Institute for Aging Research

IGF-1 and Insulin Signaling Pathways in Aging

During evolution, the insulin/IGF1 pathways have diverged from a single receptor in invertebrates to multiple receptors and more complicated pathways and regulatory networks in mammals. IGF-1 binding proteins are important is regulation of the IGF-1 axis that also regulates peripheral glucose metabolism28 and body fat distribution (Cohen, Muzumdar, Barzilai).

Those studies coincide with the cloning of humanin (HN), a mitochondrially derived peptide that decreases with aging and binds IGF-1BP3 (Cohen). HN regulates peripheral glucose metabolism through central29 and peripheral (in ß cell) mechanisms (Muzumdar, Barzilai, Cohen). Of particular interest is IGF-1 signaling in aging brain that is important for cognitive30 and numerous other functions (Etgen), including in control of female reproductive aging (Neal-Perry)31,32. IGF-133 and insulin induce inflammation and cancer (Yakar), while insulin resistance/hyperinsulinemia34 causes tumorigenesis in aging rodents (LeRoith). Mechanistically, insulin receptor transmembrane downstream intracellular signaling pathways are impaired with aging (Pessin), and in addition to insulin, serotonin, also modulates FOXO35 with aging (Sze). Human genetic studies have led to identification of novel functional mutation36 in the IGF-1 receptor (Suh, Cohen, and Barzilai), and the search for additional mutations in the GH/IGF-1 signaling pathway and longevity, and also in FOXO3 gene37 and its function (Brunet).  Collection of IGF-1/insulin phenotype and DNA from Ashkenazi Jews (Rajpathak) and Hispanics (Kaplan) in the Bronx will lead to elucidation of genomic mechanism38,39 controlling the GH/IGF-1 system.

  1. Muzumdar, R. H., Huffman, D. M., Atzmon, G., Buettner, C., Cobb, L. J., Fishman, S. et al. Humanin: a novel central regulator of peripheral insulin action. PLoS ONE 4, 7:e6334, doi:10.1371/journal.pone.0006334 (2009).
  2. Traub, M. L., De Butte-Smith, M., Suzanne Zukin, R. & Etgen, A. M. Oestradiol and IGF1 reduce cell loss after global ischemia in middle-aged female rats. J Neuroendocrinol, doi:JNE1927 [pii]10.1111/j.1365-2826.2009.01927.x (2009).
  3. Todd, B. J., Fraley, G. S., Peck, A. C., Schwartz, G. J. & Etgen, A. M. Central insulin-like growth factor 1 receptors play distinct roles in the control of reproduction, food intake, and body weight in female rats. Biol Reprod 77, 3:492-503, doi:biolreprod.107.060434 [pii]10.1095/biolreprod.107.060434 [doi] (2007).
  4. Neal-Perry, G. S., Zeevalk, G. D., Shu, J. & Etgen, A. M. Restoration of the luteinizing hormone surge in middle-aged female rats by altering the balance of GABA and glutamate transmission in the medial preoptic area. Biol Reprod 79, 5:878-888, doi:biolreprod.108.069831 [pii]10.1095/biolreprod.108.069831 (2008).
  5. Olivo-Marston, S. E., Hursting, S. D., Lavigne, J., Perkins, S. N., Maarouf, R. S., Yakar, S. et al. Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice. Mol Carcinog, doi:10.1002/mc.20577 (2009).
  6. Yakar, S., Nunez, N. P., Pennisi, P., Brodt, P., Sun, H., Fallavollita, L. et al. Increased tumor growth in mice with diet-induced obesity: impact of ovarian hormones. Endocrinology 147, 12:5826-5834, doi:en.2006-0311 [pii]10.1210/en.2006-0311 (2006).
  7. Kim, N., Dempsey, C. M., Kuan, C. J., Zoval, J. V., O'Rourke, E., Ruvkun, G. et al. Gravity force transduced by the MEC-4/MEC-10 DEG/ENaC channel modulates DAF-16/FoxO activity in Caenorhabditis elegans. Genetics 177, 2:835-845, doi:genetics.107.076901 [pii]10.1534/genetics.107.076901 [doi] (2007).
  8. Suh, Y., Atzmon, G., Cho, M. O., Hwang, D., Liu, B., Leahy, D. J. et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 105, 9:3438-3442, doi:0705467105 [pii]10.1073/pnas.0705467105 (2008).
  9. Tran, H., Brunet, A., Grenier, J. M., Datta, S. R., Fornace, A. J., Jr., DiStefano, P. S. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 5567:530-534, doi:10.1126/science.1068712296/5567/530 [pii] (2002).
  10. Rajpathak, S. N., McGinn, A. P., Strickler, H. D., Rohan, T. E., Pollak, M., Cappola, A. R. et al. Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults. Growth Horm IGF Res 18, 2:166-173, doi:S1096-6374(07)00113-X [pii]10.1016/j.ghir.2007.08.004 (2008).
  11. Kaplan, R. C., Fitzpatrick, A. L., Pollak, M. N., Gardner, J. P., Jenny, N. S., McGinn, A. P. et al. Insulin-Like Growth Factors and Leukocyte Telomere Length: The Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci, doi:glp036 [pii]10.1093/gerona/glp036 [doi] (2009).



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