Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, United States.
Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China.
Elife. 2018 Mar 20;7:e34701. doi: 10.7554/eLife.34701.
Tumor suppressor p53 prevents early death due to cancer development. However, the role of p53 in aging process and longevity has not been well-established. In humans, single nucleotide polymorphism (SNP) with either arginine (R72) or proline (P72) at codon 72 influences p53 activity; the P72 allele has a weaker p53 activity and function in tumor suppression. Here, employing a mouse model with knock-in of human gene carrying codon 72 SNP, we found that despite increased cancer risk, P72 mice that escape tumor development display a longer lifespan than R72 mice. Further, P72 mice have a delayed development of aging-associated phenotypes compared with R72 mice. Mechanistically, P72 mice can better retain the self-renewal function of stem/progenitor cells compared with R72 mice during aging. This study provides direct genetic evidence demonstrating that p53 codon 72 SNP directly impacts aging and longevity, which supports a role of p53 in regulation of longevity.
抑癌基因 p53 可预防因癌症发展而导致的早逝。然而，p53 在衰老过程和寿命延长中的作用尚未得到充分证实。在人类中，密码子 72 处的精氨酸（R72）或脯氨酸（P72）单核苷酸多态性（SNP）影响 p53 活性；P72 等位基因在肿瘤抑制中的 p53 活性和功能较弱。在这里，我们利用携带密码子 72 SNP 的人 基因敲入的小鼠模型发现，尽管癌症风险增加，但逃避肿瘤发展的 P72 小鼠比 R72 小鼠寿命更长。此外，与 R72 小鼠相比，P72 小鼠的衰老相关表型发展延迟。从机制上讲，与 R72 小鼠相比，P72 小鼠在衰老过程中能更好地保持干细胞/祖细胞的自我更新功能。这项研究提供了直接的遗传证据，证明 p53 密码子 72 SNP 直接影响衰老和寿命，这支持了 p53 在调节寿命中的作用。
