Summary
The molecular pathways leading from genomic instability to cellular senescence and/or cell death remain incompletely characterized. Using mouse embryonic fibroblasts with constitutively increased DNA damage due to the absence of the full-length form of the tumor suppressor Brca1 (Brca1Δ11/ Δ11), we show that deletion of p53 binding protein 1 (53BP1) selectivity abrogates senescence and cell death stimulated by reduced Brca1 activity. Furthermore, the embryonic lethality induced by Brca1 mutation can be alleviated by 53BP1 deletion. Adult Brca1Δ11/ Δ1153BP1-/- manifest constitutively high levels of genomic instability, yet age relatively normally with a surprisingly low incidence of overall tumor formation. Together, these in vitro and in vivo data suggests that 53BP1 is specifically required for the development of premature senescence and apoptosis induced by Brca1 deficiency. These observations may have important implications for Brca1 mediated tumor formation as well as for the molecular pathway leading from genomic instability to organismal aging.
We analyzed a new hypomorphic mouse model containing a targeted intronic insertion of a neomycin cassette within the mechanistic target of rapamycin (mTOR) locus. Mice with two hypomorphic (mTORΔ/Δ) alleles are viable but express mTOR at approximately 25% of wild type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximate 20% increase in median survival. While mTORΔ/Δ mice are smaller than wild type mice, these animals do not demonstrate any alterations in normalized food intake, glucose homeostasis or metabolic rate. Consistent with their increased lifespan, mTORΔ/Δ mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that as mTORΔ/Δ mice age, they exhibit a marked functional preservation in many but not all organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.
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