DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat

Boughey, Harvey; Jurga, Mateusz; El‐Khamisy, Sherif F.

doi:10.3390/ijms22116011

Cited by 5 publications

(1 citation statement)

References 110 publications

(148 reference statements)

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“…The naked mole rats' natural habitat is in the hypoxic environment underground in constant darkness. Despite their extremely long lifespan of up to 30 years, naked mole rats show very little biological decline, neurodegeneration, and senescence [74]. The hyperstability of the naked mole rat's p53 when compared to murine p53, which is independent of genotoxic stress, might be a consequence of the change in the amino acid sequence in the p53 protein.…”

Section: Discussionmentioning

confidence: 99%

The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity

Bartas

Brázda

Volná

et al. 2021

IJMS

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Recently, the quest for the mythical fountain of youth has produced extensive research programs that aim to extend the healthy lifespan of humans. Despite advances in our understanding of the aging process, the surprisingly extended lifespan and cancer resistance of some animal species remain unexplained. The p53 protein plays a crucial role in tumor suppression, tissue homeostasis, and aging. Long-lived, cancer-free African elephants have 20 copies of the TP53 gene, including 19 retrogenes (38 alleles), which are partially active, whereas humans possess only one copy of TP53 and have an estimated cancer mortality rate of 11–25%. The mechanism through which p53 contributes to the resolution of the Peto’s paradox in Animalia remains vague. Thus, in this work, we took advantage of the available datasets and inspected the p53 amino acid sequence of phylogenetically related organisms that show variations in their lifespans. We discovered new correlations between specific amino acid deviations in p53 and the lifespans across different animal species. We found that species with extended lifespans have certain characteristic amino acid substitutions in the p53 DNA-binding domain that alter its function, as depicted from the Phenotypic Annotation of p53 Mutations, using the PROVEAN tool or SWISS-MODEL workflow. In addition, the loop 2 region of the human p53 DNA-binding domain was identified as the longest region that was associated with longevity. The 3D model revealed variations in the loop 2 structure in long-lived species when compared with human p53. Our findings show a direct association between specific amino acid residues in p53 protein, changes in p53 functionality, and the extended animal lifespan, and further highlight the importance of p53 protein in aging.

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Section: Discussionmentioning

confidence: 99%