Patel Sandip Kumar, Bons Joanna, Rose Jacob P, Chappel Jessie R, Beres Rebecca L, Watson Mark A, Webster Corey, Burton Jordan B, Bruderer Roland, Desprez Pierre-Yves, Reiter Lukas, Campisi Judith, Baker Erin S, Schilling Birgit
The Buck Institute for Research on Aging, Novato, CA 94945, USA.
Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University, Raleigh, NC 27606, USA.
Aging (Albany NY). 2025 Jul 30;17(8):1929-1965. doi: 10.18632/aging.206292.
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.
衰老已成为衰老及与年龄相关疾病的重要机制，为临床干预提供了一个有吸引力的靶点。衰老细胞会释放一种衰老相关分泌表型（SASP），包括可能作为远端组织间信号转导分子的外泌体，并引发继发性衰老。然而，外泌体SASP成分的组成仍未得到充分研究。我们鉴定了由三种不同衰老诱导剂诱导的衰老原代人肺成纤维细胞释放的约1300种外泌体蛋白。同时，一项针对年轻（20 - 26岁）和老年（65 - 74岁）个体的小型人体血浆队列研究显示，老年个体中有1350种外泌体蛋白和171种血浆外泌体蛋白发生了改变。在受年龄调节的血浆外泌体蛋白中，我们观察到52种外泌体SASP因子在衰老成纤维细胞的外泌体中也受到调节，包括丝氨酸蛋白酶抑制剂、凝血酶原、凝血因子V、纤溶酶原和Reelin。我们鉴定了247种外泌体脂质。衰老诱导后，磷脂酰胆碱、磷脂酰乙醇胺和鞘磷脂显著增加，表明细胞膜发生了变化。显著变化的蛋白质与细胞外基质重塑和炎症有关，这两条潜在的有害途径都可能损害周围组织，甚至诱导继发性衰老。我们的原理验证研究——尽管最初来自一个相当小的人体队列——提出了潜在的衰老生物标志物候选物，为未来监测老年人群中的衰老负担提供了可能。
