Genomic Stability in the Naked Mole-Rat: A Role for Cancer Resistance and Extended Longevity
2006 senior Scholar Award in aging
Naked Mole Rats (NMRs) are the longest-living rodents known; they live >28y in captivity which is ~9x longer than similarly-sized mice. NMRs show attenuated age-related declines in both morphology (e.g. bone loss) and function ( e.g. vascular function). Furthermore, we have never seen any evidence of cancer in our large 25-y captive NMR colony. In preliminary studies we have found that NMR cells are more resistant to neoplastic transformation by combinations of oncogenes (SV40 large T antigen and activated Ras) that routinely convert both mouse and human cells into cancer cells. The remarkable resistance of the naked mole-rat (NMR) to cancer may also result from interspecies differences (from mice, in particular) in intracellular pathways, that must be targeted in order to convert a normal cell to a cancer cell. We hypothesize that NMRs have both more efficient DNA repair, and reduced mutagenesis leading to genomic stability; these traits may contribute to abrogated cancer susceptibility and slow aging. In this study we will test three specific aims:
Aim 1: To assess if NMRs have low levels of DNA damage, and employ efficient DNA repair mechanisms in response to DNA damaging agents. We will measure changes in accrued DNA damage (double strand breaks (DSB) in peripheral blood cells drawn at known time intervals after irradiating animals. We will also measure these variables in fibroblasts of four rodent species treated with agents known to induce DNA damage. In addition, DNA damage (DSB and 8-OHdG) and repair processes (beta-polymerase activity, base excision and nucleotide excision), as well as markers of surveillance, apoptosis, senescence and repair will be monitored in both tissues and cells after exposure to DNA damaging agents.
Aim 2: To determine if NMRs are more resistant to cell transformation and tumorigenesis following exposure to known oncogenes or carcinogens than shorter-living rodents. We will assess fibroblast susceptibility to transduction and if these cells, when implanted into renal capsules of immunodeficient mice, induce tumors. In addition, comparative interspecific susceptibility to known mutagens will be determined by painting skin of mice and mole-rats with potent mutagens, DMBA and TPA.
Aim 3: To clone tumor suppressor genes in NMRs and assess if these diverge from cancer-prone mice. We will clone p53, MDM2 and the CDKN2A locus.
This integrative organismic, cellular and molecular approach may elucidate mechanisms that facilitate resistance to carcinogenesis, retard aging and facilitate the prolonged longevity of NMRs.