Abstract
Diminished growth hormone/ insulin–like growth factor-1 (GH/IGF-1) signaling extends lifespan. In humans, low IGF-1 is also linked to less cancer risk while mutations associated with less GH/IGF-1 signaling are enriched in centenarians. Paradoxically, low IGF-1 in humans is associated with increased risk for cardiovascular disease, type 2 diabetes, osteoporosis and frailty in some studies, suggesting that strategies designed to modulate this axis will need to be ‘fine tuned’ to promote successful aging in humans. We have recently reported that targeting the IGF-1 pathway with an IGF-1R mAb improves health and lifespan in female mice, even though treatment was not initiated until relatively later in life. While male mice largely failed to benefit from this treatment, mAb-treated female mice lived 9% longer, had more youthful cardiac function, exercise tolerance, grip strength, and motor coordination, and developed less cancer. This suggests that IGF-1Rs are a viable drug target that can be modulated to extend healthy lifespan. It also suggests that IGF-1R mAbs represent a feasible class of drug to ‘fine tune’ this pathway, which could be leveraged and optimized for use in women to improve health, even at older ages. Future efforts should be aimed at determining the possibility of harnessing these drugs to target human aging. Furthermore, the consistent observation of sex differences in this pathway continues to perplex the field. Therefore, it will be important to establish what is unique to females that confers a beneficial response to low IGF-1, and if these drugs can eventually be optimized to work in males.