Gong Yi, Wang Yunong, Delgado-Peraza Francheska, Nogueras-Ortiz Carlos, Noren Hooten Nicole, Croteau Deborah L, Temre Mithlesh, Molnar Abigail E, Bodogai Monica, Zou Ainslee, Abdelmohsen Kotb, Zhu Wei, Zhang Yongqing, Gorospe Myriam, Weng Nan-Ping, Evans Michele K, Kapogiannis Dimitrios, Liu Yie
Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
iScience. 2025 May 13;28(6):112661. doi: 10.1016/j.isci.2025.112661. eCollection 2025 Jun 20.
Telomere shortening is a hallmark of aging associated with various diseases, yet its impact on extracellular vesicles (EVs) remains poorly understood. We investigated EV abundance, size, cargo content, and functional implications in a human aging cohort and the telomerase reverse transcriptase null ( ) mice. Human plasma EVs showed reduced telomeric DNA cargo with age. In generation 3 (G3) mice with shortened telomeres, we observed a significant reduction in plasma EV concentration and tissue-specific changes in EV levels and telomeric DNA content. Proteomic analysis revealed altered protein levels related to inflammation and lipid metabolism in plasma- and tissue-derived EVs. Functionally, EVs from G3 mice stimulated a pro-inflammatory response in bone marrow-derived macrophages and exhibited neurotoxic effects on primary cultured neurons. These findings highlight the intricate interplay between telomere shortening and EV biology, underscoring the potential of EVs as intercellular mediators, biomarkers, and therapeutic targets for conditions associated with telomere loss.
端粒缩短是与多种疾病相关的衰老标志，但其对细胞外囊泡（EVs）的影响仍知之甚少。我们在一个人类衰老队列和端粒酶逆转录酶缺失（）小鼠中研究了EVs的丰度、大小、货物含量及其功能意义。人类血浆EVs的端粒DNA货物随年龄增长而减少。在端粒缩短的第3代（G3）小鼠中，我们观察到血浆EV浓度显著降低，以及EV水平和端粒DNA含量的组织特异性变化。蛋白质组学分析显示，血浆和组织来源的EVs中与炎症和脂质代谢相关的蛋白质水平发生了改变。在功能上，G3小鼠的EVs在骨髓来源的巨噬细胞中刺激了促炎反应，并对原代培养的神经元表现出神经毒性作用。这些发现突出了端粒缩短与EV生物学之间的复杂相互作用，强调了EVs作为细胞间介质、生物标志物以及与端粒丢失相关疾病的治疗靶点的潜力。
