UC Berkeley

Although functional organ stem cells persist in the elderly, tissue damage invariably overwhelms tissue repair, ultimately leading to the failure of major organ systems. It has been demonstrated that the microenvironment, or niche in which adult stem cells reside critically influences stem cell function. The delicate balance between positive and negative signaling regulators controls the decision of adult stem cells to remain quiescent, self-renew or differentiate, a crucial balance for the maintenance of tissue homeostasis. In this dissertation, we provide evidence that the same key morphogenic signaling pathways become deregulated with age and contribute to the decline of both hippocampal neurogenesis and skeletal muscle regeneration with aging, leading to the decline in regenerative performance of both brain and muscle tissue stem cells. Furthermore, we demonstrate that the aged tissue niches can be rejuvenated to enhance native stem cell function in muscle and brain by youthful calibration of the intensity of these morphogenic signaling pathways. In particular, local attenuation of BMP signaling in the aged hippocampus, systemic and local attenuation of TGF-beta signaling in both the aged hippocampus and aged skeletal muscle, and specific proteins secreted by human embryonic stem cells that act through MAPK and Notch signaling rejuvenate brain and muscle tissue precursor cell function by normalizing the signaling strength of the pathways that are chronically overexpressed or underexpressed with aging. Summarily, by better understanding the age-imposed decline in the regenerative capacity of stem cells, the debilitating lack of organ maintenance in the old, including decline in neurogenesis and skeletal muscle regeneration, can be ameliorated.