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 increases with age and is a robust senescence marker in numerous mouse and human tissues, often coinciding with SA-β-gal activity.
“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
The Expression of Ink4a/Arf in vivo section reports that p16INK4a increases with age across varied mouse cell types, and the caloric-restriction section reports overlapping p16INK4a expression and SA-β-gal activity in aging rodent kidney. Table 1 compares the mouse findings with published human tissue staining, but this paper does not establish age-related increases across numerous human tissues. It also proposes p16INK4a as a robust marker of aging rather than demonstrating it as a robust senescence marker across all those tissues. The citing sentence separately attributes the SA-β-gal-marker point to Dimri et al. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCaloric restriction, which extends health span and life span, reduces the accumulation of senescent cells.
“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]
In “Caloric restriction retards p16 INK4a accumulation” (page not provided), the paper reports that caloric restriction abolished an age-related increase in a senescence marker in mouse and rat kidneys. It also reduced age-related Ink4a/Arf expression in some tissues, but not others. The study measured markers rather than directly counting senescent cells, so it does not establish a general decrease in their accumulation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCaloric restriction lowers p16 levels and the expression of senescence-associated genes, including SASP genes, in mice and in the colon of healthy humans.
“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]
The section “Caloric restriction retards p16 INK4a accumulation” reports that caloric restriction significantly reduced p16 and Arf expression in mouse kidney. It does not report reduced SASP-gene expression or findings in healthy human colon; those parts of the sentence are not supported by this source. (LLM, conf=0.90)
Experimental — accuracy not yet measuredp16Ink4a expression increases with ageing in several rodent and human tissues.
“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]
The 'Expression of Ink4a/Arf in vivo' section reports increased p16INK4a expression with age across many mouse and rat tissues. Table 1 compares those findings with published human tissue staining, but does not show age-related increases across several human tissues; the References name evidence for aging human kidney specifically. The claim's extension to several human tissues is therefore not established by this copy (no page numbers available). (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn ovaries from mice of advanced reproductive age, cells classified as senescent have increased Cdkn2a, Cdkn1a, Serpine1 and Hmgb1.
“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]
Table 1 (IHC and SA-β-gal staining; page unavailable) reports a 30.5-fold increase in p16INK4a expression in old mouse ovaries and staining in ovarian stroma, supporting the Cdkn2a portion. The paper does not establish that the ovarian cells were classified as senescent or report increased ovarian Cdkn1a, Serpine1, or Hmgb1. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The levels of p16 expression and incidence of p16-positive cells increase with age in many mouse and rat tissues.
“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
The “Expression of Ink4a/Arf in vivo” section (page unavailable) reports increased p16 expression with age in 26 of 27 organs examined across mouse and rat tissues. Its staining results show p16-positive cells in aged mouse tissues, but the passages do not establish that the incidence of p16-positive cells increases across many tissues in both species. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCaloric restriction, which retards aging in rodents and other species, attenuated the accumulation of p16-positive cells.
“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
The “Caloric restriction retards p16 INK4a accumulation” section reports that caloric restriction reduced age-related p16 expression in several rat tissues, and Figure 3 includes p16 staining of kidney sections. It does not establish a general reduction in the number of p16-positive cells: some tissues showed no reduction, and uterine expression increased. (LLM, conf=0.85)
Experimental — accuracy not yet measuredExpression of Ets-1, a transcriptional activator of p16, correlated with p16 expression, although absolute levels of Ets-1 did not necessarily increase with age.
“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
The section on Ets-1 and Ink4a/Arf regulation reports a strong correlation between Ets-1 and p16 expression (r = 0.62, P < 0.001), and the Discussion describes the same relationship across aging tissues. The cited passages do not establish the separate claim that absolute Ets-1 levels did not necessarily increase with age; Figure 4 analyzes old-to-young expression ratios rather than stating that conclusion. No page numbers are available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredp16 is considered the best marker of senescent cells.
“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 Introduction links p16 to senescence in several cell types, and the discussion (“Ink4a/Arf-repressing”; page unavailable) calls it a potentially robust marker of aging. The paper does not establish that p16 is the best marker of senescent cells; it describes SA-β-gal as a well-described marker of senescence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAgeing is associated with the steady accumulation of senescent cells.
“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]
The Abstract reports that expression of p16 INK4a and Arf, mediators of cellular senescence, increases with age in almost all rodent tissues. The section “Caloric restriction retards p16 INK4a accumulation” also reports increased senescence-marker activity in aging rodent kidneys. These findings support an age-related increase in senescence markers, but do not establish a steady accumulation of senescent cells generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredp16 and ARF are upregulated in many tissues during aging and reflect chromatin-level regulation.
“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]
Figure 1 and the discussion of Ink4a/Arf expression report that p16INK4a and Arf increase with aging across many tissues. The Discussion infers an unknown shared regulator, but does not establish a shared enhancer or show that chromatin-level regulation explains the age-related increase; it also reports no significant correlation with Bmi-1 in most aging tissues. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe paper states that p16 is a key trigger of cellular senescence and has been proposed as a biomarker of mammalian aging.
“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]
At least some cells express p16 in vivo, during long-term culture, and at elevated levels upon replicative senescence.
“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
At least in rodents, the expression of ARF increases with age, suggesting that cells with chronic p53 activity might accumulate.
“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
p16 expression is upregulated in many tissues during ageing.
“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 expression levels of p16 and Ets1 simultaneously increase and are positively correlated during aging.
“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 young tissues, CDKN2A locus is expressed at very low undetectable level, whereas it becomes derepressed leading to high-level expression upon aging.
“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
p16INK4a is a widely accepted marker of ageing and cellular senescence.
“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]
p16 is a biomarker of natural aging, with expression increasing in various tissues over time.
“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]
Senescent cells accumulate during ageing and have an abnormal secretory phenotype that includes inflammatory cytokines and contributes to inflammageing.
“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]
Senescent cells are more common in the normal tissues of aged individuals, especially in skin and adipose tissue.
“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]
Increased expression of tumor suppressor proteins such as p16Ink4a and ARF occurs in aging cells from multiple tissues.
“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]
Age-related increases in Ink4a and Arf expression have been reported in many tissues.
“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]
p16INK4A levels correlate with chronological age in most tissues analyzed, both in mice and in humans.
“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
p16Ink4a is differentially expressed in aging tissues and has been shown to restrict islet growth.
“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]
The two genes are largely coregulated in rodents, although some stimuli can selectively regulate p16 or ARF alone, whereas co-regulation of human p16 and p14ARF is uncommon.
“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]
Senescent cells share detectable features including activation of senescence-associated β-galactosidase and transcriptional upregulation of cyclin-dependent kinase inhibitors p16Ink4a, p19Arf and p21waf1/cip1.
“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]
Senescent cells are viable for long periods and accumulate with age in various organs and tissues.
“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]
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.
“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]
Senescent cells accumulated in different tissues of aged mice, consistent with observation that SA-β-gal-positive cells increased in aged livers, kidneys and lungs.
“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]
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.
“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]
Strategies such as caloric restriction, which extend lifespan, also seem to reverse the age-dependent increase in p16INK4a transcription.
“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]
The CDKN2a locus is normally expressed at very low levels in most tissues of young organisms.
“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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- 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
- 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
- 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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