Table of Contents 21-3

JNK vs Insulin/IGF Signaling: Mediating the Effects of Stress and Nutrition on Longevity

Insulin/IGF signaling (IIS) promotes growth and energy storage when nutrients are abundant, but the life span of different eukaryotic organisms (mice, Drosophila, C. elegans) is actually increased when IIS is reduced by calorie restriction or by mutations in its pathway components. It seems that resistance to oxidative stress underlies this paradox. Environmental insults such as UV irradiation and oxidative stress activate, among other molecules, Jun-N-terminal kinase (JNK), a component of mitogen-activated protein kinase (MAPK) cascade, that induces a protective gene expression profile and thereby confers tolerance to oxidative stress and prolongs life span.

Wang and colleagues studied the opposing effects of IIS and JNK on oxidative stress tolerance and longevity in Drosophila. The Drosophila genome contains 7 insulin-like peptides, of which dilp2 most closely resembles human insulin. Dilp2 is secreted by insulin-producing cells (IPC) that form a small cluster of neuroendocrine cells in the fly brain. Specific elimination of IPCs leads to growth retardation, developmental delays, and decreased late-life mortality. Similar to humans, Drosophila IIS leads to activation of PI3 kinase and Akt, which in turn phosphorylates the Forkhead transcription factor, causing its cytoplasmic retention and down-regulation of its target genes. The Drosophila Forkhead transcription factor DFoxo extends lifespan when over-expressed.

The authors provided evidence that DFoxo is required for JNK-mediated life span extension in Drosophila. Further, JNK signaling affected DFoxo function as shown by modulation of DFoxo-dependent phenotypes in eye development and expression of the DFoxo target genes thor (a translational repressor that suppresses growth when IIS is inactive) and l(2)efl (a small heat shock protein that enhances survival of cells exposed to oxidative damage). Finally, the authors found that JNK and DFoxo restrict IIS systemically by repressing dilp2 expression in IPCs. When JNK activity was specifically increased in the IPCs only, there was a DFoxo-dependent decrease in body size and increase in life span. Thus, the JNK-DFoxo effects on aging and lifespan occur at 2 levels. In peripheral tissues, JNK activates DFoxo to prevent senescence cell-autonomously through expression of genes protective against oxidative damage (eg, preventing age-related declines in cardiac or neurologic function). JNK activation of DFoxo in IPCs represses dilp2 expression, thereby decreasing IIS systemically and coordinating cellular responses to environmental changes, which impacts the life span of the organism as a whole.

Wang MC, Bohmann D, Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell. 2005;121:115−125.

Editor’s Comment: In this intriguing paper, the authors made a strong case for Foxo being the convergence point of the opposing effects of IIS and JNK activity on longevity and stress response in Drosophila. They speculated whether Foxo homologs may play a similar role in mammals, and they cited prior evidence that JNK can inhibit IIS by phosphorylating and inhibiting the insulin receptor substrate.^1,2

Another unmentioned convergence point in mammals is the tumor suppressor, p53. Inactive JNK binds the N-terminus of p53, leading to p53 ubiquitination and degradation; this is one of the principal mechanisms by which the tumor suppressor is kept at very low concentrations under normal circumstances. However, when JNK is activated by radiation or oxidative stress, it phosphorylates p53 on threonine 81, thereby activating it.³ By repressing transcription of IGF-II and the IGF receptor while activating transcription of IGF binding protein (IGFBP)-3, p53 directly inhibits IGF signaling.⁴ As well, p53 has been implicated in issues of senescence, longevity, and responses to nutrition and stress. Mice harboring a carboxy-terminus p53 fragment that augments activity of the wild-type p53 allele displayed enhanced resistance to spontaneous tumors, but early onset of aging phenotypes, including osteoporosis, lordokyphosis, generalized organ atrophy, decreased stress tolerance and reduced longevity.⁵

Adda Grimberg, MD

References - (linked to )

1. Wang MC, Bohmann D, Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell. 2005;121:115-125.
2. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420:333–336.
3. Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem. 2003;278: 2896–2902.
4. Pluquet O, Hainaut P. Genotoxic and non-genotoxic pathways of p53 induction. Cancer Lett. 2001;174:1-15.
5. Grimberg A. p53 and IGFBP-3: Apoptosis and Cancer Protection. Molec Genet Metab. 2000;70:85-98.
6. Tyner SD, Venkatachalam S, Choi J, et al. p53 mutant mice that display early ageing-associated phenotypes. Nature. 2002;415:45-53.