The antagonistic pleiotropy of insulin‐like growth factor 1

Abstract

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.

Abstract

Using a large dataset from the UK Biobank, we show that serum IGF‐1 is associated with risk for mortality and age‐associated morbidity in a manner consistent with antagonistic pleiotropy. While the risk associated with IGF‐1 is U‐shaped at all ages studied, the risk associated with high IGF‐1 increases with age, and the risk associated with low IGF‐1 decreases with age, suggesting that higher serum IGF‐1 may be beneficial in youth but harmful in older age.