p53 has dual functions on longevity. p53 plays a crucial role in tumor suppression to prevent early death due to cancer. However, it has been suggested by animal models that constitutively increased p53 activity accelerates the decline of stem/progenitor cells’ self-renewal function during aging process, which leads to a reduced lifespan. In humans, the role of p53 in aging and longevity has not been well established. As a haplo-insufficient gene, p53 is under the tight regulation in cells. Attenuation of p53 function contributes greatly to tumorigenesis. p53 codon 72 single nucleotide polymorphism (SNP) with either an arginine (R72) or a proline (P72) at codon 72 is a naturally occurring common SNP that can influence the activity of p53. The P72 allele is weaker than the R72 allele in inducing apoptosis and suppressing cellular transformation. Individuals with the P72 allele have increased cancer risk compared to the R72 allele. However, it is unclear whether the change of p53 activity in humans by functional SNPs could impact upon longevity. A perspective study with an aging human population showed that P72 allele is associated with longer survival despite its increased risk for cancer development. These findings strongly suggest that p53 activity is reversely associated with aging, and SNPs in the p53 pathway could impact upon the life span in humans. In this study, we employed a mouse model system with knock-in of human p53 gene (Hupki) carrying either R72 or P72 SNP to investigate the impact of p53 codon 72 SNP upon longevity and its underlying mechanism. Mice with p53 P72 allele showed weaker transcriptional activity than the R72 allele toward a subset of p53 target gene, suggesting that these mice retain the function of p53 codon 72 SNP in human. We found that although mice with p53 P72 have increased cancer risk compared to mice with p53 R72, mice with p53 P72 that escaped tumor development showed longer lifespan compared to mice with p53 R72 that do not develop tumor. Mice with p53 P72 displayed a delay in aging process compared to mice with p53 R72; mice with p53 P72 have slower reduction in bone density, dermal thickness and wound healing ability during aging process. We compared the effects of p53 codon 72 SNPs on stem cell population and function as a possible mechanism that contributes to their difference in longevity. Compared to mice with p53 R72, mice with p53 P72 allele have lower number of long-term stem/progenitor cells and better self-renewal function during aging process. Consistently, aging mice with p53 P72 allele exhibited better long-term stem cell ability of engraftment and repopulation than aging mice with p53 R72 allele as evaluated by bone marrow transplantation assay. Taken together, results from this study demonstrate that p53 codon 72 SNP has a direct impact on aging and longevity, and strongly support the role of p53 in regulation of stem/progenitor cells’ function and longevity.

Citation Format: Yuhan Zhao, Lihua Wu, Xuetian Yue, Cen Zhang, Jun Li, Jianming Wang, Zhaohui Feng, Wenwei Hu. The impact of p53 codon 72 SNP upon aging and longevity in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3417. doi:10.1158/1538-7445.AM2017-3417