Sci. Aging Knowl. Environ., 11 August 2004
Vol. 2004, Issue 32, p. nf74
[DOI: 10.1126/sageke.2004.32.nf74]


Eating Yourself to Life

Signaling mechanisms that delay death induce starvation response in fruit flies

John Davenport

Hungry flies sometimes recycle their own cells, and new studies unearth some of the molecular intricacies behind this self-consuming tendency. Cellular cannibalism--called autophagy--slows with age in mammals, and the findings might help researchers gauge its contribution to decrepitude.

Nutrient scarcity prompts many organisms to devour portions of their own cells. The creatures wall off parts of a cell's interior and digest the contents for emergency fuel. Autophagy might also help creatures reach old age. Mammals use the process to trash damaged molecules that apparently spur aging, and autophagy slows in cells from older animals (see "Picky Eater"). Moreover, defects in the protein TOR, which normally quells autophagy, extend worm and fly longevity (see "More Without TOR" and Cuervo Perspective). Quashing the insulin-related signaling pathway similarly prolongs life and stimulates autophagy, but scientists weren't sure how the regulators intertwined.

Two teams investigated how autophagy supplies a Drosophila maggot with fuel by dissolving the fat body, a liverlike organ. Geneticist Thomas Neufeld of the University of Minnesota, Twin Cities, and colleagues bred larvae with mutations that alter autophagy and then starved or fed the maggots. The researchers found that glitches in the genes for TOR or PI3K, part of the insulin-related signaling pathway, spurred self-consumption in the fat body even when the larvae were full. Boosting PI3K activity or overproducing a protein that goads TOR dampened autophagy in starved maggots. But the PI3K surplus didn't work when TOR was missing, suggesting that PI3K activates TOR.

Some findings hint that autophagy stunts cell growth. For instance, TOR mutants grow slowly. And in cancer cells, which divide vigorously, autophagy lags. To probe connections between cellular reproduction and self-consumption, the team blocked an autophagy gene in flies that lack TOR. If the absence of TOR hinders growth by inducing autophagy, crippling both genes should restore normal fly development. But these larvae were even smaller than TOR-only mutants, suggesting that the protein's absence doesn't retard cell division by inducing autophagy. Instead, Neufeld proposes, autophagy might kick in to help cells survive when they turn sluggish from an absence of TOR.

In the second study, Rusten and colleagues found that PI3K quashes autophagy during a particular larval stage. They also discovered that blocking ecdysone, a hormone that spurs larvae to mature, cripples autophagy. Simultaneously inhibiting PI3K restored fat-body breakdown, suggesting that ecdysone works through PI3K.

Previous studies in mammalian cells suggest a role for PI3K in autophagy, but until now, that idea "hadn't been tested in a rigorous genetic manner," says autophagy researcher Beth Levine of the University of Texas Southwestern Medical Center in Dallas. The work helps strengthen connections between autophagy and signaling mechanisms that influence aging, she adds. Cell biologist Ana Maria Cuervo of Albert Einstein College of Medicine in New York City praises the studies' whole-animal approach. "For the last 10 years, it's been all about the yeast," says Cuervo, but the single-celled fungus might not reveal how autophagy works in multicellular organisms. Future studies in such creatures might help scientists understand how communication between cells tweaks autophagy, she says. That approach might reveal how a predilection for eating in enhances longevity.

August 11, 2004
  1. T. E. Rusten et al., Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev. Cell 7, 179-192 (2004). [CrossRef][Medline]
  2. R. C. Scott, O. Shuldiner, T. P. Neufeld, Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167-178 (2004). [CrossRef][Medline]
Citation: J. Davenport, Eating Yourself to Life. Sci. Aging Knowl. Environ. 2004 (32), nf74 (2004).

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