Sci. Aging Knowl. Environ., 19 November 2003
Vol. 2003, Issue 46, p. nw157
[DOI: 10.1126/sageke.2003.46.nw157]


Visceral Reaction

A nematode's intestine, not just its neurons, dictates its aging rate

Mitch Leslie;2003/46/nw157

Key Words: GFP • AB blastomere • dauer

When it comes to aging, nematodes listen to their gut as well as their head, according to new work. The study indicates that the intestine helps determine how fast the animal grows old, adding a new twist to previous work that implicated the worm's neurons.

In nematodes, disabling the daf-2 gene, the first link in the insulin-related signaling pathway, doubles life span. Several studies have suggested that daf-2's activity in nerve cells alone guides aging in the whole animal. For example, in 2000 geneticist Catherine Wolkow of Harvard Medical School in Boston and colleagues genetically altered daf-2 mutant worms so that they made DAF-2 exclusively in neurons, muscles, or intestine. Only neuron-produced DAF-2 shrank life span to normal. Similarly, molecular geneticist Cynthia Kenyon's lab at the University of California, San Francisco, found that a worm missing daf-2 in a handful of neurons--and nowhere else--was long-lived. Daf-2-lacking worms gain no time unless they also carry a working version of a gene called daf-16, which DAF-2 normally muzzles. In some long-lived strains, the DAF-16 protein accumulates particularly in intestinal cells, so Kenyon and colleagues wondered whether the intestine also influences aging rate.

To find out, the researchers hitched daf-16 to a genetic switch that activates the gene in specific tissues, then slipped the manipulated DNA into worms without functional copies of daf-2 and daf-16. When the investigators flipped on the gene only in muscle, the animals lived no longer than controls. Rousing daf-16 in neurons hiked life span up to 20% over controls, and turning it on in the intestine increased longevity by 50% to 60%. This result suggests that in aging at least, the gut trumps the head. To investigate whether daf-16 communicates with cells far from where it's made, the researchers measured its ability to spur production of an antioxidant protein called SOD-3, whose only known trigger is DAF-16. They used the same genetic switches to activate daf-16 in particular tissues. In worms that lacked working daf-2 and daf-16, turning on daf-16 in the intestine spurred SOD-3 output only in that organ. Then the researchers tried the experiment in worms that carried functional daf-2 and daf-16. Switching on daf-16 in the intestine increased sod-3 activity not only there but in the skin and muscles. Similarly, cranking up daf-16 in the neurons turned up sod-3 in other tissues. "The coolest part is that daf-16 controls signals that can activate daf-16 in other cells ... to extend life span," says Kenyon.

"I think it's a terrific paper," says geneticist Thomas Johnson of the University of Colorado, Boulder. It's not surprising that the intestine is so influential, he says. It exudes hormones and provides the raw materials so that a worm can pump out its weight in eggs every 2 hours. Kenyon says "it's difficult to reconcile" her results with the previous work; given that daf-2 acts through daf-16, those observations indicated that neurons, not intestinal cells, control aging. But Wolkow, who is now at the National Institute on Aging in Bethesda, Maryland, says, "I think we're missing pieces of the pathway." Filling in these gaps might help researchers capitalize on the discovery that aging in worms is more than a head trip.

--Mitch Leslie

November 19, 2003
  1. N. Libina, J. R. Berman, C. Kenyon, Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489-502 (2003). Suggested by Greg Liszt. [Abstract] [Full Text][CrossRef][Medline]
Citation: M. Leslie, Visceral Reaction. Sci. Aging Knowl. Environ. 2003 (46), nw157 (2003).

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