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., eLife digest How long most animals live depends on the balance between the biological processes that allow them to regenerate their tissues when damaged and those that prevent them from developing cancer. Regeneration relies mostly on cells, in particular stem cells, dividing to make new cells, while cancer occurs when cell division becomes uncontrolled. Tumor suppressor genes protect against cancer. One such gene encodes a protein called p53 that eliminates damaged cells before they can become cancerous. The p53 protein is also believed to be involved in regulating how quickly an animal ages and how long it lives, but this second role has not yet been clearly established. Previous studies using different strategies to change the activity of p53 in several mouse models have led to inconsistent results. However, the mouse models used in these earlier studies did not reflect how p53 works under normal conditions. Zhao et al. have now used mice in which the mouse gene for p53 was replaced with one of two versions of the equivalent human gene to study its impact on lifespan and the aging process. The two versions of p53 only differ slightly; a single building block of the protein, the amino acid at position 72, is a proline in one version but an arginine in the other. This difference makes one version of p53 weaker than the other; in other words, it is less able to eliminate damaged cells. Zhao et al. revealed that the mice with the weaker p53 lived for longer and appeared to age more slowly too. Further experiments showed that the stem cells in the mice with a weaker p53 were able to keep dividing and create new cells for longer. This is important because a decline in this activity – which is known as self-renewal – is a hallmark of aging. Together these findings show that a small yet common change in p53 impacts both aging and lifespan, possibly by altering how stem cells are regulated. Further work is now needed to better understand why the different versions of p53 have different effects on stem cells.