Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice.
Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice.
复制标题
Trp53 的单倍体不足可显着延长 Sirt6 缺陷小鼠的寿命。
作者：
Ghosh S;Wong SK;Jiang Z;Liu B;Wang Y;Hao Q;Gorbunova V;Liu X;Zhou Z
哺乳动物sirtuin 6（Sirt 6）是一种保守的NAD+依赖性脱酰基酶和单ADP核糖基化酶，已知其参与DNA损伤修复、代谢稳态、炎症、肿瘤发生和衰老。小鼠Sirt 6的缺失会导致衰老加速并在一个月内过早死亡。在这里，我们表明单倍不足（即，Trp 53的缺失（杂合缺失）显著延长了雌性和雄性Sirt 6缺陷小鼠的寿命。Sirt 6缺陷小鼠中Trp 53的单倍不足挽救了Sirt 6缺陷小鼠的几种年龄相关表型，包括减小的体型和体重、脊柱后凸、结肠炎、早衰、细胞凋亡和骨髓干细胞下降。在机制上，SIRT 6在赖氨酸381处使p53脱乙酰基以负调节p53的稳定性和活性。这些发现证实，升高的p53活性显著促进Sirt 6缺陷小鼠的加速衰老。我们的研究表明p53是SIRT 6的底物，并强调了SIRT 6-p53轴在衰老调节中的重要性。
Mammalian sirtuin 6 (Sirt6) is a conserved NAD+-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency (i.e., heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6-deficient mice. Haploinsufficiency of Trp53 in Sirt6-deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline. Mechanistically, SIRT6 deacetylates p53 at lysine 381 to negatively regulate the stability and activity of p53. These findings establish that elevated p53 activity contributes significantly to accelerated aging in Sirt6-deficient mice. Our study demonstrates that p53 is a substrate of SIRT6, and highlights the importance of SIRT6-p53 axis in the regulation of aging.