Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling.
GH/insulin/IGF-1 signaling is a vital pathway e.g. in the regulation of protein synthesis and glucose metabolism. However, mouse dwarf strains which exhibit reduced GH secretion and subsequently a decline in IGF-1 signaling can live longer than their wild type counterparts. There is striking evidence indicating that the IGF-1/PI-3K/AKT signaling enhances growth of animals during development but later in life can potentiate the aging process. This conserved pleiotropy has been called the insulin/IGF-1 paradox. In Caenorhabditiselegans, the decline in this pathway activates the DAF-16 gene, an ortholog of mammalian FoxO genes, which regulate stress resistance and longevity. The mammalian PI-3K/AKT pathway also activates the NF-kappaB signaling that inhibits apoptosis and triggers inflammatory responses. Many longevity genes, e.g. FoxOs and SIRT1, are inhibitors of NF-kappaB signaling. We will discuss the evidence that insulin/IGF-1 signaling can enhance the NF-kappaB signaling and subsequently potentiate the aging process and aggravate age-related degenerative diseases.
Salminen
Antero
A
Department of Neurology, Institute of Clinical Medicine, University of Kuopio, P.O. Box 1627, Kuopio FIN-70211, Finland. antero.salminen@uku.fi
Kaarniranta
Kai
K
D000375:Aging; D000818:Animals; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D007328:Insulin; D016328:NF-kappa B; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase