Keeping up with IGF-I and FOXO

Ever since the discovery that loss-of-function daf-2 mutations extend lifespan in C. elegans (a phenotype for which the forkhead-like transcription factor daf-16 is required), biogerontologists have devoted a tremendous amount of attention to the pathway, both in worm and in mammal (where DAF-2 and DAF-16 have homologs: insulin-like growth factor receptor (IGF-I-R) and various FOXO proteins, respectively).

As I mentioned yesterday, this week I’m clearing the backlog of articles that has accumulated over the past couple of months. Lots has been happening on the IGF/FOXO front. As always, each of these papers probably deserves its own post, but time is not permitting. Quoted passages are excerpts from the abstracts.

Low IGF-I decreases cancer: Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Low Circulating Insulin-Like Growth Factor I Levels, Moore et al.:

These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

Downregulating IGF-I enhances stress tolerance: Cellular conditioning with trichostatin A enhances the anti-stress response through up-regulation of HDAC4 and down-regulation of the IGF/Akt pathway, Chu et al.:

Interestingly, the insulin signaling pathway mediated by Akt was inhibited in the TSA-resistant cells, mirroring the effect of glucose deprivation on this pathway. … Together, these findings suggest that cellular conditioning with TSA may represent a useful approach to mimic the effects of caloric restriction.

Inflammation: Regulation of IGF-I function by proinflammatory cytokines: At the interface of immunology and endocrinology, O’Connor et al.:

Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-1β, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I).

Gonadal regulation: Drosophila germ-line modulation of insulin signaling and lifespan, Flatt et al.:

Here we report that eliminating germ cells (GCs) in Drosophila melanogaster increases lifespan and modulates insulin signaling. … These results suggest that signals from the gonad regulate lifespan and modulate insulin sensitivity in the fly and that the gonadal regulation of aging is evolutionarily conserved.

Target genes: Identification of Direct Target Genes Using Joint Sequence and Expression Likelihood with Application to DAF-16, Yu et al.:

We found that 189 genes were tightly regulated by DAF-16. In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification.

Stem cells: FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System, Tothova and Gilliland:

… FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems.

As therapeutic targets: OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins, Malese et al.:

Forkhead transcription factors have a ‘winged helix’ domain and regulate processes that range from cell longevity to cell death. … Here we discuss recent advances that have elucidated the unique cellular pathways and clinical potential of targeting FoxO proteins to develop novel therapeutic strategies and avert potential pitfalls that might be closely intertwined with its benefits for patient care.

There’s plenty to chew on. Tomorrow: telomeres.