Exchange transfusion (apheresis) is a routine strategy for the management of several diseases, such as sickle cell disease, hemolytic disease of newborns, autoimmune disorders, etc. Interestingly, the body of published work on heterochronic parabiosis, the surgical joining of two animals of different ages, and more recently, our study on heterochronic blood exchange, suggest that blood apheresis can be repositioned and used as a new modality: restoring the circulatory environment of aged mammals back to a productive, young, composition, may help to rapidly and broadly enhance the maintenance and repair of multiple organs, combatting a number of degenerative diseases of brain, muscle, liver, etc. and inflammatory disorders. In contrast to the permanent anastomosis of parabiosis, in our small animal blood exchange system animals are connected and disconnected at will, removing the influence of shared organs, adaptation to being joined, etc. Unlike parabiosis, where joint circulation is stochastically established in ~7-10 days, our procedure is less invasive and accurately controlled, the exchange volumes are easily programmed and measured; and the onset and duration of the effects can be accurately and with ease interrogated. The cells versus plasma heterochronicity can be studied and immuno-affinity modules enable removal of specific inhibitory molecules from the old circulation prior to return of such ?rejuvenated? blood into the old animal; as well as a screen for candidate systemic proteins, removal of which from young circulation inhibits tissue maintenance and repair. We will (1) determine the onset and duration of the effects of heterochronic blood apheresis on health and maintenance of muscle, liver and brain, animal performance (strength and cognition), and systemic cytokine profile, also defining the minimal functional dose of exchanged blood that significantly influence these parameters; (2) engineer the V2 device where, in continuous apheresis between two animals of different age, circulating leukocytes are separated from plasma, studying how a cross-match of the age of cells and plasma influences tissue maintenance and repair; (3) engineer the V3 device with imunoaffinity modules allowing to screen and attenuate to young ? healthy levels candidate systemic proteins, using IL6 and TNF-a as the first candidates, that when elevated with age have negative effects on tissue health and regeneration.
The goal of these collaborative studies is to develop the next generation small animal blood exchange devices and to use them as experimental platform for understanding the age-specific influences of systemic milieu on regeneration and health of multiple mammalian tissues. Ultimately, this new in vivo animal research platform can be used for repositioning FDA approved human apheresis to treat degenerative pathologies of muscle, liver and brain, and inflammatory diseases.
|Sadlowski, Corinne; Balderston, Sarah; Sandhu, Mandeep et al. (2018) Graphene-based biosensor for on-chip detection of bio-orthogonally labeled proteins to identify the circulating biomarkers of aging during heterochronic parabiosis. Lab Chip 18:3230-3238|