title: Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span.
abstract: Disruption of the insulin/IGF-I pathway increases life span in invertebrates. However, effects of decreased IGF-I signaling in mammalian models remain controversial. Using a rodent model with a specific and limited deficiency of GH and IGF-I, we report that GH and IGF-I deficiency throughout life [GH deficiency (GHD)] has no effect on life span compared with normal, heterozygous animals. However, treatment of GHD animals with GH from 4-14 wk of age [adult-onset (AO) GHD] increased median and maximal life span by 14% and 12%, respectively. Analysis of end-of-life pathology indicated that deficiency of these hormones decreased tumor incidence in GHD and AO-GHD animals (18 and 30%, respectively) compared with heterozygous animals and decreased the severity of, and eliminated deaths from, chronic nephropathy. Total disease burden was reduced by 24% in GHD and 16% in AO-GHD animals. Interestingly, the incidence of intracranial hemorrhage increased by 154 and 198% in GHD and AO-GHD animals, respectively, compared with heterozygous animals. Deaths from intracranial hemorrhage in AO-GHD animals were delayed by 14 wk accounting for the increased life span compared with GHD animals. The presence of GH and IGF-I was necessary to maximize reproductive fitness and growth of offspring early in life and to maintain cognitive function and prevent cartilage degeneration later in life. The diverse effects of GH and IGF-I are consistent with a model of antagonistic pleiotropy and suggest that, in response to a deficiency of these hormones, increased life span is derived at the risk of functional impairments and tissue degeneration.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157-1083, USA. wsonntag@wfubmc.edu
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.forename: Christy S
authors.initials: CS
authors.lastname: Carter
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeno
authors.forename: Kari
authors.initials: K
authors.lastname: Ekenstedt
authors.forename: Cathy S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Richard F
authors.initials: RF
authors.lastname: Loeser
authors.forename: Shilla
authors.initials: S
authors.lastname: Chakrabarty
authors.forename: Shuko
authors.initials: S
authors.lastname: Lee
authors.forename: Colleen
authors.initials: C
authors.lastname: Bennett
authors.forename: Rhonda
authors.initials: R
authors.lastname: Ingram
authors.forename: Tracy
authors.initials: T
authors.lastname: Moore
authors.forename: Melinda
authors.initials: M
authors.lastname: Ramsey
mesh_terms: D000375:Aging; D000818:Animals; D001823:Body Composition; D001831:Body Temperature; D002940:Circadian Rhythm; D004392:Dwarfism / Q000235:genetics; D013006:Growth Hormone / Q000172:deficiency* / Q000494:pharmacology; D018737:Hand Strength; D006579:Heterozygote; D006720:Homozygote; D007334:Insulin-Like Growth Factor I / Q000172:deficiency*; D008136:Longevity / Q000187:drug effects; D008297:Male; D018782:Maze Learning; D009043:Motor Activity; D009369:Neoplasms / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D012098:Reproduction; D043202:Steroid Metabolism, Inborn Errors / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone