The yin and yang of the Cdkn2a locus in senescence and aging
Open accessAbstract
Senescence of cultured cells involves activation of the p19(Arf)-p53 and the p16(Ink4a)-Rb tumor suppressor pathways. This, together with the observation that p19(Arf) and p16(Ink4a) expression increases with age in many tissues of humans and rodents, led to the speculation that these pathways drive in vivo senescence and natural aging. However, it has been difficult to test this hypothesis using a mammalian model system because inactivation of either of these pathways results in early death from tumors. One approach to bypass this problem would be to inactivate these pathways in a murine segmental progeria model such as mice that express low amounts of the mitotic checkpoint protein BubR1 (BubR1 hypomorphic mice). These mice have a five-fold reduced lifespan and develop a variety of early-aging associated phenotypes including cachetic dwarfism, skeletal muscle degeneration, cataracts, arterial stiffening, (subcutaneous) fat loss, reduced stress tolerance and impaired wound healing. Importantly, BubR1 hypomorphism elevates both p16(Ink4a) and p19(Arf) expression in skeletal muscle and fat. Inactivation of p16(Ink4a) in BubR1 mutant mice delays both cellular senescence and aging specifically in these tissues. Surprisingly, however, inactivation of p19(Arf) has the opposite effect; it exacerbates in vivo senescence and aging in skeletal muscle and fat. These mouse studies suggest that p16(Ink4a) is indeed an effector of aging and in vivo senescence, but p19(Arf) an attenuator. Thus, the role of the p19(Arf)-p53 pathway in aging and in vivo senescence seems far more complex than previously anticipated.
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The rapidly ageing BubR1 hypomorphic mouse model has been valuable for showing that senescent cells cause ageing and disease.
“The rapidly ageing BubR1 hypomorphic mouse model has been valuable to demonstrate that cellular senescent cells cause ageing and disease191,192.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [192]
The Introduction (page unavailable) identifies BubR1 hypomorphic mice as a rapidly aging model suited to investigating whether cellular senescence contributes to aging. “Linking cellular senescence in vivo to aging” reports that senescent cells accumulate in affected muscle and fat and links senescence to aging in those tissues. It does not establish the broader claim that senescent cells cause aging and disease generally; the Introduction says their direct contribution to organismal aging remains a matter of debate. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAdipose tissue, skeletal muscle and eyes of BubR1 hypomorphic mice express high p16 levels and other senescence-associated features.
“Adipose tissue, skeletal muscle and the eyes of BubR1 hypomorphic mice express high levels of p16 and other senescence-associated features192.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [192]
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“This cluster expresses known senescent markers CDKN2A (p16) and CDKN1A (p21) (Figure 5B), and G2 cell cycle markers like KI67, TOP2A, and CENPF, and DNA damage/replication genes like RRM1, BUB1B, and H2AFX (Figure S5A,S5B,S5C) 74,75 .”
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- Authors
- Baker, D. J., Jin, F., & van Deursen, J. M.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Baker, Darren J.
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2008-09-15
- Volume
- 7
- Issue
- 18
- Pages
- 2795-2802
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC2987737
- OpenAlex
- W2077116358
- Cited by
- 56
- References
- 48
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA-96985, R01CA096985)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- CDKN2A, cellular senescence, aging, p16INK4a, p19ARF, p53, Rb pathway, tumor suppressor pathways, skeletal muscle, adipose tissue, lifespan
- MeSH terms
- Aging, Animals, Humans, Mice, Mutant Strains, Tumor Suppressor Protein p53, Yin-Yang, Cellular Senescence, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Aging, Premature, Cyclin-Dependent Kinase Inhibitor p16, Mice
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