ABSTRACT Normal aging is characterized by deficits in cognition particularly in the domains of memory (1-6) and executive function.(1, 2, 7-11) Evidence suggests these changes are not a consequence of widespread cortical neuronal loss, but rather are attributable to alteration and/or loss of white matter myelin, axons, synapses and dendrites, and changes in oxidative metabolism and inflammation.(12-18) Further there is growing evidence that accumulation of pathological Tau and A-Beta are related to age-related cognitive decline, even in the absence of Alzheimer’s Disease and Related Dementias (ADRD). Thus, one potential therapy, mesenchymal stem cells (MSCs), have recently received attention as a possible intervention in aging,(19-22) as they are known to suppress inflammation and facilitate tissue repair and remyelination. (19, 23, 24) Further, we have demonstrated that human umbilical- derived cells, and MSC-derived extracellular vesicles (EVs), the active product of MSCs, reduce inflammation and enhance recovery of motor function in non-human primates (NHP) and rodents following cortical injury(25, 26) and promote axonal growth and myelination in vitro.(27-37) Similarly, EVs have been shown to improve cognitive deficits in diabetic rats and APP/PS1 mice (model of Alzheimer’s disease).(24, 38, 39) Whether these EV-mediated beneficial effects can be applied to normal aging and age-related neuropathology in primates is largely unknown. However, our pilot data show that administration of MSC-EVs in aged female rhesus monkeys decreases A-Beta deposition. Based on this evidence and our data showing EV-mediated enhancement of recovery after cortical injury in NHPs, we build upon on our experience over the past three decades (NIH-NIA Program Project AG00001-34) characterizing cognitive function in the rhesus monkey across the life-span and age-related changes in the brain (40, 41) to assess the impact of MSC-EVs in our rhesus monkey model of aging. Specifically, we will investigate the efficacy of EVs to slow or reverse age-related cognitive decline and reduce markers of inflammation, myelin atrophy, and tau and A-Beta deposition. We will then quantify the effects of EVs on reducing age-related synaptic dysfunction and changes in electrophysiological properties of neurons. Finally, we will conduct an in-depth proteomic analysis of treatment and endogenous EVs to establish the profile of the active biological cargo load responsible for treatment efficacy. This longitudinal, multi-disciplinary study will shed light on the relationships of neuroinflammatory pathways, myelin damage and ADRD like pathology and cognitive decline associated with normal aging, and test the efficacy of EVs in ameliorating these age-related deficits in neural structure and function.

Narrative Normal aging is associated with deficits in cognition that correlate with myelin damage and inflammation and ADRD-like pathology, such as accumulation of pathological Tau and A-Beta. Our recent work with our monkey models of aging and cortical injury demonstrated the mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are highly efficacious in facilitating recovery and reducing inflammation, myelin damage and tau and A-Beta. In the current study, we will test whether administration of MSC-EVs in aged monkeys will enhance cognitive performance and reduce age-related markers of inflammation, myelin damage and ADRD-like pathology in blood and CSF and post-mortem brain tissue. !