衰老的特点是免疫功能逐渐下降和疾病风险增加。基因组不稳定被认为是衰老过程的核心，但DNA损伤的潜在机制尚未明确定义。细胞在受限环境中经历核内力的作用，导致瞬时的核包裹层破裂（NER）和DNA损伤。在这里，我们展示了Lamin A/C如何保护肺泡巨噬细胞（AMs）免受NER和衰老的标志。AMs在肺内的狭窄空间中移动。免疫特异性抑制Lamin A/C导致AMs选择性减少，更容易受到流感病毒诱发的发病和肺癌生长的影响。Lamin A/C缺乏的AMs显示持续的NER标记、DNA损伤和p53依赖的衰老现象。来自年老的野生型和Lamin A/C缺乏小鼠的AMs共享一个包含CD63的溶酶体特征。CD63被要求在巨噬细胞中限制受损DNA。我们提出NER诱导的基因组不稳定性是AMs衰老机制的一个因素。 © 2023. 该作者， 授予斯普林格自然美国公司独家使用许可。

Aging is characterized by gradual immune dysfunction and increased disease risk. Genomic instability is considered central to the aging process, but the underlying mechanisms of DNA damage are insufficiently defined. Cells in confined environments experience forces applied to their nucleus, leading to transient nuclear envelope rupture (NER) and DNA damage. Here, we show that Lamin A/C protects lung alveolar macrophages (AMs) from NER and hallmarks of aging. AMs move within constricted spaces in the lung. Immune-specific ablation of lamin A/C results in selective depletion of AMs and heightened susceptibility to influenza virus-induced pathogenesis and lung cancer growth. Lamin A/C-deficient AMs that persist display constitutive NER marks, DNA damage and p53-dependent senescence. AMs from aged wild-type and from lamin A/C-deficient mice share a lysosomal signature comprising CD63. CD63 is required to limit damaged DNA in macrophages. We propose that NER-induced genomic instability represents a mechanism of aging in AMs.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.