Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice

Abstract

Aging is associated with an increased risk of frailty, disability, and mortality. Strategies to delay the degenerative changes associated with aging and frailty are particularly interesting. We treated old animals with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement in several parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function, as well as an important decrease in frailty. ADSC-sEVs induced proregenerative effects and a decrease in oxidative stress, inflammation, and senescence markers in muscle and kidney. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and their metabolome changed to a youth-like pattern. Last, we gained some insight into the microRNAs contained in sEVs that might be responsible for the observed effects. We propose that young sEV treatment can promote healthy aging.

Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases

“…Some studies have shown a promising therapeutic effect of EVs from healthy, non-senescent cells, such as stem cells, in the modulation of senescence. EVs from healthy cells can decrease senescence both in vivo and in vitro [ 22 , 23 , 24 ] through several proposed mechanisms, such as the transmission of miRNAs [ 22 , 24 ], antioxidant enzymes [ 23 ], or metabolic changes [ 25 ]. Due to their immunomodulatory roles, EVs can act through the modulation of the SASP, decreasing the pro-inflammatory changes in the microenvironment induced by the accumulation of senescent cells.…”

“…Due to their immunomodulatory roles, EVs can act through the modulation of the SASP, decreasing the pro-inflammatory changes in the microenvironment induced by the accumulation of senescent cells. One of the proposed mechanisms that might explain the effects of EVs on senescence is viewing EVs from healthy cells as senomorphics, factors that can decrease the burden of senescent cells, not by directly inducing their selective apoptosis as senolytics but by modifying the extracellular environment and inhibiting the SASP [ 24 , 26 ].…”

“…This damage contributes to the development of age-related pathologies, such as Alzheimer’s [ 29 ] or frailty [ 30 , 31 ]. EVs are now viewed as important factors that regulate the redox status through the transfer of molecules with antioxidant properties between cells, protecting against oxidative damage in several models of acute damage and during aging [ 23 , 24 , 32 ]. The different conditions associated with the culture of cells can modify EVs release, and the content of the oxygen tension in the culture is of the utmost importance [ 33 , 34 ].…”

“…As stated before, the beneficial effect of EVs observed in many models of disease, such as myocardial infarction, stroke, chronic kidney disease (CKD), or liver injury, is typically accompanied by a suppression of pro-inflammatory cytokines, with an increase in anti-inflammatory molecules. In physiological aging, the treatment with EVs has been shown to decrease inflammatory cytokines that are associated with aging, such as IL-6, IL-1β, or TNF-α [ 24 , 26 , 57 , 58 ]. As we have described, EVs are important factors of the SASP that lead to paracrine senescence and contribute to the chronic inflammation observed during aging [ 20 ].…”

“…As we have described, EVs are important factors of the SASP that lead to paracrine senescence and contribute to the chronic inflammation observed during aging [ 20 ]. One of the proposed mechanisms through which EVs from healthy cells could decrease inflammation and senescence is the inhibition of the SASP, acting as “senomorphics”, linking their effect both in cellular senescence and inflammation [ 24 , 26 ].…”