Exosomes released from senescent cells and circulatory exosomes isolated from human plasma reveal aging-associated proteomic and lipid signatures.

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Senescence emerged as significant mechanism of aging and age-related diseases, offering an attractive target for clinical interventions. Senescent cells release a senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, and propagate secondary senescence. However, the composition of exosomal SASP components remains underexplored. We identified ~1,300 exosome proteins released by senescent primary human lung fibroblasts induced by three different senescence inducers. In parallel, a small human plasma cohort from young (20-26 years) and old (65-74 years) individuals revealed 1,350 exosome proteins and 171 plasma exosome proteins were altered in old individuals. Of the age-regulated plasma exosome proteins, we observed 52 exosomal SASP factors that were also regulated in exosomes from the senescent fibroblasts, SERPINs, Prothrombin, Coagulation factor V, Plasminogen, and Reelin. We identified 247 exosome lipids. Following senescence induction phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins increased significantly indicating cellular membrane changes. Significantly changed proteins were related to extracellular matrix remodeling and inflammation, both potentially detrimental pathways that can damage surrounding tissues and even induce secondary senescence. Our proof-of-principle study - even though initially from a rather small human cohort - suggested potential senescence biomarker candidates, enabling future surveillance of senescence burden in the aging population.

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