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Updated: Aug 11, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice
Darren J Baker1, Karthik B Jeganathan, Liviu Malureanu
1Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Abstract:
Aging is a highly complex biological process that is believed to involve multiple mechanisms. Mice that have small amounts of the mitotic checkpoint protein BubR1 age much faster than normal mice, but whether other mitotic checkpoint genes function to prevent the early onset of aging is unknown. In this study, we show that several aging-associated phenotypes appear early in mice that are double haploinsufficient for the mitotic checkpoint genes Bub3 and Rae1 but not in mice that are single haploinsufficient for these genes. Mouse embryonic fibroblasts (MEFs) from Bub3/Rae1 haploinsufficient mice undergo premature senescence and accumulate high levels of p19, p53, p21, and p16, whereas MEFs from single haploinsufficient mice do not. Furthermore, although BubR1 hypomorphic mice have less aneuploidy than Bub3/Rae1 haploinsufficient mice, they age much faster. Our findings suggest that early onset of aging-associated phenotypes in mice with mitotic checkpoint gene defects is linked to cellular senescence and activation of the p53 and p16 pathways rather than to aneuploidy.
Insights
Defects in mitotic checkpoint genes Bub3 and Rae1 cause premature aging phenotypes in mice, linked to cellular senescence and specific protein pathways, not aneuploidy.
Area of Science:
- Cellular and Molecular Biology
- Genetics and Genomics
- Aging Research
Background:
- Aging is a complex biological process influenced by multiple mechanisms.
- Mitotic checkpoint genes, like BubR1, are implicated in aging.
- The role of other mitotic checkpoint genes in preventing premature aging remains unclear.
Purpose of the Study:
- To investigate the role of Bub3 and Rae1 mitotic checkpoint genes in aging.
- To determine if haploinsufficiency of Bub3 and Rae1 leads to aging-associated phenotypes.
- To explore the relationship between mitotic checkpoint gene defects, cellular senescence, and aging.
Main Methods:
- Generation and analysis of mice with single and double haploinsufficiency for Bub3 and Rae1.
- Assessment of aging-associated phenotypes in these mice.
- Analysis of cellular senescence and protein pathways (p19, p53, p21, p16) in mouse embryonic fibroblasts (MEFs).
- Comparison with BubR1 hypomorphic mice regarding aging and aneuploidy.
Main Results:
- Double haploinsufficiency for Bub3 and Rae1, but not single haploinsufficiency, resulted in early aging phenotypes.
- MEFs from Bub3/Rae1 haploinsufficient mice exhibited premature senescence and elevated p19, p53, p21, and p16 levels.
- BubR1 hypomorphic mice aged faster than Bub3/Rae1 haploinsufficient mice despite having less aneuploidy.
Conclusions:
- Defects in mitotic checkpoint genes Bub3 and Rae1 can accelerate aging.
- Early aging phenotypes in these mice are associated with cellular senescence and activation of the p53 and p16 pathways.
- Aneuploidy is not the primary driver of early aging in the context of these specific mitotic checkpoint gene defects.
