The human brain undergoes significant changes during aging, which lead to decline in cognitive functions and increase in age-dependent degenerative disease, such as Alzheimer’s. Research within the last decade large revealed a large number of gene expression changes accompanying brain aging (Lee et al. 2000; Lu et al. 2004). However, neither the physiological and molecular mechanisms, nor the phenotypic effect of these aging-related expression changes are yet understood. These expression changes could be responses to accumulating somatic damage with age, or alternatively, might represent processes which themselves lead to functional degeneration (de Magalhaes and Church 2005; Zahn et al. 2007). Further, aging-related expression changes in the brain, like developmental changes, might be conserved among different species, or alternatively, they might show diversity. In the Khaitovich lab I have been studying age-related expression changes in humans and other mammals, with the goal of understanding the regulatory processes driving these changes. We recently focused on one such regulator type, microRNA (miRNA), which are suppressors of gene expression and are critical regulators of diverse processes, from tissue differentiation to cell proliferation (Bartel 2009). We found that miRNA can play large-scale roles in leading gene expression changes during human brain aging, especially in relation to genes involved in neuronal function (Somel et al. 2010). Further, we found indication that these regulated expression changes are conserved among primates, which is intriguing, as most previous studies had reported little or no correlation among aging-related expressin changes in different species (Fraser et al. 2005; Zahn et al. 2007; Loerch et al. 2008). In the proposed project, we aim to (1) determine the degree of conservation in aging-related expression changes and regulatory interactions in primate and mouse brains, (2) identify the roles played by miRNA in brain aging. For this, we will first test the presence of the identified regulatory interactions in mouse brain aging. Second, we will investigate the miRNA effects directly in cell lines. Third, we will study how these miRNA themselves are regulated during aging. Finally, we will establish transgenic mouse models to study the phenotypic effects of these regulatory processes in vivo. The results will greatly expand our understanding of miRNA roles in mammalian brain aging.