Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease

Abstract

Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

Keywords: blood plasma administration; brain rejuvenation; caloric restriction; exercise; healthspan; neurodegenerative disease.

Figure 1.. Systemic brain rejuvenation strategies.

Hallmarks of brain aging amenable to rejuvenation (middle panel) include decreased regenerative capacity (neurogenesis), impaired synaptic plasticity, increased inflammation, vascular remodeling, increased protein aggregation, and impaired cognitive function. Systemic interventions (top panel), such as caloric restriction, exercise, and blood plasma administration, have been shown to rejuvenate hallmarks of brain aging (left panel) and ameliorate exacerbated pathology in models of neurodegenerative disease (right panel). Cellular or functional rejuvenation elicited by systemic interventions is denoted by a check (✔), lack of rejuvenation is denoted by a dash ( –), and yet-to-be-determined effects are denoted by a question mark (?).