Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 ( Oct4 ), sex-determining region Y-box 2 ( Sox2 ), Kruppel-like factor 4 ( Klf4 ), and cellular myelocytomatosis oncogene ( cMyc ) ( OSKM ) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a ( Cdkn2a ) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a - OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A - OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.

中文翻译：

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年龄相关细胞状态的靶向部分重编程可改善小鼠衰老模型中的健康标志物


衰老是一个复杂的多因素过程，与表观基因组失调、细胞衰老增加和年轻化能力下降有关。野生型小鼠八聚体结合转录因子 4 （Oct4） 、性别决定区 Y-box 2 （Sox2） 、Kruppel 样因子 4 （Klf4） 和细胞骨髓细胞瘤癌基因 （cMyc） （OSKM） 的短期循环表达可改善健康状况，但无法区分细胞状态，对健康细胞构成风险。在这里，我们在细胞周期蛋白依赖性激酶抑制剂 2a （ Cdkn2a ） 启动子的控制下递送了单剂量的腺相关病毒 （AAV），以特异性地部分重编程 Hutchinson-Gilford 早衰综合症 （HGPS） 小鼠模型中的衰老和应激细胞。小鼠在老年细胞特异性 OSK 表达后表现出促炎细胞因子表达降低和寿命延长。特别是骨髓和脾脏显示出明显的基因表达变化，老年 HGPS 小鼠的部分重编程导致造血干细胞区室的细胞组成向年轻小鼠的细胞组成转变。将携带 Cdkn2a-OSK 的 AAV 施用于自然衰老的野生型小鼠也延缓了衰老表型并延长了寿命，而不会改变肿瘤发展的发生率。此外，皮内注射携带 Cdkn2a - OSK 的 AAV 可改善老年野生型小鼠的伤口愈合。CDKN2A - OSK 在衰老或应激人原代成纤维细胞中的表达导致炎症相关基因的表达降低，但不会改变细胞周期相关基因的表达。因此，这种有针对性的部分重新编程方法可能有助于制定改善健康和寿命以及增强老年人复原力的策略。