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

Abstract

Extracellular vesicles (EVs) have emerged as important regulators of inter‐cellular and inter‐organ communication, in part via the transfer of their cargo to recipient cells. Although circulating EVs have been previously studied as biomarkers of aging, how circulating EVs change with age and the underlying mechanisms that contribute to these changes are poorly understood. Here, we demonstrate that aging has a profound effect on the circulating EV pool, as evidenced by changes in concentration, size, and cargo. Aging also alters particle function; treatment of cells with EV fractions isolated from old plasma reduces macrophage responses to lipopolysaccharide, increases phagocytosis, and reduces endothelial cell responses to vascular endothelial growth factor compared to cells treated with young EV fractions. Depletion studies indicate that CD63+ particles mediate these effects. Treatment of macrophages with EV‐like particles revealed that old particles increased the expression of EV miRNAs in recipient cells. Transfection of cells with microRNA mimics recapitulated some of the effects seen with old EV‐like particles. Investigation into the underlying mechanisms using bone marrow transplant studies revealed circulating cell age does not substantially affect the expression of aging‐associated circulating EV miRNAs in old mice. Instead, we show that cellular senescence contributes to changes in particle cargo and function. Notably, senolytic treatment of old mice shifted plasma particle cargo and function toward that of a younger phenotype. Collectively, these results demonstrate that senescent cells contribute to changes in plasma EVs with age and suggest a new mechanism by which senescent cells can affect cellular functions throughout the body.

DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

“…Senescent cells are metabolically active in a state of stable cell cycle arrest; they accumulate in the living body during the aging process [9][10][11]. These cells have been reported to play both beneficial and deleterious roles in our health through secreting SASP factors [12][13][14][15][16][17], and they also release many types of EVs, such as exosomes, microvesicles, nucleosomes, and apoptotic bodies, which are characterized by their size and secretory machinery [60][61][62][63]. Previously, we and other groups have reported that small EVs are actively released from senescent cells, functioning as harmful SASP factors by regulating the growth and viability of cancer cells [24,25,31].…”

“…Previously, we and other groups have reported that small EVs are actively released from senescent cells, functioning as harmful SASP factors by regulating the growth and viability of cancer cells [24,25,31]. According to recent studies, the biological functions of small EVs released from senescent cells change drastically because of changes in the composition of their proteins, lipids, and nucleic acids during cellular senescence [25,26,60,[62][63][64]. In this study, we demonstrated that DNA damage is a key trigger, not only of senescence induction but also of small EV biogenesis via ceramide synthesis in senescent cells.…”

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

“…Most recent evidence has demonstrated that the SASP includes extracellular vesicles (EVs) through which senescent cells exert central effector functions in the local environment. Senescent cells secrete EVs with a distinctive, but still incompletely characterized, content of miRNA, proteins, and DNA that can spread senescence in surrounding and even distant tissues [44][45][46][47], thus promoting further inflammation and catastrophic consequences for the organism [48]. Interestingly, it has been documented that exosomes are crucial components in the pathogenesis of virus infection, but specific studies for SARS-CoV or SARS-CoV are still lacking [49].…”

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

“…For example, EVs isolated from M1 activated macrophages induced neonatal rat cardiomyocyte death in-vitro in an NF-κB-dependent manner, suggesting that the adverse effects of M1 cells on cardiac viability may in-part be mediated through EVs [189]. As aging influences EV cargo, including microRNA that regulates inflammatory pathways [190], their use as biomarkers, targets or treatments in cardiovascular aging may offer more robust opportunities to improve health.…”

“…With increasing age, there is an accumulation of these dysfunctional cells within tissues and this accumulation is associated with organ dysfunction in multiple organ systems. The deleterious effect of senescent cells is primarily attributed to increased secretion of pro-inflammatory cytokines, chemokines, growth factors, extracellular vesicles, and proteolytic enzymes by these cells which, in turn, disrupts tissue microenvironments and promotes cellular dysfunction [190,221,222]. This unique secretory profile is termed the senescent-associated secretory profile (SASP).…”