Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T‐cell immunotolerance

Abstract

Biologic aging results in a chronic inflammatory condition, termed inflammaging, which establishes a risk for such age-related diseases as neurocardiovascular diseases; therefore, it is of great importance to develop rejuvenation strategies that are able to attenuate inflammaging as a means of intervention for age-related diseases. A promising rejuvenation factor that is present in young blood has been found that can make aged neurons younger; however, the component in the young blood and its mechanism of action are poorly elucidated. We assessed rejuvenation in naturally aged mice with extracellular vesicles (EVs) or exosomes extracted from young murine serum on the basis of different spectrums of microRNAs in these vesicles from young and old sera. We found that EVs extracted from young donor mouse serum, rather than EVs extracted from old donor mouse serum or non-EV supernatant extracted from young donor mouse serum, were able to attenuate inflammaging in old mice. Inflammaging is attributed to multiple factors, one of which is thymic aging-released self-reactive T cell-induced pathology. We found that the attenuation of inflammaging after treatment with EVs from young serum partially contributed to the rejuvenation of thymic aging, which is characterized by partially reversed thymic involution, enhancement of negative selection signals, and reduced autoreactions in the periphery. Our results provide evidence for understanding of the potential rejuvenation factor in the young donor serum, which holds great promise for the development of novel therapeutics to reduce morbidity and mortality caused by age-related inflammatory diseases.-Wang, W., Wang, L., Ruan, L., Oh, J., Dong, X., Zhuge, Q., Su, D.-M. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance.

Melatonin Enhances the Therapeutic Effect of Plasma Exosomes Against Cerebral Ischemia-Induced Pyroptosis Through the TLR4/NF-κB Pathway

“…The results revealed that the administration of exosomes clearly inhibited caspase-1 activation, which subsequently prevented GSDMD cleavage and membrane GSMDM pore formation that leads to the secretion of inflammatory cytokines, including IL18, IL-1β, TNF-α, IL-6, and HMGB1. Previous studies have shown that coalescing young and old vessels inhibited inflammation reactions in older mice (Wang et al, 2018;Zhang and Jin, 2020), indicating that there is an anti-inflammatory effect of plasma exosomes. In contrast to cell type-specific exosomes in a highly controlled process, the diversity of plasma cells determines its functional diversity.…”

Thymic rejuvenation via FOXN1-reprogrammed embryonic fibroblasts (FREFs) to counteract age-related inflammation

“…The autoimmune regulator (Aire) gene is expressed by mTECs to mediate self-antigen expression and to promote central immune tolerance via thymocyte negative selection and Treg generation (39,40). In the aged thymus, Aire-expressing mTECs are disrupted and/or decreased (7,29). Because transplantation of FREFs enhanced biological All of the data are from 3 independent experiments.…”

“…These factors are produced from cells of mesenchymal or hematopoietic origin, but target nonhematopoietic TECs associated with upregulating FoxN1 expression in TECs. Finally, epigenetically based rejuvenation, via extracellular vesicles and exosomes extracted from young, healthy serum, has been shown to rejuvenate not only the peripheral T cell system, but also the thymus by enhancing FoxN1 expression (29). Therefore, potential exists for rejuvenating thymic aging by primarily targeting the restoration of TEC homeostasis through rescuing age-related decreased FoxN1 expression.…”

Age-Related Thymic Atrophy: Mechanisms and Outcomes

“…(2) cytokine-to-TEC based therapy, such as keratinocyte growth factor (KGF) [116,117] and IL-22 [118][119][120]; (3) genetically-based methods (enhancement of exogenous FoxN1 expression with FoxN1 cDNA plasmid and FoxN1 transgene) [79][80][81], and (4) epigenetically-based methods (via exosomes extracted from young healthy serum) [121].…”