Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.

中文翻译：

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Midkine 是年龄相关变化和乳腺肿瘤发生增加的驱动因素


衰老是癌症的关键危险因素，但其潜在机制仍不清楚。在这里，我们通过单细胞多组学探索大鼠乳腺中与年龄相关的变化。我们的发现包括上皮增殖增加、管腔身份丧失以及随着年龄的增长，幼稚 B 细胞和 T 细胞减少。我们发现了老年大鼠特有的管腔祖细胞群，其特征反映了癌前变化，并将 midkine （Mdk） 确定为随年龄上调的基因和年龄相关管腔祖细胞的调节因子。幼大鼠的 Midkine 治疗通过激活 PI3K-AKT-SREBF1 通路模拟与年龄相关的变化，并促进亚硝基-N-甲基脲诱导的乳腺肿瘤发生。人类血液和乳腺上皮细胞中的 Midkine 水平随着年龄的增长而增加，正常乳腺组织中较高的 MDK 与年轻女性患乳腺癌的风险较高有关。我们的研究结果揭示了衰老与肿瘤发生易感性之间的联系，并确定 midkine 是乳腺肿瘤发生年龄依赖性增加的介质。