Sci. Aging Knowl. Environ., 30 March 2005
Vol. 2005, Issue 13, p. nf24
[DOI: 10.1126/sageke.2005.13.nf24]


Feeling Spunky With JNK

Protein funnels stress signals into insulin pathway and extends life

R. John Davenport

Only a masochist would choose a life of stress and starvation, yet organisms can last unusually long if they exploit molecular pathways that respond to these pressures. Now, scientists reveal how one molecule connects two such pathways and lengthens the lives of worms and flies. The protein is linked to diabetes in mammals, suggesting that what benefits invertebrates might not be good for humans. Researchers need to probe deeper to understand how it shapes mammalian longevity, experts say.

When nutrients are abundant, the insulin and insulin-like growth factor 1 signaling pathways in mammals spur cells to absorb sugar and grow. During lean times, the pathways shut down, and cells enter survival mode. Blocking an analogous pathway in flies and worms extends longevity. The long-lived animals are often better at resisting stresses such as oxidizing chemicals. Two years ago, geneticist Heinrich Jasper of the University of Rochester in New York and colleagues found that an extra shot of a protein called JNK fortifies flies against oxidative stress and prolongs survival. Now, two teams of researchers have investigated how JNK influences insulin-related signaling.

Geneticist Heidi Tissenbaum of the University of Massachusetts Medical School in Worcester and colleagues investigated JNK's contribution to nematode life span. Upping JNK production extended worm life by 40%, they found. Blunting insulin-related signaling switches on a gene-control protein called FOXO. The researchers discovered that worms with extra JNK but no functioning FOXO did not live long, suggesting that the two proteins collaborate. Similarly, flies with hyperactive JNK only live long if they tote a full dose of FOXO, Jasper's team found in a separate study. Further experiments by Tissenbaum's team bolster the connection: FOXO clings to JNK in cultured cells engineered to produce both proteins.

FOXO switches on when it receives a phosphate group, which pushes the protein into the cell's nucleus. Jasper's team observed that sparking fly insulin-like signaling restrained FOXO in the cytoplasm. But upon activation of JNK, cells trucked FOXO to the nucleus. Similarly, Tissenbaum and colleagues found that nuclei contained more of the protein when worms also carried extra JNK. In addition, her group reported that JNK stitches a phosphate onto FOXO in a test tube. Together, the results suggest that JNK delays aging by activating FOXO.

The direct connection between JNK and FOXO is surprising, says diabetes researcher Morris White of Harvard University. Diabetes researchers have investigated the JNK-insulin link and found that JNK squelches insulin signaling, but it does so by inactivating components of the pathway other than FOXO. However, there are some hints that the new findings will hold true in mammals. In November 2004, cell-signaling researcher Boudewijn Burgering of the University of Utrecht in the Netherlands and colleagues reported that when mammalian cells are exposed to oxidants, JNK phosphorylates a FOXO protein. The two new papers "provide the genetic data for our biochemical analysis," says Burgering, making "quite a compelling case" that the proteins work together. Whether JNK promotes long life in mammals is unclear. Nixing JNK fends off diabetes, says White, but vigorous JNK might protect certain tissues. For instance, the protein might render muscle or fat insensitive to insulin, but it might stifle insulin production in the pancreas, which can damage the organ if left unchecked. Clarifying JNK's contribution to human aging might reveal a stress-free way for us to ride to long life.

March 30, 2005
  1. M. A. Essers et al., FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 23, 4802-4812 (2004). doi:10.1038/sj.emboj.7600476 [CrossRef][Medline]
  2. S. W. Oh et al., JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl. Acad. Sci. U.S.A. 102, 4494-4499 (2005). doi: 10.1073/pnas.0500749102 [Abstract/Free Full Text]
  3. M. C. Wang, D. Bohmann, H. Jasper, JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell, 24 March 2005 [e-pub ahead of print]. [Abstract] [PDF] doi:10.1016/S0092867405001972
Citation: R. J. Davenport, Feeling Spunky With JNK. Sci. Aging Knowl. Environ. 2005 (13), nf24 (2005).

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