Diverse Roles of Growth Hormone and Insulin-Like Growth Factor-1 in Mammalian Aging: Progress and Controversies

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M ORE than three decades have passed since the initial report demonstrating that circulating growth hormone (GH) decreases with age and almost as many years since the reports of the age-related decline in insulin-like growth factor-1 (IGF-1) both in laboratory animals and humans. Despite the 100s of primary studies and numerous reviews related to the importance of adequate levels of circulating GH and IGF-1 for healthy aging, the role of these potent anabolic hormones in the genesis of the aging phenotype remains highly controversial. Initially, the age-related decrease in GH and IGF-1 were considered to contribute to many aspects of aging including, but not limited to, accumulation of fat mass, cardiovascular dysfunction, as well as the decline in immune function, cellular protein synthesis, and muscle mass. Later studies indicated that reduction in levels of these hormones has an important role in the decline in cognitive function and increased risk for neurodegenerative diseases and stroke. Despite the clear evidence that GH/IGF-1 deficiency contributes to specific aspects of aging, subsequent studies revealed that some, but not all, rodent models with impaired GH/IGF-1 signaling exhibit an increased life span. Based on studies initially conducted in invertebrate organisms, such as Caenorhabditis elegans and Drosophila melanogaster, the corresponding data in mutant and transgenic mouse models supported the conclusion that IGF-1 signaling is part of a "conserved mechanism of aging" with decreased levels of GH/IGF-1 delaying, rather than accelerating, the aging process. Thus, two disparate concepts evolved and remain present in the literature (a) that the presence of normal levels of GH and IGF-1 accelerate aging and lack of these hormones or disruption of the signaling pathways governed by these hormones exert antiaging effects and (b) that the age-related decline in GH and IGF-1 contribute to the deterioration of physiological function and replacement of these hormones delay or reverse the aging phenotype.