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.
Highlights
Aging is the major risk factor for dementia-related neurodegenerative disease in the elderly
It is important to take into account that, along with cellular and functional decline in the aged brain, organismal aging is broadly associated with global “hallmarks of aging” across all tissues in the body, such as stem cell dysfunction, genomic and protein instability, and altered intracellular communication, to name a few[1]
Age-related vulnerability to neurodegenerative disease occurs on a background of organismal-level functional decline, and as such interventions to counteract this vulnerability in the aged brain will benefit from a more systemic approach
Summary
Aging is the major risk factor for dementia-related neurodegenerative disease in the elderly. While the potential for human application exists, limitations should be noted, with evidence in humans indicating that the perception of physical frailty or poor health alone can decrease adherence in the elderly[78] Notwithstanding, these studies point to the capacity of exercise to extend healthspan and rejuvenate cellular and functional hallmarks of brain aging, with direct relevance to neurodegenerative diseases, such as Alzheimer’s disease. Systemic interventions: young blood and neurodegenerative disease Current neurodegenerative disease animal models recapitulate many pathologies observed in humans, including amyloid plaque deposition, tau phosphorylation, increased neuroinflammation, altered synaptic plasticity, and cognitive impairments[88] Despite their success in dissecting cellular and molecular changes involved in disease progression, current models are limited by the increasing array of transgenes they rely on, complicating interpretations and translation to human disease[88]. While any of these studies has yet to yield results, the outcomes from the young plasma administration trials, coupled with the perspective gained from the extensive biomarker studies, will provide a more complete picture of potential pro-aging and rejuvenating circulating factors that can be targeted to increase healthspan and ameliorate neurodegenerative disease in the elderly
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