In the context of aging and age-related disease, forms of plasma transfusion remain therapies in search of conclusive proof that the benefits are worth it. Efforts focusing on transfer of young donor plasma into old individuals conducted over the past decade or so have so far failed to produce convincing results in clinical trials. The blood products industry is a large one, and the larger entities in that industry appear to view this as a discovery problem, that somewhere in the fractionation of donor blood there is a way to produce a product that will be modestly useful for some aspects of aging. Looking at the lengthy history of research to establish the production of medical products from donor blood, this may be a reasonable expectation. So far the results have been disappointing, however.
This is the context in which researchers here write an editorial to argue for the assessment of plasma from individuals who are fit and have recently exercised. Physical activity produces beneficial effects throughout the body in large part through altered secretion of signal molecules and vesicles carried in blood. One might reasonably argue that plasma from a fit young donor fresh from the gym could be more beneficial to the recipient than plasma from a sedentary young donor fresh from a bed. Effect sizes and proof matter, however, and thus the need for more data and more rigorous data.
Is it time for exercise-conditioned plasma to enter human trials?
Skeletal muscle contraction during an acute bout of exercise elicits a complex array of molecular responses in multiple organ systems. Such molecular signals continue to persist, after the exercise and thus the long-term accumulation of such exercise sessions culminate in systemic adaptations that extend beyond the musculoskeletal system – remodeling of organ systems occur and improvement in healthspan. Acute exercise mobilizes thousands of proteins and peptides, mRNA, extracellular vesicles (EVs), and non-coding RNA systemically, transporting them to distant sites, and exert modulatory effects on the organs, including brain, adipose tissue, liver, etc.
Recent studies in pre-clinical mouse models reveal promising evidence that plasma obtained after exercise training directly improves physiological outcomes in non-exercised recipients. Transfused plasma from exercised rats improved neuronal viability, decreased cell atrophy and increased neurogenesis by three-fold in transgenic Alzheimer’s Disease (AD) rat recipients. Furthermore, exercised young (three-month old) murine plasma administered intravenously to old (18-month-old) mice resulted in increased proliferation of hippocampal neurons. Exciting work on plasmapheresis is being pioneered in the United States of America (USA) and Norway. In the former, young male donors provided 1 unit (~250mL) of fresh frozen plasma (FFP) to patients with Alzheimer’s disease in a once per week infusion, followed by a 6-week washout period and crossover with saline treatment. The primary endpoints were safety, tolerability and feasibility of the intervention – all of which were met at the conclusion of the trial. In the latter, the ongoing study involved blood plasma obtained from young, healthy and well-trained (aerobically fit) individuals and transfused intravenously to older adults with Alzheimer’s disease at intervals of 3 months.
Such recent investigations have given a glimpse of a novel translational application of exercise-induced adaptations for chronic disease management, particularly in oncology and neurology. The putative molecular mechanisms that underlie the therapeutic effects of exercise-induced plasma transfusion therapy provide a foundation for their potential translational use in cancer, cardiovascular diseases, and neurodegenerative diseases. Furthermore, there is an opportunity to translate the benefits of exercise-induced plasma for bedridden or paralyzed patients who are unable or intolerant to exercise training. In conclusion, we believe it is time for early-phase clinical trials to test exercise-conditioned plasma for different chronic diseases.
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