Altered senescence, apoptosis, and DNA damage response in a mutant  p53 model of accelerated aging.
The tumor suppressors p16(INK4a) and p53 have been implicated as contributors to age-associated stem cell decline. Key functions of p53 are the induction of cell cycle arrest, senescence, or apoptosis in response to DNA damage. Here, we examine senescence, apoptosis, and DNA damage responses in a mouse accelerated aging model that exhibits increased p53 activity, the p53(+/m) mouse. Aged tissues of p53(+/m) mice display higher percentages of senescent cells (as determined by senescence-associated beta-galactosidase staining and p16(INK4a) and p21 accumulation) compared to aged tissues from p53(+/+) mice. Surprisingly, despite having enhanced p53 activity, p53(+/m) lymphoid tissues exhibit reduced apoptotic activity in response to ionizing radiation compared to p53(+/+) tissues. Ionizing radiation treatment of p53(+/m) tissues also induces higher and prolonged levels of senescence markers p16(INK4a) and p21, suggesting that in p53(+/m) tissues the p53 stress response is enhanced and is shifted away from apoptosis toward senescence. One potential mechanism for accelerated aging in the p53(+/m) mouse is a failure to remove damaged or dysfunctional cells (including stem and progenitor cells) through apoptosis. The increased accumulation of dysfunctional and senescent cells may contribute to reduced tissue regeneration, tissue atrophy, and some of the accelerated aging phenotypes in p53(+/m) mice.
Hinkal
George W
GW
Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Gatza
Catherine E
CE
Parikh
Neha
N
Donehower
Lawrence A
LA
D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D005347:Fibroblasts; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D016159:Tumor Suppressor Protein p53