A polymorphism in the tumor suppressor p53 affects aging and longevity in mouse models

Author:

Zhao Yuhan1ORCID,Wu Lihua1,Yue Xuetian1,Zhang Cen1,Wang Jianming1,Li Jun1,Sun Xiaohui12,Zhu Yiming2,Feng Zhaohui13,Hu Wenwei13ORCID

Affiliation:

1. 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

2. Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China

3. Department of Pharmacology, Rutgers, the State University of New Jersey, Piscataway, United States

Abstract

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 TP53 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.

Funder

National Institutes of Health

New Jersey Commission on Cancer Research

Lawrence Ellison Foundation

U.S. Department of Defense

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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