Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse.
Document Type
Article
Publication Date
2002
First Page
1245
Last Page
1255
JAX Location
see Journal Collection
JAX Source
Mech Ageing Dev 2002 May; 123(9):1245-55.
Abstract
Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell dwarf (Pit1(dw)/Pit1(dw)) mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the dwarf mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85alpha to IRS-2; (c) docking of p85alpha to p110alpha or p110beta, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRbeta-IRS-1-PI3K pathway is attenuated in the Snell dwarf mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InRbeta and the docking of p85alpha to IRS-1 are attenuated in the aged Snell dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell dwarf mouse and conforms to the nematode longevity paradigm.
Recommended Citation
Hsieh CC,
DeFord JH,
Flurkey K,
Harrison DE,
Papaconstantinou J.
Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse. Mech Ageing Dev 2002 May; 123(9):1245-55.