Functionally significant insulin-like growth factor I receptor mutations in centenarians

Yousin Suh*, Gil Atzmon†, Mi-Ook Cho*, David Hwang‡, Bingrong Liu‡, Daniel J. Leahy§, Nir Barzilai†¶, and Pinchas Cohen‡

Suh*, Gil Atzmon†, Mi-Ook Cho*, David Hwang‡, Bingrong Liu‡, Daniel J. Leahy§, Nir Barzilai†¶,

*Departments of Medicine and Molecular Genetics, and †Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY 10461; ‡Mattel Children’s Hospital, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and §Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Edited by Cynthia J. Kenyon, University of California, San Francisco, CA, and approved January 18, 2008 (received for review June 11, 2007)

tance of this regulatory network for exceptional longevity in human populations is uncertain, especially because living to 100 years of age is a rare phenotype in humans with a prevalence of 1 in 10,000 individuals in the general population (9). Even if we adopt the premise that the basic mechanisms that modulate longevity and determine the rate of aging are common to all multicellular organisms, it is possible that the observed effects on longevity of candidate gene variants will prove to be exclusively associated with laboratory strains and may have fitness cost (10, 11). Thus, it remains to be demonstrated whether candidate loci with major effects on longevity in model organisms such as genes involved in the insulin/IGFI pathway will show segregating allelic variation in human populations.

Rather than being a passive, haphazard process of wear and tear, lifespan can be modulated actively by components of the insulin/ insulin-like growth factor I (IGFI) pathway in laboratory animals. Complete or partial loss-of-function mutations in genes encoding components of the insulin/IGFI pathway result in extension of life span in yeasts, worms, flies, and mice. This remarkable conserva- tion throughout evolution suggests that altered signaling in this pathway may also influence human lifespan. On the other hand, evolutionarytradeoffspredictthatthelaboratoryfindingsmaynot be relevant to human populations, because of the high fitness cost during early life. Here, we studied the biochemical, phenotypic, and genetic variations in a cohort of Ashkenazi Jewish centenar- ians, their offspring, and offspring-matched controls and demon- strated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous muta- tions in the IGF1R gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan.

Previous studies in humans have reported on levels of IGFI and related molecules in the oldest old (12); however, interpret- ing these values was difficult because of the lack of adequate controls. To overcome this shortcoming, we established a unique cohort of individuals with exceptional longevity and their off- spring (approximate age 70 years) and age- and sex-matched controls without a family history of unusual longevity; all of Ashkenazi Jewish descent. This group of offspring of individuals with exceptional longevity and their matched controls is a powerful tool for identifying genetically controlled longevity traits and led to the identification of longevity phenotypes such as lipoprotein sizes and the subsequent discovery of correspond- ing longevity genotypes (13, 14). Here, we report the use of this unique cohort to identify partial loss-of-function mutations in the IGF1 receptor (IGF1R) gene that are overrepresented among centenarians compared with controls, suggesting a role for the IGF signaling pathway in human longevity.

he role of reduced insulin/insulin-like growth factor I (IGFI) signaling in lifespan extension is well established in inverte- brates (1). During evolution, the insulin/IGFI pathways have diverged from a single receptor in invertebrates to multiple receptors and more complicated pathways and regulatory net- works in mammals (2). Insulin regulates metabolic pathways, whereas IGFI and growth hormone (GH), the main regulator of circulating IGFI, control growth and differentiation (3). In mice, knockout models of the insulin receptor (IR) pathway have a negative impact on lifespan and age-related diseases (4). In contrast, both spontaneous and targeted genetic disruptions of the GH/IGF pathway are associated with small size (dwarfism), numerous indices of delayed aging, enhanced stress resistance, and a major increase in lifespan (5), suggesting a role for the GH/IGF pathway in murine longevity. Furthermore, caloric restriction, the measure linked to life extension and retardation of aging-related pathology, is also associated with reduced circulating IGFI levels (6). On the other hand, reduced levels of IGFI in humans, while protective against cancer, constitute a risk factor for cardiovascular disease and diabetes (7). Moreover, human aging is associated with a decline in the levels of GH and IGFI, and it has been proposed that GH therapy may reverse some of the physiological features of aging (8). Therefore, at the current time, the role of IGF signaling in human longevity is far from clear.

Results