Predisposed to a Long Life?

Abstract

Mutations that disrupt growth hormone production or sensitivity and thereby lead to decreased serum concentrations of insulin-like growth factor 1 (IGF-1) are associated with increased longevity in mice. Furthermore, decreased abundance of the IGF-1 receptor (IGF1R) is associated with increased life span in female mice, and mutations that decrease the activity of components of the insulin/IGF-1 system are associated with increased longevity in invertebrates. The role of IGF-1 signaling in human longevity, however, is less clear. Indeed, growth hormone secretion and serum concentrations of IGF-1 decline with age, and administration of growth hormone (which increases circulating IGF-1) may reverse some physiological correlates of aging. Suh et al . found that the daughters of centenarians had 35% higher serum IGF-1 concentrations than age-matched women of similar ethnic background (Ashkenazi Jews) from families that were not so long-lived. Additionally, the average maximum height attained by the centenarians’ daughters was 2.5 cm less than that of their control group. Sequence analysis revealed no variations in the IGF1 genes of 79 female centenarians who were shorter than the mean height but showed 20 IGF1R sequence variants. Two nonsynonymous heterozygous mutations of IGF1R coding regions were more common in centenarians than in controls and were associated with increased serum IGF1. Immortalized lymphocytes from three centenarians, each carrying a different IGF1R mutation, showed decreased IGF1R abundance compared with lymphocytes from centenarians without IGF1R mutations and decreased phosphorylation of Akt in response to IGF-1. Thus, the authors conclude that human IGF1R mutations that affect IGF signaling may be associated with a predisposition toward long life. Y. Suh, G. Atzmon, M.-O. Cho, D. Hwang, B. Liu, D. J. Leahy, N. Barzilai, P. Cohen, Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl. Acad. Sci. U.S.A. 105 , 3438-3442 (2008). [Abstract] [Full Text]