedure, researchers feed the worms bacteria loaded with double-stranded RNA, which smothers specific messenger RNAs and prevents them from making protein.
Using RNAi, Cynthia Kenyon, a molecular geneticist at the University of California, San Francisco, and colleagues determined which genes on chromosome 1 influence aging. Curbing production of three components of the respiratory chain--which help convert food into ATP--extended life-span but produced small animals that ate and defecated sluggishly. "We're hitting the respiratory chain in different ways," says Kenyon, yet all of the mutants behave similarly and live extra-long. "It's not just a quirk of one of these guys."
Defective versions of a gene called daf-2 can double a worm's life-span, provided a second gene, daf-16, is operational (see "Stay Mellow, Stay Young"). To test whether daf-2 and the energy conversion machinery act in the same pathway, the researchers suppressed the respiratory chain genes in worms that carried mutated daf-2 or daf-16. The animals lived about three times longer than daf-2-defective nematodes. The additive effect demonstrates that the pathways function independently, Kenyon says.
Kenyon previously demonstrated that decreasing daf-2 activity in adult worms, but not larvae, defers death (see Sonntag and Ramsey Perspective). To determine whether the new results also depend on timing, the researchers conducted RNAi experiments at different developmental stages. When they suppressed the respiratory chain component cco-1 during the larval phase, then let mRNA quantities recover during adulthood, worms still lived unusually long. Conversely, worms with normal rations of cco-1 as larvae, but reduced quantities as young adults, did not gain time, even though ATP concentrations dropped, indicating that the investigators had disrupted respiratory chain activity. "It's a nice demonstration that it's what you've done in development that counts," says Siegfried Hekimi, a molecular geneticist at McGill University in Montreal, Canada. He cautions, however, that the respiratory chain might not be directly responsible for prolonging life, as energy deprivation during larval development could cause multiple unseen defects.
Respiratory chain components also cropped up in a similar gene hunt by a different group (see Melov Perspective). Because almost all the genes identified in the two screens impair ATP production, Hekimi suggests that reducing energy output "is one of the major ways by which one can increase life-span." So young worms take note: Producing less energy as a larva might yield more time to use it as an adult.
A. Dillin, A.-L. Hsu, N. Arantes-Oliveira, J. Lehrer-Graiwer, H. Hsin, A. Fraser, R. Kamath, J. Ahringer, C. Kenyon, Rates of behavior and aging specified by mitochondrial function during development. Science Express, 5 December 2002 [e-pub ahead of print]. [Abstract/PDF]
December 11, 2002 Citation: K. Ramsayer, Long Life Starts Early. Science's SAGE KE (11 December 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/49/nw163
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