SenNet recommendations for detecting senescent cells in different tissues

In the paper

“In humans, mice and some other species, cellular senescence has been shown to contribute to various physiological and pathological processes1.”

What the sources say

• Supported

  The Introduction says cellular senescence has a clear role in physiological and pathological states and describes senescent cells in mammalian species, including humans. The section on Other Age-Related Disease discusses effects in humans and mice, supporting the claim's species scope. (LLM, conf=0.91)

  cites [1] He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). source

In the paper

“Activation of RB and p53 (encoded by TP53 in humans, Trp53 in mice) also occurs in other forms of cell cycle arrest14, and CDKN2A is expressed in certain non-senescent cells15 and is not expressed in all senescent cells16.”

What the sources say

• Supported

  The citation to this source is attached to the final clause, that CDKN2A is not expressed in all senescent cells. In “What defines a senescent cell?”, the paper says that some senescent cells do not express p16INK4a. The preceding claims about RB/p53 activation and expression in non-senescent cells carry different citations. (LLM, conf=0.94)

  cites [14] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011). source
• ?Not checked — no full text of the sourcecites [15] Sharpless, N. E. & Sherr, C. J. Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 (2015). source
• Supported

  The Cyclin-Dependent Kinase Inhibitors and Cell Cycle Arrest section identifies p16 as encoded by CDKN2A and used as a senescence marker. The Highlights state that no universal senescence marker exists, supporting the cited point that p16 is not expressed in every senescent cell. Citation 16 is attached to that point, not to the preceding claims about RB, p53, or non-senescent cells. (LLM, conf=0.84)

  cites [16] Hernandez-Segura, A., Nehme, J. & Demaria, M. Hallmarks of cellular senescence. Trends Cell Biol. 28, 436–453 (2018). source

In the paper

“The composition and strength of the SASP can vary depending on the duration of senescence, the origin of the senescence stimulus and specific cell types17,21.”

What the sources say

• Supported

  The Macromolecular Damage passage states that SASP composition and strength vary with senescence duration, the origin of the pro-senescence stimulus, and cell type. This directly supports the attributed paraphrase. (LLM, conf=0.95)

  cites [17] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). source
• Supported

  The Introduction section on cell-autonomous and non-autonomous effects says the SASP is variable and plastic, depends on cell type and senescence inducer, and changes characteristics over time. This supports the cited claim about variation in its composition and strength. (LLM, conf=0.92)

  cites [21] Wiley, C. D. & Campisi, J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat. Metab. 3, 1290–1301 (2021). source

In the paper

“Senescent cells in both human and mouse adipose tissue have been characterized by expression of CDKN2A and CDKN1A, higher SA-β-gal activity, DNA damage (γH2AX) foci and arrest of cell proliferation (MKI67), and by expression of SASP factors including IL-6, CXCL8 (also known as IL-8), IL-1β, TNF, CCL2, SERPINE1, MMP3 and MMP12 (refs. 119–122).”

What the sources say

• ?Could not verify

  The paper’s Significance passage (page unavailable) describes a capillary analogue of muscle contraction, not senescence in adipose tissue. Searches for the adipose-tissue senescence markers and listed SASP factors found no passage addressing the claim in our copy. (LLM, conf=0.78)

  cites [119] Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015). sourceExperimental — accuracy not yet measured
• Partly supported

  The mouse-adipose Results report increased CDKN2A expression, SA-β-gal-positive cells and telomere-associated DNA-damage foci. The human-adipose Results identify p16INK4A, SA-β-gal and those foci as senescence markers, and report secretion of IL-6, IL-8, MCP-1 and PAI-1 (corresponding to CCL2 and SERPINE1). The cited paper does not establish the claimed CDKN1A or MKI67 markers, or the full listed set of SASP factors, in both human and mouse adipose tissue. (LLM, conf=0.88)

  cites [120] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (‘Senescent cell clearance improves glucose homeostasis and insulin sensitivity’; page not supplied) identify p16Ink4a- and p21Cip1-expressing senescent cells in mouse adipose tissue. The adipose-tissue methods assay SA-β-gal, and the Results discuss IL-1β, TNF-α and MCP-1. Our copy does not establish the full marker profile in both human and mouse adipose tissue: it does not document γH2AX foci or MKI67 arrest there, or identify CXCL8, SERPINE1, MMP3 and MMP12 as adipose-cell SASP factors. (LLM, conf=0.88)

  cites [121] Palmer, A. K. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18, e12950 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion describe p21-high cells in mouse adipose tissue as having higher SA-β-gal activity, reduced proliferation and a SASP; the paper also examines γH2AX-positive telomere-associated foci. It treats p21-high and p16-high cells as partly distinct populations, rather than establishing that senescent cells express both markers. Although it uses human adipose tissue for transplantation, the cited passages do not establish the full marker profile in human tissue or substantiate the entire listed SASP panel or MKI67 specifically. Page numbers were not available in our copy. (LLM, conf=0.87)

  cites [122] Wang, L. et al. Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 34, 75–89.e8 (2022). sourceExperimental — accuracy not yet measured

In the paper

“In humans, cardiac progenitor cells defined as KIT+PECAM1−PTPRC− (also known as c-kit+CD31−CD45−) showed increased levels of CDKN2A, SA-β-gal activity, γH2AX foci, reduced BrdU incorporation into DNA (S phase marker; reduced incorporation indicates cell cycle arrest) and induction of the SASP during ageing62.”

What the sources say

• Partly supported

  Section 2.1 (p. 4) reports age-related increases in p16INK4A (CDKN2A), SA-β-gal and γH2AX-positive human cardiac progenitor cells; the Discussion (p. 10) also reports a senescence-associated secretory phenotype. Figure 2 (p. 6) shows diminished proliferation in cells from aged hearts, but the BrdU result in section 2.3 (p. 8) concerns cells in hearts injected with progenitor cells, not BrdU incorporation by the human progenitor cells themselves. Thus, the specific reduced-BrdU-incorporation claim is unsupported. (LLM, conf=0.89)

  cites [62] Lewis-McDougall, F. C. et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell 18, e12931 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Two mechanisms of transmission have been described: paracrine senescence is mediated by the SASP24, whereas juxtracrine senescence, involving direct cell to cell contact, is mediated by NOTCH1–JAG1 signalling25,26.”

What the sources say

• Supported

  The section “Multiple components of the SASP mediate paracrine senescence” reports that factors secreted by senescent cells mediate paracrine senescence. This source is cited for the SASP clause; the NOTCH1–JAG1 clause carries separate citations. (LLM, conf=0.94)

  cites [24] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). source
• Partly supported

  The Introduction says SASP can induce secondary senescence through paracrine signaling, and the Discussion identifies Notch signaling as cell-to-cell contact–mediated (juxtacrine). The paper does not establish the specific NOTCH1–JAG1 pairing attributed to it; its reported ligand finding concerns Jag2 instead. Our copy provides section labels but no page numbers. (LLM, conf=0.86)

  cites [25] Teo, Y. V. et al. Notch signaling mediates secondary senescence. Cell Rep. 27, 997–1007.e5 (2019). sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [26] Evans S. A. et al. Single-cell transcriptomics reveals global markers of transcriptional diversity across different forms of cellular senescence. AgingBio 1, 1–13 (2023).

In the paper

“Increased levels of SA-β-gal activity and expression of apoptosis (Bcl2) and DNA damage (γH2AX and phosphorylated p38 MAPK) regulators, and the downregulation of LMNB1, are additional characteristics of age-associated or neurodegeneration-associated neuronal and glial cells102,105–108.”

What the sources say

• Partly supported

  The Results section reports an age-dependent increase in LMNB1-negative hippocampal neurons in mice, supporting the LMNB1 part of the claim. The passages do not establish increased SA-β-gal, Bcl2, γH2AX, or phosphorylated p38 MAPK in neuronal or glial cells, nor do they establish this marker pattern in neurodegeneration. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [102] Ogrodnik, M. et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports increased SA-β-Gal activity in senescent astrocyte cultures, and the Discussion reports lamin-B1 loss in senescent astrocytes and aging hippocampal tissue (page numbers unavailable). These passages support those two features in astrocytes, but not the attributed increases in Bcl2, γH2AX, or phosphorylated p38 MAPK, nor the full extension of this marker list to neurons and neurodegeneration-associated cells. (LLM, conf=0.88)

  cites [105] Matias, I. et al. Loss of lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus. Aging Cell 21, e13521 (2022). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results sections on Parkinsonian substantia nigra astrocytes and paraquat-induced senescence report reduced lamin B1 in astrocytes and increased SA-β-gal activity in paraquat-treated astrocytes. The paper reports 53BP1 foci as a DNA-damage marker, but the passages found do not establish increased Bcl2, γH2AX, or phosphorylated p38 MAPK as features of these cells, nor do they establish the listed features in neurons. Page numbers were not available in our copy. (LLM, conf=0.87)

  cites [106] Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 22, 930–940 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports elevated γ-H2ax in tauNFT mouse brains, and the Discussion describes loss of lamin B as associated with tau pathology. But the Results section on SA β-gal reports fewer positive cells than controls and says its activity did not correlate with other senescence markers or brain atrophy. Our copy does not establish increased Bcl2 or phosphorylated p38 MAPK, or these features specifically in glial cells. (LLM, conf=0.88)

  cites [107] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [108] Dong, C. et al. ATM modulates subventricular zone neural stem cell maintenance and senescence through Notch signaling pathway. Stem Cell Res. 58, 102618 (2022). source

In the paper

“In a mouse model of acute myeloid leukaemia, qPCR of bone marrow cells showed upregulation of the senescence markers Cdkn2a, Cdkn1a and SASP factors, and downregulation of Lmnb1 (ref. 94).”

