Grant: Operating Grant : Adv Theoretical Meth Innov Hlth Res-Longitudinal Studies Aging

Aging researchers still do not know what mechanisms are responsible for aging. The main theories put forward have not been well supported by evidence. It now appears that aging is not caused by any single process, but rather by the declining ability of the body to properly regulate many biological processes. This decline arises from the difficulty in maintaining the complex systems necessary for normal functioning, systems that involve large numbers of molecules integrated in precisely regulated networks. Although this idea has the potential to explain the aging process, the large number of molecules, the extensive interactions and feedback relationships among them, and the long timescales make experimental approaches unfeasible, and no one has yet tested this "dysregulation" hypothesis of aging. A novel approach is required to simultaneously incorporate information about many molecules, their changes over time, and their relationships to each other. This project, the first such study, uses hundreds of blood and clinical measures collected in several long-term human datasets. We have access to three of the best such datasets in the world, a unique resource that allowing us to test whether results can be generalized across different populations. We apply novel statistical and informatics methods designed for high-dimensional data, including techniques to (a) find clusters of similar individuals and identify their shared biological patterns, (b) detect a faint signal among noise, and (c) assess causal effects among pathways across years. Preliminary analyses have identified multiple new pathways involved in aging and support our hypothesis of dysregulation. Our project will further test this hypothesis, identifying which pathways are involved and how. Understanding biological pathways will in turn allow us to identify social determinants of aging rate, develop clinical tools for measuring patient aging, and further biomedical research on chronic disease pathways.