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.
Highlights
Aging is a complex process of time-dependent series of progressive loss of functions and structures of all systems, which leads to an increased vulnerability to death (Lopez-Otın et al, 2013)
Previous studies including ours showed that the P72 allele in these mice has a weaker transcriptional activity towards a subset of p53 target genes than the R72 allele, suggesting that these mice retain the function of p53 codon 72 single nucleotide polymorphism (SNP) in human (Feng et al, 2011; Kung et al, 2016; Azzam et al, 2011)
Because the lifespan of mice varies among different inbred strains, Hupki mice with p53 codon 72 SNP were backcrossed to mice with different genetic backgrounds, including 129SVsl and C57BL/6J, for ten generations to establish p53 codon 72 SNP Hupki mice in 129SVsl and C57BL/6J backgrounds, respectively
Summary
Aging is a complex process of time-dependent series of progressive loss of functions and structures of all systems, which leads to an increased vulnerability to death (Lopez-Otın et al, 2013). Cancer is an age-associated disease, which can lead to both premature death and age-associated increase in morbidity and mortality (Campisi and Yaswen, 2009). Tumor suppressor p53 plays a pivotal role in tumor prevention (Feng et al, 2008; Vousden and Prives, 2009). Loss or disruption of p53 function is often a prerequisite for tumor initiation and development. Loss of both Trp alleles (p53-/-) leads to the development of tumors early in life and a reduced lifespan compared with wild type mice (Donehower et al, 1992). P53 ensures longevity by preventing cancer development early in life
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