What the sources say

• Supported

  The ‘AML induces a senescent phenotype in vivo’ section (p. 8) reports real-time PCR of sorted mouse bone marrow stromal cells from AML-engrafted mice. It found increased p16INK4a (Cdkn2a), p21 (Cdkn1a), and the SASP factors IL-6 and MIP3, alongside decreased lamin B1 expression. The claim’s ‘bone marrow cells’ refers more specifically to those sorted stromal cells. (LLM, conf=0.93)

  cites [94] Abdul-Aziz, A. M. et al. Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Blood 133, 446–456 (2019). source

In the paper

“During normal ageing, mouse cardiomyocytes accumulate the following senescence-associated markers: TAF, cyclin-dependent kinase inhibitors (CDKN1a, CDKN2B (also known as p15INK4b) and CDKN2a), SA-β-gal activity, SADS and a pro-fibrotic SASP60.”

What the sources say

• Supported

  The Results report that mouse cardiomyocytes accumulate TAF with age (Fig. 1) and show age-dependent increases in p21, p15 and p16 expression, SA-β-gal activity, and SADS (Fig. 4). They also identify a non-typical secretory phenotype in aged cardiomyocytes whose factors promote myofibroblast activation (Fig. 5), supporting the description of a pro-fibrotic SASP. (LLM, conf=0.93)

  cites [60] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). source

In the paper

“Adipose tissue-derived mesenchymal stem cells from older donors (human and mouse) exhibit senescence properties and impaired regenerative potential123,124.”

What the sources say

• Partly supported

  The Conclusions report senescent features and reduced osteogenic and chondrogenic potential in adipose-derived MSCs from older donors. The Methods identify the donors as human; the Background’s mouse finding concerns bone marrow-derived MSCs, not adipose-derived MSCs. This source therefore does not support the claim’s mouse-adipose component. (LLM, conf=0.90)

  cites [123] Choudhery, M. S., Badowski, M., Muise, A., Pierce, J. & Harris, D. T. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. J. Transl. Med. 12, 8 (2014). sourceExperimental — accuracy not yet measured
• Supported

  The paper reports a senescent-like population in ADSCs from old mouse donors and notes comparable senescent-cell percentages in ADSCs from old human donors (Abstract; no page provided). It also states that emerging evidence suggests reduced regenerative potential in ADSCs from aged donors. The human finding and regenerative-potential point are reported as prior evidence, rather than tested directly in this study. (LLM, conf=0.86)

  cites [124] Wang, B. et al. Transplanting cells from old but not young donors causes physical dysfunction in older recipients. Aging Cell 19, e13106 (2020). source

In the paper

“Needle biopsies containing tissue of the bone and bone marrow analysed by qPCR revealed increased levels of CDKN2A and CDKN1A, and the SASP increased with age93.”

What the sources say

• Partly supported

  The Results (page not provided) report that rt-qPCR of bone needle biopsies from older versus younger women found significantly higher p16Ink4a (CDKN2A) and p21 (CDKN1A) expression. Twelve SASP factors were also higher, but the 36-factor panel did not show a statistically significant increase as a group; the authors call the human SASP findings preliminary. The claim overstates that part as a general increase in the SASP. (LLM, conf=0.90)

  cites [93] Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Additionally, the expression of CDKN1A, CDKN2A and the presence of TAF has been found in the context of non-alcoholic fatty liver disease159,161, and TAF have been reported in livers from individuals with alcoholic liver disease162.”

What the sources say

• Partly supported

  The Results section, “Hepatocyte senescence correlates with severity of NAFLD” (page unavailable), reports TAF and p21—the protein encoded by CDKN1A—in biopsies from nine patients with NAFLD. It does not report CDKN2A expression in those patients. The alcoholic-liver-disease statement is attached to a different citation, so it is not assessed against this paper. (LLM, conf=0.88)

  cites [159] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [161] Aravinthan, A. et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J. Hepatol. 58, 549–556 (2013). source
• Supported

  Citation 162 is attached to the alcoholic-liver-disease part of the sentence. In the Results section (“Neutrophils promote hepatocellular telomere damage,” Fig. 5b; page not provided), the paper reports telomere-associated DNA damage foci in hepatocytes from human alcoholic liver disease, with negligible TAF-positive hepatocytes in normal human liver. The preceding non-alcoholic fatty liver disease claim is attributed to citations 159 and 161, not this source. (LLM, conf=0.94)

  cites [162] Wilson, C. L. et al. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat. Commun. 6, 6818 (2015). source

In the paper

“Serpine1 overexpression causes podocyte detachment and apoptosis, resulting in glomerulosclerosis140.”

What the sources say

• Partly supported

  The Results sections report increased PAI-1 expression in aged mouse kidneys, PAI-1-dependent podocyte detachment and apoptosis in cell experiments, and protection from glomerulosclerosis after endothelial PAI-1 deletion in aged mice (page not available). These findings support the proposed pathway, but the paper does not show that experimentally overexpressing Serpine1 causes the entire sequence; its evidence concerns age-associated endothelial PAI-1 elevation and loss-of-function experiments. (LLM, conf=0.84)

  cites [140] Cohen, C. et al. Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1. EMBO Mol. Med. 13, e14146 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Different animal models of kidney disease exhibit increased SA-β-gal activity and overexpression of Cdkn2a, Cdkn1a, Trp53 and SASP components, including SERPINE1, IL-1β, IL-6, TNF and MMP13 (refs. 140,148).”

What the sources say

• Partly supported

  The Results sections on aging nephropathy and glomerular endothelial senescence (page unavailable) report SA-β-gal staining, increased p16 activity and p21-positive cells in mouse kidneys. They also report increased PAI-1 (encoded by SERPINE1), IL-1β, IL-6 and MMP13 in old versus young mice. The copy does not establish increased Trp53 or TNF, nor does it show that the full list is overexpressed across different kidney-disease models. (LLM, conf=0.86)

  cites [140] Cohen, C. et al. Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1. EMBO Mol. Med. 13, e14146 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The figure captions in the section labelled “4 Days” (page unavailable) report increased SA-β-gal activity, p16INK4a (Cdkn2a), p21 (Cdkn1a), and PAI-1 (SERPINE1) in streptozotocin-diabetic rats. This paper studies one animal model, not different models, and the cited passages do not establish overexpression of Trp53, IL-1β, IL-6, TNF, or MMP13. (LLM, conf=0.90)

  cites [148] Satriano, J. et al. Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am. J. Physiol. Cell Physiol. 299, C374–C380 (2010). sourceExperimental — accuracy not yet measured

In the paper

“Importantly, Cdkn1ahigh and Cdkn2ahigh cells exist as two distinct cell populations122,125, indicating the heterogeneity and complexity of senescent cell populations in adipose tissue.”

What the sources say

• Partly supported

  The Results section reports that p21-high (Cdkn1a-high) and p16-high (Cdkn2a-high) cells were distinguishable in mouse visceral adipose tissue after 10 months of high-fat feeding, despite some overlap. The Discussion calls them distinct populations, but explicitly limits that conclusion to at least the context of obesity; the citing sentence does not retain that qualifier. (LLM, conf=0.84)

  cites [122] Wang, L. et al. Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 34, 75–89.e8 (2022). sourceExperimental — accuracy not yet measured
• Supported

  The Results section ('p16high and p21high cells are two distinct cell populations') reports different distributions of these cells in aged visceral fat and concludes that they are distinct populations in aged tissues. Extended Data Fig. 1 identifies p21 as Cdkn1a and p16 as Cdkn2a. The evidence is specifically from aged mouse adipose tissue. (LLM, conf=0.91)

  cites [125] Wang, B. et al. An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo. Nat. Aging 1, 962–973 (2021). source

In the paper

“Studies on aged mouse hepatocytes have shown the presence of senescence-associated markers such as SA-β-gal activity157, TAF54,158, karyomegaly and SADS159, LINE-1 expression23 and expression of SASP factors141.”

What the sources say

• ?Not checked — no full text of the sourcecites [157] Wang, C. et al. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8, 311–323 (2009). source
• Supported

  The Results section, “TAF increase with age irrespective of telomere length,” reports TAF in mouse liver hepatocytes and an increase in TAF per cell with age. This citation is attached to TAF in the citing sentence, not to the other listed markers. (LLM, conf=0.94)

  cites [54] Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on physiological ageing in primates reports telomere-associated DNA-damage foci in liver hepatocytes from old baboons, supporting the TAF portion of the citation. It does not establish TAF in aged mouse hepatocytes; its mouse experiment examined irradiated hippocampal neurons. The other listed markers have separate citations and are not attributed to this source. (LLM, conf=0.88)

  cites [158] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). sourceExperimental — accuracy not yet measured

In the paper

“Most human renal nephropathies are associated with accelerated cellular senescence142,145,147,149,154,155, with CDKN2A being most overexpressed in TECs.”

