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Investigating Systemic Aging and its Effects on Aged Tissues by Utilizing a Small Animal Blood Exchange Model

Abstract

Aging is characterized as a progressively worsening loop where an accumulation of aberrant molecules and cells lead to a plethora of ailments. Tissue homeostasis gradually falters leading to inadequate resident stem cell responses, persistent inflammation, fibrosis, and metabolic derangements. Furthermore, organ secretome profiles of aging individuals shift from factors that bolster tissue health and regeneration to a milieu that progressively impairs tissue function. These harmful factors accumulate in the blood and are distributed throughout the body. Heterochronic parabiosis experiments have shown that the systemic environment can impact organ regeneration. Young blood can rejuvenate the performance of aged tissue stem cells, whereas old blood can negatively affect those of the young. This work strongly reinforces the paradigm which maintains that mammalian aging is plastic, yet the translatability of this work remains elusive. It is also unclear whether young blood factors are necessary for rejuvenation. In this dissertation, a preclinical model that mimics plasmapheresis was developed to enable immediate translation to therapies for aged humans. Plasmapheresis is an FDA-approved treatment modality where plasma is extracorporeally separated from the blood, replaced with a physiologic fluid, and transfused back into the bloodstream. We demonstrate that the dilution of aged blood plasma rejuvenated the muscle and brain. The plasma dilution studies introduced a novel paradigm which holds that young blood factors may not be essential for rejuvenation; a neutral-age physiological fluid could suffice in this regard. These works broaden our understanding of systemic aging and suggest a novel repositioning of plasmapheresis to improve the health span of aged people.

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