Abstract
In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.
Highlights
The role of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in lifespan has been studied in detail along the evolutionary lineage
To understand how reductions in serum IGF-1 levels affect overall lifespan, we used the liver IGF-1-deficient (LID) mouse model, where the Cre recombinase was expressed under the albumin promoter, in the liver (Yakar et al, 1999)
We found that reductions in serum IGF-1 levels in inducible LID (iLID) mice at one year resulted in significant loss of cortical bone
Summary
The role of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in lifespan has been studied in detail along the evolutionary lineage. Disruption of insulin/IGF-like signaling in yeast, worms, and flies has been conclusively shown to increase lifespan. In these lower order species, insulin and IGF-1 axis exists as a single axis. Reductions in IGF-1 associate with higher incidence of diabetes (Barzilai et al, 2012), osteoporosis (Lombardi et al, 2005), dementia, and Alzheimer disease (O’Neill et al, 2012). Decline in GH/IGF-1 axis has been shown to be associated with decreased incidence of tumors (Bartke et al, 2013). Human subjects with mutations in the GHR (Laron dwarfs) who show congenital IGF-1 deficiency do not exhibit increases in lifespan, but show protection from development of malignancies and diabetes when compared to their healthy siblings (Laron, 2005; Guevara-Aguirre et al, 2011)
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