What the sources say

• Partly supported

  The Results sections report increased senescence markers in kidneys of hyperglycaemic mice, and the References list a study of accelerated senescence in patients with type 2 diabetic nephropathy. That does not establish the claim about most human renal nephropathies. The paper also does not report that CDKN2A is most overexpressed in tubular epithelial cells; its kidney-cell results emphasize endothelial cells and macrophages. No page numbers are available in our copy. (LLM, conf=0.85)

  cites [142] Prattichizzo, F. et al. Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages. Redox Biol. 15, 170–181 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [145] Sis, B. et al. Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int. 71, 218–226 (2007). source
• ?Not checked — no full text of the sourcecites [147] Verzola, D. et al. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 295, F1563–F1573 (2008). source

In the paper

“TNSF8+PDCD1+CD44hiCD4+ (CD153+PDCD+CD44hiCD4+) T cells accumulate in adipose tissue in obesity and show senescence features, including increased expression of SPP1, CDKN2A and CDKN1A and decreased expression of SATB1, DUSP10 and EEF1A1128.”

What the sources say

• Partly supported

  The section on high-fat-diet-induced T-cell accumulation (page unavailable) reports that CD153+PD-1+CD44hiCD4+ cells accumulate in the visceral adipose tissue of obese mice and show senescence features. It reports increased Spp1, Cdkn1a and Cdkn2b—not the claimed CDKN2A—and decreased Satb1, Dusp10 and Eef1a1. The finding is specifically in mice and visceral adipose tissue. (LLM, conf=0.91)

  cites [128] Shirakawa, K. et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J. Clin. Invest. 126, 4626–4639 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Upon ageing and obesity, SASP factors from the senescent cells upregulate CD38 in adipose immune cells, thereby decreasing NAD+ levels, which results in increased metabolic dysfunction and a decline in overall fitness127.”

What the sources say

• Partly supported

  The Results section, “Accumulation of CD38 in vivo can be induced by SASP” (page unavailable), reports that conditioned media from senescent pre-adipocytes increased macrophage CD38 and lowered NAD+ in mouse white adipose tissue. The Introduction links age-related NAD+ decline to metabolic dysfunction and reduced overall fitness. The paper does not establish this SASP–CD38 pathway in obesity or show that the pathway itself worsens metabolic function or fitness. (LLM, conf=0.87)

  cites [127] Chini, C. C. S. et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat. Metab. 2, 1284–1304 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Glomerular endothelial cells140 and proximal tubular epithelial cells (TECs)140,141 become senescent with ageing in mice, showing increased SA-β-gal staining and Cdkn2a expression.”

What the sources say

• Partly supported

  The Results sections on aging nephropathy and the time-course analysis show increased glomerular endothelial senescence in aged mice, more SA-βGal-positive glomeruli, increased p16 mRNA, and more p21-positive cells in both glomeruli and tubules. They do not identify the tubular cells as proximal epithelial cells or show increased SA-βGal staining and Cdkn2a expression specifically in those cells. No page numbers are available in our copy. (LLM, conf=0.87)

  cites [140] Cohen, C. et al. Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1. EMBO Mol. Med. 13, e14146 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘Renal epithial cell senescence and glomerulosclerosis’ section (page unavailable) identifies SAβ-Gal-positive cells in proximal tubules, supporting the tubular epithelial-cell portion. It says those cells were not located in the glomeruli, so it does not support the glomerular endothelial-cell portion; it also does not report increased Cdkn2a expression in either specified kidney cell type. (LLM, conf=0.88)

  cites [141] Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Senescent cells in the bone microenvironment, which consisted principally of CD24+ osteo-lineage cells and late osteoblasts/osteocytes, were defined as CDKN2A+Ki67–BCL2+ and CDKN1A+ Ki67–BCL2+, and exhibited a significant increase in other senescence markers, SASP factors and DNA damage markers56.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [56] Doolittle, M. L. et al. Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton. Nat. Commun. 14, 4587 (2023). source

In the paper

“Osteocytes have increased SADS with age, in addition to an increase of Cdkn2a, Cdkn1a and Trp53 and numerous SASP transcripts93.”

What the sources say

• Supported

  The Results report more SADS-positive osteocytes in old than young mouse bone cortices (Fig. 3A–G). They also report higher osteocyte expression of p16Ink4a (Cdkn2a), p21 (Cdkn1a), and p53 (Trp53) with age (Fig. 2A–C), and higher levels of 23 of 36 SASP genes in old osteocytes (Fig. 4A). (LLM, conf=0.93)

  cites [93] Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929 (2016). source

In the paper

“Recent research has demonstrated increased expression of Trp53 and Cdkn1a, and the presence of TAF in the airway smooth muscle cells from older individuals with asthma174.”

