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 toward their beneficial effects as an antiaging intervention.

Keywords: NAD+ metabolism; ageing; aging; exosome; extracellular vesicle; longevity.

FIGURE 1

Changes to circulating extracellular vesicles (EVs) with age. Together, studies suggest that there may be an age‐dependent decrease in the concentration of circulating EVs and concomitant changes to EV protein (colored oval within EVs) and EV nucleic acid (curled line within EVs) with age. It remains unknown whether these changes reflect altered secretion, uptake, or rerouting of EVs with age. Autophagy is an important regulator of aging and shares substantial regulatory overlap with EV biogenesis and degradation, but potential interactions between these relationships have not been thoroughly investigated

FIGURE 2

Extracellular vesicles (EVs) propagate the state of their source cell. As cells become senescent or enter a damaged state, EV secretion increases. EVs secreted by these unhealthy cells may induce inflammation or damage responses in the recipient cells, eventually inducing a similar unhealthy state in these cells. In contrast, EVs secreted by healthy tissue provide trophic support and promote the maintenance of homeostasis in recipient cells

FIGURE 3

An extracellular vesicle theory of aging. Early in life, extracellular vesicles (EVs) serve as beneficial signaling molecules and promote tissue health. As senescent/damaged cells accumulate over the lifespan of an organism, these cells secrete EVs carrying detrimental cargo. These aging‐promoting EVs circulate throughout the body, positively reinforcing aging‐related tissue deterioration. At the same time, as an organism ages, the number of rejuvenating or supportive EVs decreases. Beneficial effects seen with EV treatments may then reflect a shift of this balance toward rejuvenating EVs and may be one strategy for circumventing age‐related deterioration. Proteins are denoted by colored ovals and nucleic acids are denoted by curled lines. Examples of potential effector molecules found to have detrimental effects (top, aging) or beneficial effects (bottom, rejuvenating) are depicted along with supporting citation