Sci. Aging Knowl. Environ., 14 April 2004
Vol. 2004, Issue 15, p. nf40
[DOI: 10.1126/sageke.2004.15.nf40]


Fork in the Road

Separate branches in insulin-related signaling pathway control worm hibernation and life span

R. John Davenport

A protein signal takes an unexpected detour to influence worm life span, new work reveals. The study uncovers a crucial protein that separates an insulin-like pathway's effects on longevity and hibernation.

Glitches in insulin-related signaling extend the lives of worms, flies, and rodents (see "Lasting Without Fasting" and "One for All"). In worms, the pathway--headed by a cell surface protein called DAF-2 that presumably binds an insulin-like hormone--senses the presence of food and fires signals that spur growth and reproduction; when nutrients are scarce, the circuit shuts down, quenching growth and promoting survival. Scientists can simulate starvation by engineering genetic defects in the DAF-2 pathway; these perturbations push young worms into a hibernation state called dauer and promote longevity in adults. Researchers are defining the molecules in the DAF-2 pathway that influence life span. DAF-2 prods two proteins--Akt1 and Akt2--that shut off a protein called DAF-16. Disabling DAF-16 halts the life-extending effect of DAF-2 snafus, but blocking either Akt molecule does not completely shut down DAF-2 signaling, suggesting that other molecules connect DAF-2 to DAF-16. A protein called SGK quells the mammalian counterpart of DAF-16, so geneticist Ralf Baumeister of the University of Freiburg in Germany and colleagues investigated whether the worm version of SGK fits into the life-span pathway.

When the researchers blocked production of SGK, the animals laid few eggs and matured slowly, as do worms with daf-2 mutations; this observation hints that the protein operates in the DAF-2 pathway. A higher percentage of worms went into the dauer state when both Akt proteins were blocked than when SGK was blocked, suggesting that the Akt proteins bear primary responsibility for sending worms into hibernation.

Next, the scientists found that quelling SGK extended worm life span by 63%. Blocking either Akt protein did not alter survival; in addition, worms in which Akt1, Akt2, and SGK activity was blunted did not outlast worms lacking SGK alone. Long-lived worms with hiccups in insulin-like signaling resist chemical and heat stress unusually well, but the researchers found that animals with malfunctions in Akt1 or Akt2 did not. In addition, SGK mutants tolerated large amounts of oxidative stress. Furthermore, a daf-16 mutant blocked the increase in stress resistance, supporting the idea that SGK works through daf-16. Together the results suggest that SGK--but not Akt--shepherds the aging signal from DAF-2 to DAF-16.

"The data are really rather convincing," says worm-aging researcher Jacques Vanfleteren of Ghent University in Belgium. "The crucial finding is that SGK and Akt[-1 and -2] have different functions--Akt on dauer and SGK on life span. The question is, how can they produce the different outcomes?" Baumeister posits that SGK puts phosphate groups on DAF-16 in different places than do Akt1 and Akt2 and that the different pattern spurs distinct cellular responses. Other unidentified proteins might also influence which branch of the insulin-like pathway fires, he says. Exploring these new avenues should help map out an understanding of worm aging.

April 14, 2004
  1. M. Hertweck, C. Göbel, R. Baumeister, C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev. Cell 6, 577-588 (2004). [CrossRef][Medline]
Citation: R. J. Davenport, Fork in the Road. Sci. Aging Knowl. Environ. 2004 (15), nf40 (2004).

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