Abstract

Extracellular Vesicles (EVs) as Therapeutics for Extending Healthspan

Paul Robbins, Professor of Molecular Medicine, University of Minnesota Medical School

With aging, there is an inevitable and progressive loss of the ability of tissues to recover from stress, in part through loss of stem cell function. As a consequence, the incidence of chronic degenerative diseases increases exponentially starting at the age of 65. This includes neurodegeneration, cardiovascular disease, diabetes, osteoarthritis, cancers, and osteoporosis.  More than 90% of people over 65 years of age have at least one chronic disease, while 75% have at least two. Thus, it is imperative to find a way to target therapeutically the process of aging to compress the period of functional decline in old age. Such a therapeutic approach would simultaneously prevent, delay or alleviate multiple diseases of old age. We are using both naturally aged mice and the ERCC1-deficient mouse model of accelerated aging mice as a model of accelerated aging to identify therapeutic strategies for extending healthy aging. Previously we demonstrated that intraperitoneal (IP) administration muscle-derived stem/progenitor cells (MDSPCs) isolated from young wild-type mice into ERCC1-deficient mice conferred significant lifespan and healthspan extension through a paracrine/endocrine mechanism. More recently, we demonstrated that BM-MSCs from young, but not old mice, also prolonged lifespan and healthspan in ERCC1-deficient mice, similar to MDSPCs. Taken together, these results suggest that at least two types of adult stem cell populations, BM-MSCs and MDSPCs, isolated from young mice extend lifespan and healthspan following IP injection in a mouse model of accelerated aging. We also have been characterizing and identifying the factors released by young, functional stem cells important for this extension of lifespan and healthspan. Conditioned media (CM) from young, but not old MDSPCs and BM-MSCs, rescued the function of aged, dysfunctional stem cells as well as senescent fibroblasts in culture.  Moreover, this activity in the CM co-purifies with extracellular vesicles (EVs) released by young, but not old stem cells. Treatment of ERCC1-deficient mice with EVs from young stem cells is able to extend healthspan. Interestingly, EVs from the serum of young, but not old mice also can rescue cellular senescence suggesting that the effect of young serum on aging could be mediated in part by EVs. In addition, senescent cells appear to take up stem cell derived EVs more efficiently.  Progress towards developing clinically relevant approaches using stem cell-derived extracellular vesicles to treat autoimmune and age-related pathologies will be presented.