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.

Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology

“…Due to the amount of time required for improvements in our model, transfusions alone would not be sufficient but plasmapheresis, a process similar to dialysis designed to replace plasma from patients with healthy plasma, may be of use by either reducing mHTT or normalizing plasma levels of cytokines [20,68,69]. This method has already been studied for brain rejuvenation, namely with heterochronic parabiosis between an elderly mouse and a young mouse [70,71] and clinical studies are devoted to this new Fountain of Youth, whose initial results have demonstrated the safety, tolerability and feasibility of this intervention [72]. Given the large number of factors impacted by parabiosis, assessment of the clinical effects of plasmapheresis in HD would be warranted and may have implications for other disorders of the CNS.…”

Is testosterone perspective available for neurodegenerative diseases?

“…On the other hand, ketogenic diet might be beneficial for neurodegenerative diseases by reducing the oxidative damage, supplying energy for focal brain hypometabolism, and enhancing mitochondrial biogenesis. Nevertheless, the long-term effects of ketogenic diet is not known [57,58].…”

Identifying Exosomes as a Messenger Unit During Heterochronic Parabiosis for Amelioration of Huntington’s Disease

“…The positive effect ofheterochronic parabiosis originates from the shared blood circulation, [25,26] just like the other neurodegenerative diseases ameliorated by heterochronic parabiosis. [9,27,28]It is worth noting that the R6/2 mice die typically at around 3-4 months of ageaccompanied by trimming and muscle loss [10,11] and highly vulnerable to stress. Therefore minimizing the damage of parabiosis surgery were indispensableto make stable parabiotic pairs.…”