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Submitted on January 14, 2005
Accepted on March 14, 2005
Departments of Physiology and Pharmacologyand Sticht Center on Aging, Roena Kulynych Center for Memory and Cognition Research, Wake Forest University Health Sciences, Winston-Salem, NC 27012; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX; Research Service, Audie Murphy Veteran's Administration Hospital, San Antonio, TX; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN; Departments of Medicine and Biochemistry, Rush Medical College, Chicago, IL; Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX
* To whom correspondence should be addressed. E-mail: wsonntag{at}wfubmc.edu.
Disruption of the insulin/IGF-1 pathway increases lifespan in invertebrates. However, effects of decreased IGF-1 signaling in mammalian models remain controversial. Using a rodent model with a specific and limited deficiency of growth hormone and IGF-1, we report that growth hormone and IGF-1 deficiency throughout life (GHD) has no effect on lifespan compared with normal, heterozygous animals. However, treatment of growth hormone deficient animals with growth hormone from 4 to 14 weeks of age (AO-GHD) increased median and maximal lifespan 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 weeks accounting for the increased lifespan compared with GHD animals. The presence of growth hormone and IGF-1 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 growth hormone and IGF-1 are consistent with a model of antagonistic pleiotropy and suggest that, in response to a deficiency of these hormones, increased lifespan is derived at the risk of functional impairments and tissue degeneration.
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