Is Transfusion of Young Blood Essentially a Form of Extracellular Vesicle Therapy?
Are beneficial effects of transfusion of blood fractions from young individuals to old individuals observed in animal studies the result of transferring the contents of extracellular vesicles rather than any signal molecules not packaged into a vesicle? While considering this question, it is worth noting that transfusion of plasma has quite mixed outcomes in both mice and humans. It doesn't appear to be a good approach to therapy, based on the results to date.
This is unlike the robust benefits produced in old animals by heterochronic parabiosis, linking the circulatory system of an old and a young mouse. In a parabiosis study, the old mouse is getting a great deal more of everything that might be found in young blood than is the case in even repeated transfusions employed as therapy. At the same point in time potentially harmful components of old blood are being (a) diluted, and (b) passed through young kidneys, liver, and other organs that might remove them. These latter aspects of parabiosis do not occur in transfusion, and at present there is some debate as to whether there are any meaningfully beneficial factors to be found in young blood fractions.
In today's open access paper, researchers describe transfusion of serum rather plasma from young animals to old animals, and provide data to suggest that it is the contents of the extracellular vesicles in serum that mediate beneficial effects. It is worth noting that extracellular vesicles will be present in all blood fractions unless deliberately filtered out. Blood fractionation is accomplished via centrifugation, so it is possible that there is some biasing of vesicles to one fraction or another based on size. Otherwise, the same arguments might be applied to serum transfusions as to plasma transfusions; despite the existence of some studies in which benefits were shown, the data in aggregate doesn't make this appear to be a good basis for therapy.
The conventional wisdom is that a better understanding of the myriad roles of extracellular vesicles (EVs) in central nervous system (CNS) homeostasis is essential for developing novel therapeutics to alleviate and reverse the neurological disturbances of aging. Thus far, an increasing number of studies have revealed the complexities of EV-mediated cell-cell communications in the brain, predominantly emphasizing the role of EV released by brain cells under physiological conditions. It has been well established that EVs can cross brain barriers such as the blood-brain barrier (BBB) and brain-cerebrospinal fluid (CSF) barrier (BCsfB).
If isolated from CSF and plasma, brain EVs provide an array of options with which to learn about normal brain functions and monitor changes in the brain associated with aging or neurodegenerative pathology. Since humoral factors can enter the brain at the BBB and BCsfB, in vivo models, for example, heterochronic parabiosis (HB), heterochronic blood exchange (HBE), and infusions of small volumes of plasma or serum, have been used to uncover and better understand the role of those factors in aging and age-related diseases. Recently, using infusions of small volumes of serum, we evaluated the contribution of circulating EVs to the beneficial effect of young serum on aged muscle stem cell (MuSC) function and the skeletal muscle regenerative cascade. We demonstrated that young serum restored a youthful bioenergetic and myogenic profile to old muscle cell progeny and that this effect was dependent on circulating EVs. Yet, the full spectrum of effects of circulating young EVs on aged organs and tissues, including the brain, remains poorly understood.
In this study, we examined the effect of young serum on the cognitive performance of aged mice. We show that repeated infusions with small volumes of young serum significantly improved age-associated memory deficits and this effect was abrogated after the serum was depleted of circulating EVs. RNA-seq analysis of choroid plexus demonstrated effects on genes involved in barrier function and trans-barrier transport. Interestingly, the hippocampal transcriptome demonstrated a significant upregulation of Klotho (Kl) gene, which codes for the longevity protein Klotho, following young serum treatment. Notably this effect was abrogated after serum EV depletion, suggesting that EVs may serve as vehicles for Klotho messages from the periphery to the brain. Given the well-established role of Klotho in cognitive functioning, we performed transcriptional profiling of Klotho knockout (Klko) and Klotho heterozygous (Klhet) mice and found an association with downregulated categories such as transport, exocytosis, and lipid transport, while upregulated genes were associated with microglia.
To test if changes in transcriptomes represent transcriptomic rejuvenation, we correlated the transcriptomes of the treated mice to the most recently published chronological aging clocks, which revealed a reversal of transcriptomic aging in the choroid plexus. The results of our study indicate that further evaluation of EVs as vehicles for delivering signals from the periphery to the brain and coordinating the responses of different brain regions will open new avenues with which to expand the research and to better understand aging and rejuvenation.