Extracellular vesicles and aging

Abstract

AgingIt is estimated that in the next 20 years, the number of individuals in the United States over the age of 65 will double, numbering more than 70 million individuals. Unfortunately, as we age there is an unavoidable and progressive loss of the ability to maintain tissue homeostasis under stress and an attrition of functional reserve. As a consequence, the incidence of numerous debilitating diseases increases nearly exponentially with age, including cardiovascular disease, neurodegeneration, diabetes, osteoarthritis, and osteoporosis. Over 90% of individuals >65 years of age have at least one chronic disease, while >70% have at least two. These chronic diseases account for 75% of our healthcare costs, amounting to approximately $3 trillion in costs last year alone. Indeed, chronic diseases of the elderly are the greatest healthcare burden in the United States and seriously impact the quality of life of a large segment of the population. Thus, there is a significant need to understand mechanisms driving aging and to develop novel therapeutics. Given the diverse roles of blood-borne EVs in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process. This review focuses on the role EVs could play in aging, their therapeutic application for extending healthspan and their potential for use as biomarkers of unhealthy aging. Abstract: Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system. As our world population ages dramatically over the next decades, this will only increase.Hence, there is a great need to discover fundamental mechanisms of aging to enable development of strategies for minimizing the impact of aging on our health and economy. There is general agreement that cell autonomous mechanisms contribute to aging. As cells accrue damage over time, they respond to it by triggering individual cell fate decisions that ultimately disrupt tissue homeostasis and thus increase risk of morbidity. However, there are numerous lines of evidence, including heterochronic parabiosis and plasma transfer, indicating that cell non-autonomous mechanisms are critically important for aging as well. In addition, senescent cells, which accumulate in tissues with age, can display a senescence-associated secretory phenotype (SASP) that contributes to driving aging and loss of tissue homeostasis through a non-cell autonomous mechanism(s). Given the diverse roles of blood-borne extracellular vesicles (EVs) in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process through cell non-autonomous mechanisms. The fact that senescent cells release more EVs and with a different composition suggests they contribute to the adverse effects of senescence on aging. In addition, the ability of EVs from functional progenitor cells to promote tissue regeneration suggests that stem cell-derived EVs could be used therapeutica...

Systemic clearance of p16INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

“…The p16‐3MR mice were treated with GCV over a year period, preventing the accumulation of senescent cells in multiple tissues including the disc. Thus, it is possible that the GCV treatment prevented the accumulation of senescent cells in the disc through a cell nonautonomous mechanism, either systemically or locally; that is, GCV‐mediated removal of senescent cells eliminated their paracrine effects of SASP on neighbouring cells (Demaria, Desprez, Campisi, & Velarde, ; Robbins, ). However, our results unambiguously demonstrate the deleterious impact of senescent cells on intervertebral disc degeneration with natural aging.…”

Cellular senescence contributes to age‐dependent changes in circulating extracellular vesicle cargo and function

“…This is due in part to the senescent-associated secretory profile (SASP) acquired by senescent cells. More recent descriptions of the SASP have been expanded to include the secretion of EVs (Robbins, 2017;Takasugi, 2018). Extracellular vesicles derived from senescent cells exhibit multiple changes in cargo compared to healthy cells including changes in protein (Takasugi et al, 2017), and miRNA abundance (Terlecki-Zaniewicz et al, 2018).…”

Impact of Mesenchymal Stem Cell Senescence on Inflammaging

“…Aging on the cellular level may be responsible for inflammaging. Secretion of proinflammatory cytokines from senescent cells accumulated in tissues with age, the so-called 'senescence-associated secretory phenotype' (SASP), contributes to the onset of inflammaging (20). Age-associated changes in the immune system (Immunosenescence), which refers to impaired adaptive immunity and compensatory activation of the innate immune system, are also included in the sources of inflammaging (21).…”