What the sources say

• Supported

  The Results (Fig. 3D; page unavailable) report higher p53 and p21 gene expression in airway smooth muscle cells from elderly people with asthma than in cells from elderly people without asthma or younger controls. The Results (Fig. 3B; page unavailable) also report more airway smooth muscle nuclei containing telomere-associated foci (TAF) in that group. (LLM, conf=0.94)

  cites [174] Aghali, A. et al. Cellular senescence is increased in airway smooth muscle cells of elderly persons with asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 323, L558–L568 (2022). source

In the paper

“The SenMayo gene panel (Box 3) was generated and validated in bone biopsies from two aged human cohorts84.”

What the sources say

• Supported

  The Discussion states that the authors generated SenMayo and first validated it in bone biopsies from two human cohorts of young and elderly women. The Results section also reports significant SenMayo enrichment in bone samples from elderly women in both cohorts. (LLM, conf=0.94)

  cites [84] Saul, D. et al. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat. Commun. 13, 4827 (2022). source

In the paper

“These cells are characterized by expression of Cdkn1a, Ankrd1, Bcl2a1d, Ccl11, Cd68, Cxcl12 and Icam1, SA-β-gal activity, decreased Lmnb1 expression and increased γH2AX185.”

What the sources say

• Partly supported

  The Results section ('Only male MafAS64F/+ islets express markers of accelerated cellular senescence and aging'; page unavailable) reports increased p21 and γH2AX staining, increased SA-β-gal activity, and decreased LaminB1 in male mutant islets. It also reports increased aging- and senescence-related gene expression, but our copy does not identify Ankrd1, Bcl2a1d, Ccl11, Cd68, Cxcl12, or Icam1 as expressed markers. The specific gene list is therefore not fully supported by the available text. (LLM, conf=0.86)

  cites [185] Walker, E. M. et al. Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males. Cell Rep. 37, 109813 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Focal radiation therapy-induced bone loss can be alleviated by targeting senescent cells expressing Cdkn1a, but not Cdkn2a (ref. 203), suggesting the existence of functional heterogeneity between senescent cell subtypes.”

What the sources say

• Supported

  The Results section (‘Targeted removal of p21‐, but not p16‐expressing senescent cells prevents radiation‐induced bone loss’) reports that clearing p21-expressing cells prevented bone-density loss after irradiation of the right femur, whereas clearing p16-expressing cells did not. The Discussion describes distinct roles for the two cell populations, consistent with the sentence’s suggestion of functional heterogeneity. The supplied passages do not give page numbers. (LLM, conf=0.93)

  cites [203] Chandra, A. et al. Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity. Aging Cell 21, e13602 (2022). source

In the paper

“TGFβ1 has been implicated in mediating cellular senescence in the lung, as TGFβ1–IL-11–MEK–ERK signalling mediates senescence-associated pulmonary fibrosis in mice171.”

What the sources say

• Supported

  The paper’s title identifies a mouse model of Bmi-1 deficiency, and the Discussion reports that this deficiency activated TGF-β1/IL-11/MEK/ERK signaling leading to senescence-associated pulmonary fibrosis. It also reports that IL-11 mediated TGF-β1’s effects on lung-cell senescence through MEK/ERK signaling. The finding is specific to that model. (LLM, conf=0.94)

  cites [171] Chen, H. et al. TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency. Exp. Mol. Med. 52, 130–151 (2020). source

In the paper

“Whether osteoclasts also undergo senescence remains unclear, although elimination of CDKN2A-expressing osteoclast progenitors did not attenuate age-related bone loss in mice198.”

What the sources say

• Supported

  The Abstract reports that eliminating p16-expressing osteoclast progenitors in mice had no effect on age-related bone loss. This supports the finding attributed to the paper; the statement about whether osteoclasts themselves undergo senescence is the citing authors’ framing, not the result cited. (LLM, conf=0.91)

  cites [198] Kim, H.-N. et al. Elimination of senescent osteoclast progenitors has no effect on the age-associated loss of bone mass in mice. Aging Cell 18, e12923 (2019). source

In the paper

“Osteoblast progenitors and osteoblasts exhibit a significant increase of Cdkn2a, in addition to an increase of a limited number of SASP factors93.”

What the sources say

• Supported

  The Results (page unavailable) report significantly higher p16Ink4a expression with aging in mouse osteoblast progenitors and osteoblasts. The Results also report that relatively few SASP factors changed significantly with aging in those cell populations. (LLM, conf=0.91)

  cites [93] Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929 (2016). source

In the paper

“The secretion of SASP protein factors has been confirmed through proteomics analysis of senescent (SA-β-gal+) and non-senescent (SA-β-gal–) mouse and human pancreatic islet cells183, leading to the description of a unique SASP in β-cells.”

