Friends and foes: Extracellular vesicles in aging and rejuvenation

Abstract

Extracellular vesicles (EVs) are released by many different cell types throughout the body and play a role in a diverse range of biological processes. EVs circulating in blood as well as in other body fluids undergo dramatic alterations over an organism's lifespan that are only beginning to be elucidated. The exact nature of these changes is an area of active and intense investigation, but lacks clear consensus due to the substantial heterogeneity in EV subpopulations and insufficiencies in current technologies. Nonetheless, emerging evidence suggests that EVs regulate systemic aging as well as the pathophysiology of age-related diseases. Here, we review the current literature investigating EVs and aging with an emphasis on consequences for the maintenance of human healthspan. Intriguingly, the biological utility of EVs both in vitro and in vivo and across contexts depends on the states of the source cells or tissues. As such, EVs secreted by cells in an aged or pathological state may impose detrimental consequences on recipient cells, while EVs secreted by youthful or healthy cells may promote functional improvement. Thus, it is critical to understand both functions of EVs and tip the balance towards their beneficial effects as an anti-aging intervention. Accepted ArticleNo copyright is required Biogenesis of small versus large EVs occurs via divergent pathways that nonetheless involve some of the same regulatory molecules. Small EVs are generated by a secondary invagination of the luminal membrane of endosomes following endocytosis, forming multivesicular bodies (MVBs).These MVBs then fuse with the cellular outer plasma membrane, emptying their contents including the nascent small EVs into the extracellular space. In contrast, large EVs form by directly budding from the external cellular plasma membrane (15). Description of current knowledge regarding the biogenesis, uptake, and basic biological functions of EVs are beyond the scope of this review, but are reviewed in detail elsewhere (5,15). Importantly, EVs can serve as both local and long-range transport and intertissue signaling mechanisms for mRNA, miRNA, protein, and lipids and are a major source for cell-free DNA and RNA in humans (15)(16)(17)(18)(19)(20). In this review article, we will focus on the biological significance of EVs in the systemic regulation of mammalian aging and longevity and also in the pathogenesis of age-associated dysfunctions. II. Changes to extracellular vesicles with ageEV quantification: Recent evidence suggests that there are substantial changes to EVs with age.Nevertheless, the extent of these changes and whether they represent a cause or effect of aging remain largely unanswered questions in the field. Such changes could be viewed as potential boons to our understanding of the aging process as well as in our search for viable aging biomarkers in humans. Analysis of plasma from 74 humans including young (30-35 years old), middle-aged (40-55 years old), and old (55-64 years old) revealed gradually decreasing quantities of circu...

Sex Differentially Alters Secretion of Brain Extracellular Vesicles During Aging: A Potential Mechanism for Maintaining Brain Homeostasis

“…A study that investigated mouse plasma EVs has shown an age-related decrease in lipoproteins but an increase with age of specific types of EVs using western blot analysis [ 34 ]. Given that the plasma particles analyzed by NTA contain lipoproteins, the finding by another study by NTA of an age-associated decrease of particle numbers in human and rodent plasma may be affected by an age-related decrease in lipoproteins [ 35 ]. Similarly, the particles analyzed by NTA in our study may contain lipoproteins.…”

Extracellular Vesicles in Aging: An Emerging Hallmark?

“…As previously introduced, in the last decades it has been widely recognized that EVs secreted from senescent cells can transfer the aging phenotype to the recipient cells by regulating their gene expression or changing their energy metabolism [146]. To date, just some studies underline the properties of specific EVs in delaying aging processes.…”

“…Recent data from J. A. Fafian-Labora and colleagues [146] demonstrate the potential of small EVs isolated from primary fibroblasts of young human donors (sEV-Ys) as regenerative therapy in aging. Specifically, they reported that sEV-Ys possess glutathione-S-transferase (GST)-intrinsic activity and ameliorated cellular biomarkers of senescence by increasing the antioxidant capacity of old fibroblasts both in vitro and in vivo in old mice [146].…”

Mechanisms of immune aging in HIV

“…For instance, mi-RNAs such as mi-RNA-21/ 29/ 34 modulate regeneration and tissue functionality by targeting various tissues and involving different pathways which might interfere with long life expectancy (127). Despite, substantial changes to extracellular vesicles with age, it is not clear whether these changes represent a cause or effect of aging or associated comorbidities (128). On the contrary, the role of exosome in HIV infection is critical since this pathway releases intracellular material and exchanges material and information between cells.…”