PAPP-A and Aging

Diverse species with specific mutations in IGF signal transduction have enhanced resistance to oxidative stress and extended life spans. Our overall hypothesis is that the aging process can be regulated by PAPP-A, which degrades inhibitory IGFBP-4, thereby increasing IGF-I bioavailability. The corollary is that PAPP-A-deficiency, by decreasing IGF availability and receptor signaling, would result in increased longevity. Our preliminary data indicate that PAPP-A knock-out mice live 40 percent longer than their wild-type littermates. In this project we are determining the physiological mechanism(s) underlying the life span extension in PAPP-A knock-out mice by critically assessing the contribution of pre-natal programming, metabolism, resistance to oxidative stress, preservation of immune competence, and prevention of tumor growth. We have the models and the technology to enable us to make significant contributions to the understanding of PAPP-A and the IGF system in the fundamental biology of aging, with implications for novel strategies to slow the aging process and enhance longevity.