What the sources say

• Supported

  In “Senescent β-Cells Exhibited a Unique Secretory Phenotype,” the paper describes proteomic analysis of conditioned media from senescent mouse and human β-cells, with primary islet cells sorted into β-gal-positive and β-gal-negative populations. It reports that this analysis defined a β-cell SASP protein signature. (LLM, conf=0.93)

  cites [183] Midha, A. et al. Unique human and mouse β-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors. Diabetes 70, 1098–1116 (2021). source

In the paper

“Following fracture in mice, cells from the fracture callus exhibit an initial increase in Cdkn1a mRNA expression, followed by Cdkn2a and accompanied by a SASP consisting of numerous interleukins, NF-κB-downstream factors and, specifically, TGFβ1 expression200,201.”

What the sources say

• Partly supported

  The Results sections on murine fracture healing and callus SASP expression report an early Cdkn1a mRNA increase followed by a progressive Cdkn2a increase, alongside changes in interleukins and Tgfb1. They report increased expression of Nfkb1 itself, but do not identify the measured factors as downstream of NF-κB; that specific characterization is unsupported. (LLM, conf=0.84)

  cites [200] Saul, D. et al. Modulation of fracture healing by the transient accumulation of senescent cells. eLife 10, e69958 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on senescent cells in fracture callus reports that p21 (Cdkn1a) and p16 (Cdkn2a) both increased after fracture and both peaked on day 10; it does not establish that one rose before the other. The Results section on SASP factors reports elevated Il1a and Tgfb1 in aged callus, supporting that portion of the claim, but it does not identify the measured factors as NF-κB downstream factors or establish numerous interleukins. (LLM, conf=0.88)

  cites [201] Liu, J. et al. Age-associated callus senescent cells produce TGF-β1 that inhibits fracture healing in aged mice. J. Clin. Invest. 132, e148073 (2022). sourceExperimental — accuracy not yet measured

In the paper

“This expression pattern correlates with lower MKI67 expression and only slightly with telomere length reduction210.”

What the sources say

• Supported

  The Results section on proliferation reports an inverse correlation between H2A.J-positive and Ki67-positive epidermal cells. The paper also reports only slight age-related telomere attrition and, in the Discussion, a much more pronounced age-related increase in H2A.J-positive keratinocytes. It does not report a direct correlation coefficient between H2A.J expression and telomere length, but the claim is consistent with its reported pattern. (LLM, conf=0.88)

  cites [210] Rube, C. E. et al. Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis. NPJ Aging Mech. Dis. 7, 7 (2021). source

In the paper

“In the mouse skin chemical carcinogenesis model, tumour promotion with the phorbol ester TPA features an increase in SA-β-gal+ keratinocytes with high CDKN2A levels, accompanied by increased levels of Mmp3, Mmp9 and Cxcl10 and downregulation of Lmnb1 (ref. 223).”

What the sources say

• Partly supported

  The Results section, “TPA induces senescence and a SASP in human keratinocytes and mouse skin” (page unavailable), reports increased SA-β-gal-positive cells and elevated p16, Mmp3, Mmp9 and Cxcl10 mRNAs in TPA-treated mouse skin. It does not identify the SA-β-gal-positive mouse cells specifically as keratinocytes. Reduced Lamin B1 is reported for TPA-treated human keratinocytes, not mouse skin. (LLM, conf=0.88)

  cites [223] Alimirah, F. et al. Cellular senescence promotes skin carcinogenesis through p38MAPK and p44/42MAPK signaling. Cancer Res. 80, 3606–3619 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, extravillous trophoblasts display nuclear enlargement247, and syncytiotrophoblasts exhibit characteristics of senescence and ageing, such as increased syncytial knots and fibrinoid deposition254 and reorganization of their cytoskeleton255.”

What the sources say

• Supported

  Citation 247 is attached to the claim that extravillous trophoblasts display nuclear enlargement; the syncytiotrophoblast claims have separate citations. The Discussion reports that EVT differentiation is associated with a significant increase in nuclear volume. (LLM, conf=0.94)

  cites [247] Velicky, P. et al. Genome amplification and cellular senescence are hallmarks of human placenta development. PLoS Genet. 14, e1007698 (2018). source
• ?Not checked — no full text of the sourcecites [254] Wang, Y. et al. SIRT1 regulates trophoblast senescence in premature placental aging in preeclampsia. Placenta 122, 56–65 (2022). source
• ?Not checked — no full text of the sourcecites [255] Ishikawa, A. et al. Cell fusion mediates dramatic alterations in the actin cytoskeleton, focal adhesions, and E-cadherin in trophoblastic cells. Cytoskeleton 71, 241–256 (2014). source

In the paper

“The ovary ages earlier than other organs in the human body, as reproductive function begins declining in women in their midthirties and ceases completely at the time of menopause.”

