Systemic regulation of synaptic, regenerative, and cognitive dysfunction during aging

Aging is a prominent risk factor for cognitive decline and neurodegenerative disease. Particularly sensitive to the effects of aging are functions governed by the hippocampus and indeed, impairments in hippocampal-dependent episodic and spatial memories have been observed in aged rodents, monkeys, and humans. While the mechanisms by which age-related cognitive impairments emerge are multifaceted, neuronal dysfunction and impaired plasticity are frequent hallmarks of brain aging thought to underlie cognitive decline. In the hippocampus, this is manifested as a loss of neurogenesis and decreased long-term potentiation, which is accompanied by corresponding decreases in synaptic density and synaptic protein expression. As the human population ages, understanding mechanisms governing hippocampal aging is increasingly important as means of identifying therapeutic targets to slow or even reverse aging in the brain. While significant work has characterized intrinsic cellular changes that contribute to age-related loss of neurogenesis, synaptic dysfunction, and cognitive decline, recent studies posit age-related changes in blood as a critical regulator of brain aging. Indeed, emerging studies utilizing the model of heterochronic parabiosis - in which the circulatory system of a young and old mouse is surgically joined - have revealed bidirectional pro- and anti- aging effects of old or young blood exposure on hippocampal neurogenesis, synaptic plasticity, and cognition. To date, studies have focused on age-related changes in blood-borne factors as regulators of hippocampal aging, and whether other components of blood contribute to hippocampal aging remains to be fully elucidated. Here, we assess the role of cellular aging of the hematopoietic system in driving hippocampal aging (Chapter 2) and test whether circulating exosomes in young blood contain rejuvenating capacity on the aged brain (Chapter 3). We find that cellular aging of the hematopoietic system, and downstream changes in blood-borne factors, drive age-related impairments in hippocampal cognition. Additionally we find that systemic administration of young plasma-derived exosomes fail to rejuvenate the aged hippocampus, but increase synaptic protein expression in the aged cortex