Despite evidence for a substantial genetic component, the inherited biological factors that promote extended life span (longevity) in humans remain unknown. We have comprehensively characterized over 450 Ashkenazi Jewish families with exceptional longevity (survival in good health to at least age 95) and have identified several biological markers that may be causative in their longevity. These subjects and their offspring have 2-3 fold increases in rates of polymorphism in 3 genes all validated by other in other studies. Two genes are regulating lipoprotein--cholesterol ester transfer protein (CETP) and apolipoprotein C-3 (APOC-3)--and decrease in plasma levels CETP and APOC-3. Another gene is Adiponectin (ADIPOQ) regulating insulin action and inflammation. We have also demonstrated that these genotypes and phenotypes are associated with less hypertension (HTN), cardiovascular disease (CVD) and metabolic syndrome (MS), and improved cognitive function. However, these genes have not been shown yet to protect against cancer.

Modulation of GH/IGF-1 axis is conferring longevity in mamalians and low IGF-1 levels is associated with decreased rates of cancers in humans. We demonstrated 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 mutations 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, possibly by protecting against cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED04-02.

Seventh AACR International Conference on Frontiers in Cancer Prevention Research-- Nov 16-19, 2008; Washington, DC