PO.MCB04.02 · 分子与细胞生物学
衰老抑制性Δ133p53alpha减轻小鼠的加速衰老
Senescence-inhibitory Δ133p53alpha mitigates accelerated ageing in mice
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Hutchinson-Gilford早老综合征（HGPS）是一种由新发LMNA G608G突变引起的早衰性疾病，其特征为DNA损伤累积和持续性炎症，二者驱动加速衰老并导致严重的临床表现，包括皮肤萎缩、脱发以及由于血管平滑肌细胞丧失导致的主动脉壁进行性退化，从而使寿命严重缩短。HGPS小鼠模型再现了这些病理性衰老表型，包括心血管缺陷、细胞衰老增加、DNA损伤累积、全身性炎症以及寿命缩短。人类p53异构体Δ133p53alpha缺失N端133个氨基酸，是一种天然存在的截短变体，具有独特的生物学功能。在HGPS患者来源的成纤维细胞中，Δ133p53alpha抑制细胞衰老、减少促炎性IL-6产生、限制DNA损伤累积并延长复制寿命。这些发现提示Δ133p53alpha选择性地减弱p53介导的细胞周期阻滞和衰老，同时保留DNA修复功能。在此，在杂合子HGPS小鼠模型中，我们表明Δ133p53alpha的转基因表达在体内多个器官中重现了这些体外观察到的效应，并将中位寿命延长约10%（387天对358天，P = 0.0235）。在主动脉和皮肤中，Δ133p53alpha减轻早老相关的病理性改变并保持组织完整性。Δ133p53alpha还减轻HGPS小鼠表型特征性的脊柱后凸。RNA测序分析提示Δ133p53alpha促进线粒体功能和代谢适应性。Δ133p53alpha在自然衰老小鼠中的作用正在研究中。我们对人类表达数据库的分析显示，Δ133p53alpha在包括主动脉和皮肤在内的多种人体组织中随年龄相关性下调。本研究不仅提示了针对HGPS的基于Δ133p53alpha的治疗方法，也提示了预防或延缓衰老的更广泛干预措施。
查看英文原文 English abstract
Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder caused by a de novo LMNA G608G mutation, is characterized by the accumulation of DNA damage and persistent inflammation, which drive accelerated aging and lead to severe clinical manifestations, including skin atrophy, alopecia, and progressive deterioration of the aortic wall due to loss of vascular smooth muscle cells, resulting in severely shortened lifespan. Mouse models of HGPS recapitulate these pathological aging phenotypes, including cardiovascular defects, increased cellular senescence, DNA damage accumulation, systemic inflammation, and shortened lifespan.The human p53 isoform Δ133p53alpha, which lacks the N-terminal 133 amino acids, is a naturally occurring truncated variant with distinct biological functions. In HGPS patient-derived fibroblasts, Δ133p53alpha suppresses cellular senescence, reduces pro-inflammatory IL-6 production, limits DNA-damage accumulation, and extends replicative lifespan. These findings suggest that Δ133p53alpha selectively attenuates p53-mediated cell-cycle arrest and senescence while preserving DNA-repair functions.Here, in a heterozygous HGPS mouse model, we show that transgenic expression of Δ133p53alpha reproduces these in vitro-observed effects across multiple organs in vivo and extends median lifespan by approximately 10% (387 vs. 358 days, P = 0.0235). In the aorta and skin, Δ133p53alpha mitigates progeria-associated pathological changes and preserves tissue integrity. Δ133p53alpha also mitigates spinal kyphosis characteristic of the HGPS mouse phenotype. RNA-sequencing analysis suggests that Δ133p53alpha promotes mitochondrial function and metabolic fitness. The effects of Δ133p53alpha in naturally aging mice are under investigation. Our human expression database analysis shows an age-associated downregulation of Δ133p53alpha in multiple human tissues, including aorta and skin.This study suggests not only a Δ133p53alpha-based therapeutic approach for HGPS but also broader interventions for preventing or delaying aging.
利益披露 Disclosure
L. Yamada, None..
H. Liu, None..
N. Von Muhlinen, None..
C. C. Harris, None..
I. Horikawa, None.