The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH-deficiency (GHD) or GH-resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH-R mutations, combined deficiency of GH, PRL, and TSH, or global deletion of GH receptors live longer than their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, due to a mutation of the GHRHR gene, in the Itabaianinha County, Brazil, provide unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty, but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years in one case. We believe that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved, may account for the normal longevity and apparent extension of healthspan in these individuals.