Extracellular vesicles (EVs) are membranous particles released from nearly all cell types into all bodily fluids evaluated to date ? including serum and plasma. Depending on tissue of origin, health state and organism age, they carry a variety of complex cargo consisting of nucleic acids, proteins and metabolites. Although resilience at a tissue level has largely been attributed to stem cells, recent evidence increasingly points to their production of EVs as mediators of their remarkable regenerative capacity. The rapid release of small EVs is induced by physical activity and believed to contribute to the long-term beneficial effects of regular exercise on muscle metabolism, the cardiovascular system as well as immune modulation. The goal of this project is to develop biomarkers of aging and resilience through analyses of EVs. Due to their coordinate regulation of tissue homeostasis and biological processes through intercellular trafficking of microRNA and protein cargo, EVs are particularly attractive for this project because they can potentially serve as DIRECT biomarkers of aging and resilience, namely indicators AND mediators of the aging process and response to stressors. We will use our newly developed 18-channel-high-resolution flow cytometric methodology with validation by nanoparticle tracking video microscopy, and fluorescence-activated particle sorting that we have established in the laboratory to evaluate our large existing extensive human sample sets (n=4213 individuals from EPESE, PALS, STRRIDE, BHS and the Duke 1KP (1000 Patient) cohort) with associated deidentified data and longitudinal follow-up (6 months to 23 years). We have preliminary data demonstrating an age-related decline in specific subsets of circulating EVs. We also have identified that a subset of EVs, including some of those declining with age, are induced with exercise training and predict a beneficial metabolic response to exercise. These data, together with our collaborators for this project, bring together extensive expertise in aging, resilience, exercise, and physical performance across the lifespan (ages 18 to 102 years). These resources and capabilities provide a unique opportunity for us to significantly advance EVs along a biomarker pipeline and to identify effectors of heathy aging and resilience. For this reason, we are responding to the funding Opportunity Announcement PA-17-088 that invites applications that employ secondary analysis of existing data sets or stored biospecimens to address clinically related issues on aging changes influencing health across the lifespan.

Public Health Relevance

Extracellular vesicles (EVs) are microscopic particles, produced by all cells in the body, that circulate in the trillions in every milliliter of blood. EVs can potentially provide signatures of aging and resilience and carry proteins and other molecules that can communicate and have effects at a distance. Using large numbers of already collected precious human specimens from individuals aged 20 to over 90 years old, this project characterizes the types and role of these vesicles in aging and develops new blood biomarker tests for these vesicles to better understand mechanisms of aging and the ability to recover from stressors with aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Raghavachari, Nalini
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Duke University
Schools of Medicine
United States
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