title: Reductions in serum IGF-1 during aging impair health span.
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.
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Gong
authors.forename: Oran
authors.initials: O
authors.lastname: Kennedy
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: YingJie
authors.initials: Y
authors.lastname: Wu
authors.forename: Garry A
authors.initials: GA
authors.lastname: Williams
authors.forename: Laura
authors.initials: L
authors.lastname: Klein
authors.forename: Luis
authors.initials: L
authors.lastname: Cardoso
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Matheny
authors.forename: Gene B
authors.initials: GB
authors.lastname: Hubbard
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeno
authors.forename: Roger P
authors.initials: RP
authors.lastname: Farrar
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Schaffler
authors.forename: Martin L
authors.initials: ML
authors.lastname: Adamo
authors.forename: Radhika H
authors.initials: RH
authors.lastname: Muzumdar
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
mesh_terms: D000375:Aging / Q000097:blood / Q000378:metabolism*; D000818:Animals; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D051379:Mice; D023421:Models, Animal; D018384:Oxidative Stress / Q000502:physiology
chemical_list: C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I
keywords: IGF; LID; aging; bone; growth hormone; insulin-sensitivity; lifespan; liver; tumor