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

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          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.

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          Restoring defective intercellular communication with young sEVs reverses aging hallmarks and improves fitness in old mice.

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          Most cited references77

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          The Hallmarks of Aging

          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

            ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
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              Frailty in Older Adults: Evidence for a Phenotype

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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draft
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing - original draft
                Role: InvestigationRole: ResourcesRole: Visualization
                Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draft
                Role: Formal analysisRole: SoftwareRole: Visualization
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Writing - review & editing
                Role: Investigation
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: Validation
                Role: Investigation
                Role: Formal analysisRole: Investigation
                Role: ConceptualizationRole: Formal analysisRole: Methodology
                Role: Investigation
                Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: SoftwareRole: Visualization
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                October 2022
                19 October 2022
                : 8
                : 42
                : eabq2226
                Affiliations
                [ 1 ]Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable-Instituto de Salud Carlos III (CIBERFES-ISCIII), INCLIVA, 46010 Valencia, Spain.
                [ 2 ]Department of Pathology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibáñez, 15, Valencia, Spain.
                [ 3 ]Epigenetic Clock Development Foundation, Torrance, CA, USA.
                [ 4 ]Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, 28029 Madrid, Spain.
                [ 5 ]Freshage Research Group, Department of Physiotherapy, Faculty of Physiotherapy, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibáñez, 15, Valencia Spain.
                [ 6 ]Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
                [ 7 ]Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
                [ 8 ]Altos Labs, San Diego, CA, USA.
                Author notes
                [* ]Corresponding author. Email: consuelo.borras@ 123456uv.es
                Author information
                https://orcid.org/0000-0002-6598-056X
                https://orcid.org/0000-0003-1131-1894
                https://orcid.org/0000-0002-4803-1573
                https://orcid.org/0000-0003-3190-6721
                https://orcid.org/0000-0001-8492-5198
                https://orcid.org/0000-0002-5396-4466
                https://orcid.org/0000-0001-5223-160X
                https://orcid.org/0000-0002-8963-4389
                https://orcid.org/0000-0003-2265-7874
                https://orcid.org/0000-0002-5328-2692
                https://orcid.org/0000-0002-4110-3589
                https://orcid.org/0000-0001-9709-0089
                https://orcid.org/0000-0003-4606-1792
                Article
                abq2226
                10.1126/sciadv.abq2226
                9581480
                36260670
                8fd6b852-7c8b-43d1-9790-e34313478bcb
                Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 31 March 2022
                : 31 August 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100008054, Fundación Ramón Areces;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: JPI HDHL INTIMIC-085
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: H2020- DIABFRAIL-LATAM (Ref: 825546)
                Funded by: FundRef http://dx.doi.org/10.13039/501100000780, European Commission;
                Award ID: GA N° 696295 of the EU Horizon 2020 Research and Innovation Programme
                Funded by: FundRef http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: PCIN-2017-117
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: CB16/10/00435
                Funded by: FundRef http://dx.doi.org/10.13039/501100004837, Ministerio de Ciencia e Innovación;
                Award ID: MCIN/AEI/ 10.13039/501100011033 PID2020-113839RB-I00
                Funded by: FundRef http://dx.doi.org/10.13039/501100004837, Ministerio de Ciencia e Innovación;
                Award ID: PID2019-108973RB-C22
                Funded by: FundRef http://dx.doi.org/10.13039/501100011596, Conselleria d’Educació, Investigació, Cultura i Esport;
                Award ID: PROMETEO/2019/097
                Funded by: Fundación Soria Melguizo;
                Funded by: FundRef http://dx.doi.org/10.13039/501100004837, Ministerio de Ciencia e Innovación;
                Award ID: PID2019-110906RB-I00/ AEI / 10.13039/501100011033
                Funded by: FundRef http://dx.doi.org/10.13039/501100004837, Ministerio de Ciencia e Innovación;
                Award ID: RED2018-102576-T
                Categories
                Research Article
                Biomedicine and Life Sciences
                SciAdv r-articles
                Diseases and Disorders
                Life Sciences
                Diseases and Disorders
                Custom metadata
                Karla Peñamante

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