Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16INK4a and frailty
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Background Cellular senescence, measured by expression of the cell cycle kinase inhibitor p16INK4a, may contribute to accelerated aging in survivors of childhood, adolescent, and young adult cancer. The authors measured peripheral blood T‐lymphocyte p16INK4a expression among pediatric and young adult cancer survivors, hypothesizing that p16INK4a expression is higher after chemotherapy and among frail survivors. Methods A cross‐sectional cohort of young adult survivors and age‐matched, cancer‐free controls were assessed for p16INK4a expression and frailty. Newly diagnosed pediatric patients underwent prospective measurements of p16INK4a expression before and after cancer therapy. Frailty was measured with a modified Fried frailty phenotype evaluating sarcopenia, weakness, slowness, energy expenditure, and exhaustion. Results The cross‐sectional cohort enrolled 60 survivors and 29 age‐matched controls with a median age of 21 years (range, 17‐29 years). The prospective cohort enrolled 9 newly diagnosed patients (age range, 1‐18 years). Expression of p16INK4a was higher among survivors compared with controls (9.6 vs 8.9 log2 p16 units; 2‐sided P = .005, representing a 25‐year age acceleration in survivors) and increased among newly diagnosed patients from matched pretreatment to posttreatment samples (7.3‐8.9 log2 p16 units; 2‐sided P = .002). Nine survivors (16%) were frail and had higher p16INK4a expression compared with robust survivors (10.5 [frail] vs 9.5 [robust] log2 p16 units; 2‐sided P = .055), representing a 35‐year age acceleration among frail survivors. Conclusions Chemotherapy is associated with increased cellular senescence and molecular age in pediatric and young adult cancer survivors. Frail survivors, compared with robust survivors, exhibit higher levels of p16INK4a, suggesting that cellular senescence may be associated with early aging in survivors.
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Ageing exacerbates the toxicity of anticancer treatments, and some treatments can accelerate the onset of age-related dysfunctions, rendering chemotherapy a potential inducer of premature ageing via induction of senescence and SASP.
“Ageing exacerbates the toxicity of these treatments and, in addition, some of them can also accelerate the onset of age-related dysfunctions, rendering chemotherapy a potential inducer of premature ageing via induction of senescence and SASP 193,194 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [193]
The Introduction and Discussion (page numbers unavailable) link cytotoxic chemotherapy to increased p16 expression, cellular senescence, and accelerated molecular aging in young cancer survivors. The copy does not establish that aging exacerbates treatment toxicity or that SASP mediates chemotherapy-related premature aging. (LLM, conf=0.86)
Experimental — accuracy not yet measuredChildhood cancer survivors have premature accumulation of T lymphocytes expressing high levels of p16 INK4a and have higher circulating concentrations of the pro-inflammatory SASP factors IL-10 and IL-17.
“Childhood cancer survivors have premature accumulation of T lymphocytes expressing high levels of p16 INK4a and have higher circulating concentrations of the pro- inflammatory SASP factors IL-10 and IL-17 (refs. 193,197 ) .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [193]
The Results report higher p16INK4a expression in peripheral blood T lymphocytes from young adult survivors of childhood, adolescent, and young adult cancers than in age-matched controls. The paper measures expression, not an accumulation of p16-high T cells, and the passages found do not report circulating IL-10 or IL-17 concentrations (searched: IL-10, IL-17, and interleukins). Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThere is strong evidence for increased senescence and accelerated aging in childhood cancer survivors treated with chemotherapies.
“In addition to studying the senotherapeutic effects of exercise in older adults, there is strong evidence for increased senescence and accelerated aging in childhood cancer survivors treated with chemotherapies (69).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [69]
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- Authors
- Smitherman, A. B., Wood, W. A., Mitin, N., Ayer Miller, V. L., Deal, A. M., Davis, I. J., Blatt, J., Gold, S. H., & Muss, H. B.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Sapere Bio Research Triangle Park North Carolina
- Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill North Carolina
- Corresponding author
- Smitherman, Andrew B.
- ORCID
- Venue
- Cancer
- Publisher
- Wiley
- Published
- 2020-08-24
- Volume
- 126
- Issue
- 22
- Pages
- 4975-4983
- ISSN
- 0008-543X (ISSN-L)
- 1097-0142
- PMC
- PMC7607511
- OpenAlex
- W3081212722
- Cited by
- 80
- References
- 25
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 17 · 2023: 12 · 2022: 17 · 2021: 9 · 2020: 2
- FWCI
- 9.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01‐CA203023)
- North Carolina Translational and Clinical Sciences Institute, University of North Carolina at Chapel Hill (KL2‐TR002490)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Childhood Cancer Survivors' Quality of Life
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Geriatrics and Gerontology › Frailty in Older Adults
- Keywords
- accelerated aging, childhood cancer survivors, adolescent cancer survivors, young adult cancer survivors, p16INK4a, cellular senescence, frailty, chemotherapy, T cells, Fried frailty phenotype, childhood cancer
- MeSH terms
- Cancer Survivors, Frailty, Adolescent, Adult, Aging, Cross-Sectional Studies, Humans, Cyclin-Dependent Kinase Inhibitor p16, Young Adult
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