The antagonistic pleiotropy of insulin-like growth factor 1

While insulin-like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF-1 levels and clinical disease. We examined prospective associations of serum IGF-1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns: First, IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF-1 are protected from disease, while older individuals with high IGF-1 are at increased risk for incident disease or death. Second, the association between IGF-1 and risk is generally U-shaped, indicating that both high and low levels of IGF-1 may be detrimental. With the exception of a more uniformly positive relationship between IGF-1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age-associated diseases. These data suggest that IGF-1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.