Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries
Open accessAbstract
Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone γ-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.
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Telomere uncapping and DNA damage within telomeres can trigger senescence independent of changes in telomere length.
“It also should be noted that telomere uncapping and DNA damage within telomeres can trigger senescence independent of changes in telomere length (5,6).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [6]
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References 52 · Cited by 115
- Authors
- Morgan, R. G., Ives, S. J., Lesniewski, L. A., Cawthon, R. M., Andtbacka, R. H. I., Noyes, R. D., Richardson, R. S., & Donato, A. J.
- Affiliations
- University of Utah (US)
- VA Salt Lake City Healthcare System (US)
- Corresponding author
- Donato, Anthony J.
- ORCID
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2013-07-15
- Volume
- 305
- Issue
- 2
- Pages
- H251-H258
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC3726958
- OpenAlex
- W2167408001
- Cited by
- 115
- References
- 52
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 7 · 2023: 9 · 2022: 17 · 2021: 18 · 2020: 11 · 2019: 7 · 2018: 13 · 2017: 6 · 2016: 5 · 2015: 5 · 2014: 2
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Creative Matter (Skidmore College) (submittedVersion)
- Funders
- National Institute on Aging (K01AG029337, R21AG043952, AG-033196, AG-040297, AG 029337, AG-033755, K01AG033196, R01AG040297, R21AG033755)
- National Heart, Lung, and Blood Institute (HL-09183, F32HL009183)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- telomere uncapping, cellular senescence, senescence-associated inflammation, arterial aging, telomere shortening, p53, p21, γH2AX, TRF2, skeletal muscle arteries, interleukin-8, MCP-1, telomere dysfunction
- MeSH terms
- Adult, Age Factors, Aged, Aging, Analysis of Variance, Arteries, Arteritis, Binding Sites, Female, Histones, Humans, Male, Middle Aged, Phosphorylation, Promoter Regions, Genetic, Risk Factors, RNA, Messenger, Chi-Square Distribution, Polymerase Chain Reaction, Tumor Suppressor Protein p53, Interleukin-8, Telomere, Cellular Senescence, Muscle, Skeletal, Chemokine CCL2, Telomeric Repeat Binding Protein 2, Chromatin Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p21, Prescription Drugs, Telomere Shortening
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