Sexual maturation is key to the evolutionary success of an organism. Evolutionary hypotheses predict that slower but fully functional female reproduction indicates slower aging and associates with extended lifespan. In humans, the age at menarche (AAM) is associated with significant health conditions later in life, and at least half the variation in AAM is determined by genetic factors that are not yet fully understood. Recently, we systematically measured age of female sexual maturation (FSM) in 32 mouse strains. The age of FSM varied dramatically among these strains, and delayed FSM correlated with lower circulating insulin like growth factor 1 (IGF1) and extended longevity. Some strains, however, had delayed FSM but higher IGF1, showing that circulating IGF1 dependent and independent mechanisms are involved. To identify the underlying genetic mechanisms, we generated 7 mouse crosses from 15 inbred strains that broadly represent the genetic diversity and variation in age of FSM across the mouse family. We have collected the age of FSM, plasma and DNA samples for 1,962 females of these crosses. And using genetic and bioinformatic methods, we identified a promising candidate gene, proprotein convertase subtilisin/kexin type 2 (Pcsk2). In this project, we propose to identify novel regulatory candidates of female sexual maturation. This project will lay a solid foundation for future investigation of FSM and its related diseases, s well as the aging process itself.
Female sexual maturation is an important life history trait that is related to aging-related diseases such as osteoporosis, breast and ovarian cancer, stroke mortality, coronary heart disease, as well as biological/pathological processes of aging. Our program is a resourceful and pragmatic way to advance our understanding of the genetic regulation of female sexual maturation, its related diseases, and aging itself. Our long-term objective is to suggest new therapeutic targets for treating aging-related diseases and extending healthy lifespan in humans.