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Ink4a/Arf expression is a biomarker of aging
Open accessAbstract
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.
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“p16INK4a also increases with age and is a robust senescence marker in numerous mouse and human tissues (Krishnamurthy et al., 2004; Ressler et al., 2006), often coinciding with another prominent senescence marker, senescence-associated beta-galactosidase (SA-β-gal) activity (Dimri et al., 1995).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Krishnamurthy et al., 2004
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“A key study demonstrating that caloric restriction, which increases health span and life span, decreases the accumulation of Sncs (18)”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [18]
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“Nevertheless, it was reported that caloric restriction reduces p16 levels and the transcriptional expression of genes associated with cellular senescence, including SASP genes, in mice and in the colon of healthy human individuals256,257.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [256]
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“Additionally, the expression of p16Ink4a is known to increase with ageing in several rodent and human tissues8.”
From Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders (2011) · cites this paper as [8]
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“In ovaries from mice of advanced reproductive age, cells classified as senescent are characterized by increased expression of Cdkn2a (refs. 238–240), Cdkn1a, Serpine1 and Hmgb1 (ref. 239).”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [238]
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“Senescent cells accumulated in different tissues of aged mice,4,40,41 which was consistent with our observation that SA-β-gal-positive cells increased in aged livers, kidneys and lungs (Supplementary information, Fig. S5a–c).”
From Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice (2020) · cites this paper as [41]
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“strategies such as caloric restriction, which extend lifespan, also seem to reverse the age-dependent increase in p16INK4a transcription 16, 18”
From The common biology of cancer and ageing (2007) · cites this paper as [16]
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“There is, however, intriguing evidence that, similar to p19/ARF, the levels of p16 expression and incidence of p16-positive cells increase with age in many mouse and rat tissues (Zindy et al., 1997; Krishnamurthy et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
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“Of particular importance, caloric restriction, which retards aging in rodents and other species, attenuated the accumulation of p16-positive cells (Krishnamurthy et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
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“In addition, expression of Ets-1, a transcriptional activator of p16 (Ohtani et al., 2001), correlated with p16 expression, although absolute levels of Ets-1 did not necessarily increase with age (Krishnamurthy et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
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“p16 is considered the best marker of senescent cells, and its expression is upregulated in many tissues during ageing [10 -12].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
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“Furthermore, as the most important risk factor for cancer, ageing is associated with the steady accumulation of senescent cells [10 -12]”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
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“Moreover, these two genes share an enhancer and regulation at the chromatin level; therefore, both genes are upregulated in many tissues during aging and reflect chromatin-level regulation [10].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
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“the levels of p16INK4a (and to a lower extent also p19ARF) correlate with the chronological age of essentially all tissues analyzed, both in mice and humans”
From The Hallmarks of Aging (2013) · cites this paper as Krishnamurthy et al., 2004
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“p16 is a key trigger of cellular senescence16, and its expression increases with aging in several rodent and primate tissues17–19, suggesting its potential use as a biomarker of mammalian aging.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [18]
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“This is in accordance with previous reports, which have found that p16INK4A levels correlate with chronological age in most tissues analyzed, both in mice (Baker et al., 2016, Krishnamurthy et al., 2004) and in humans (Ressler et al., 2006).”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Krishnamurthy et al., 2004
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“However, at least some cells express p16 in vivo (Krishnamurthy et al., 2004), during long-term culture (Benanti and Galloway, 2004), and at elevated levels upon replicative senescence (Alcorta et al., 1996; Hara et al., 1996; Brenner et al., 1998; Stein et al., 1999; Itahana et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
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“At least in rodents, the expression of ARF increases with age (Krishnamurthy et al., 2004), suggesting that cells with chronic p53 activity might accumulate.”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
The cited source says what the claim attributes to it.
In the citing paper
“p16 is considered the best marker of senescent cells, and its expression is upregulated in many tissues during ageing [10 -12].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“Interestingly, the expression levels of p16 and Ets1 simultaneously increase and are positively correlated during aging [10].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
In the citing paper
“In young tissues, the CDKN2A locus is normally expressed at a very low undetectable level whereas it becomes derepressed leading to a high-level of expression upon aging (Krishnamurthy et al., 2004).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Krishnamurthy et al., 2004
In the citing paper
“This evidence has established p16INK4a as a widely-accepted marker of ageing and cellular senescence [81,82].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [82]
In the citing paper
“Importantly, p16 INK4A is a biomarker of natural aging, as its expression increases in a variety of tissues with time (28).”
From Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives (2018) · cites this paper as [28]
In the citing paper
“senescent cells persist and accumulate during ageing82 and they display an abnormal secretory phenotype characterized by the presence of inflammatory cytokines that contributes to inflammageing.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [82]
In the citing paper
“Senescent cells are more common in the normal tissues of aged individuals, especially in certain tissue types, such as skin and adipose tissue [38,39,40].”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [38]
In the citing paper
“Increased expression of tumor suppressor proteins such as p16 Ink4a and ARF also occurs in aging cells from multiple tissues (79,80).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [79]
In the citing paper
“because an age-related increase in expression of both of these tumorsuppressor genes has been reported in numerous tissues, 13”
From Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a (2012) · cites this paper as [13]
In the citing paper
“p16Ink4a is differentially expressed in aging tissues and has been shown to restrict islet growth (27,28).”
From Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age (2009) · cites this paper as [27]
In the citing paper
“The two genes are largely coregulated in rodents, although some stimuli can selectively regulate p16 or ARF alone [128], whereas co-regulation of human p16 and p14ARF is uncommon [123].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [128]
In the citing paper
“Senescent cells share distinct detectable features, including the activation of the senescence-associated β-galactosidase (SA-β-gal) [28] and the transcriptional upregulation of cyclin-dependent kinase inhibitors (i.e., p16Ink4a, p19Arf and p21waf1/cip1) [65, 74].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [65]
In the citing paper
“senescent cells are viable for long periods of time and thereby accumulate with age in various organs and tissues5–7.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [5]
In the citing paper
“Increased expression of p16 and Arf has been implicated in mediating induction of senescence in a variety of cells including HSCs and is the most robust biomarker of senescence cells besides SA-β-gal staining.8,24,25”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [25]
In the citing paper
“It is well established that the CDKN2a locus is activated during organismal ageing in both rodents and humans, and the levels of p16INK4a constitute an impressively good overall biomarker of ageing 16, 17”
From The common biology of cancer and ageing (2007) · cites this paper as [16]
In the citing paper
“The CDKN2a locus is normally expressed at very low levels in most tissues of young organisms 16”
From The common biology of cancer and ageing (2007) · cites this paper as [16]
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Metadata
- Authors
- Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Southern Illinois University Carbondale (US)
- SIU Medicine (US)
- UNC Lineberger Comprehensive Cancer Center (US)
- Corresponding author
- Sharpless, Norman E.
- Venue
- Journal of Clinical Investigation
- Published
- 2004-11-01
- Volume
- 114
- Issue
- 9
- Pages
- 1299-1307
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC524230
- OpenAlex
- W2073429636
- Semantic Scholar
- 5b25e72d000d08a468fd5e9b4a1b4c8009757274
- Cited by
- 1,486
- References
- 64
- Citations by year
- 2026: 32 · 2025: 51 · 2024: 86 · 2023: 76 · 2022: 75 · 2021: 94 · 2020: 100 · 2019: 91 · 2018: 78 · 2017: 82 · 2016: 80 · 2015: 77 · 2014: 74 · 2013: 76 · 2012: 72
- FWCI
- 19.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- National Institutes of Health
- National Institute on Aging (AG 19899, R01AG019899)
- National Cancer Institute (K08CA090679, CA090679)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
- INK4a/ARF locus, p16INK4a, ARF, cellular senescence, aging, aging biomarkers, caloric restriction, ETS1, transcriptional regulation, tumor suppressor, kidney, ovary, heart, age-related diseases
- MeSH terms
- Aging, Animals, beta-Galactosidase, Cell Cycle, Disease Models, Animal, Humans, Immunohistochemistry, Models, Biological, Time Factors, Tissue Distribution, Biomarkers, Polymerase Chain Reaction, Cyclin-Dependent Kinase Inhibitor p16, Reverse Transcriptase Polymerase Chain Reaction, ADP-Ribosylation Factor 1, Caloric Restriction, Mice, Rats
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