What the sources say

• ?Not checked — no full text of the sourcecites [232] Lemaitre, J. F. & Gaillard, J. M. Reproductive senescence: new perspectives in the wild. Biol. Rev. Camb. Philos. Soc. 92, 2182–2199 (2017). source
• Supported

  The Introduction says the ovary ages earlier than other parts of the female body and that accelerated follicle depletion after about age 31 leads to a gradual loss of fecundity. It also describes menopause as natural sterility, supporting the claim that reproductive function ends then. The Abstract places the onset of fertility decline after age 37, so “midthirties” is an approximation rather than the paper’s precise age. (LLM, conf=0.88)

  cites [233] Dong, L., Teh, D. B. L., Kennedy, B. K. & Huang, Z. Unraveling female reproductive senescence to enhance healthy longevity. Cell Res. 33, 11–29 (2023). source

In the paper

“In fibroblasts, keratinocytes and melanocytes in vitro, the classical SASP typically includes IL-6, IL-1α, IL-1β, MMP1, MMP3, MMP9 and TNF211, whereas high levels of chemerin are found in the SASP of dermal fibroblasts in aged skin215.”

What the sources say

• Partly supported

  The ‘SASPs of Human Epithelial Cells’ passage reports overlapping SASPs in cultured fibroblasts and prostate epithelial cells, including IL-6, but says IL-1α was specific to one of those cell types. The cited paper does not establish the listed factors as a typical SASP across fibroblasts, keratinocytes and melanocytes; it studies prostate epithelial cells rather than the latter two. The chemerin clause has a different citation (215) and is not judged here. (LLM, conf=0.86)

  cites [211] Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008). sourceExperimental — accuracy not yet measured
• Supported

  The citation is attached to the chemerin clause, not the preceding list of classical SASP factors. In the Results section, the paper reports increased chemerin secretion from senescent dermal fibroblasts and more chemerin-positive fibroblasts in aged human skin than in young skin. (LLM, conf=0.92)

  cites [215] Farsam, V. et al. Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration. Oncotarget 7, 83554–83569 (2016). source

In the paper

“Despite high variability (for example, the SASP of intrinsically aged human fibroblasts in vivo includes 27 distinct proteins212), there is an association between GDF15, TNF, SPP1, TNFRSF1A, FAS, CCL3, IL-15 and activin A expression and age-related disease outcomes214.”

What the sources say

• ?Not checked — no full text of the sourcecites [212] Waldera Lupa, D. M. et al. Characterization of skin aging-associated secreted proteins (SAASP) produced by dermal fibroblasts isolated from intrinsically aged human skin. J. Invest. Dermatol. 135, 1954–1968 (2015). source
• Supported

  The Introduction (page unavailable) reports that circulating SASP proteins were associated with age, frailty and adverse postsurgical outcomes, and identifies a seven-factor panel that predicted adverse events. The results (page unavailable) also associate TNF-α with frailty. The paper measures circulating protein concentrations rather than cellular expression; the separate claim about 27 fibroblast proteins carries a different citation. (LLM, conf=0.87)

  cites [214] Schafer, M. J. et al. The senescence-associated secretome as an indicator of age and medical risk. JCI Insight 5, e133668 (2020). source

In the paper

“The expression of TNFRSF11A increases during ageing228, leading to DNA damage and senescence through Cdkn2a (ref. 229).”

What the sources say

• Supported

  The citation to this paper is attached to the first clause, about TNFRSF11A (RANK) expression increasing with age. In “RANK Expression Increases with Age and Multiparity in WT Mice,” the paper reports higher Rank mRNA in mammary glands of aged than young virgin mice. The DNA-damage and senescence clause has a separate citation and is not attributed to this source. (LLM, conf=0.92)

  cites [228] Pellegrini, P. et al. Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis. Stem Cell 31, 1954–1965 (2013). source
• Supported

  The Results section reports that Rank overexpression induces DNA damage and senescence through p16/p19 in mammary epithelial cells and fibroblasts, and identifies p16/p19 as products of the Cdkn2a locus. The increase in expression during ageing is attached to a different citation (228), not this source (229). (LLM, conf=0.92)

  cites [229] Benitez, S. et al. RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness. Dev. Cell 56, 1727–1741.e7 (2021). source

In the paper

“In sun-protected skin, melanocytes showed the highest rate of senescence, as identified by the expression of CDKN2A and increased number of TAF, and loss of nuclear HMGB1 (ref. 213).”

What the sources say

• Supported

  The Results (page unavailable) describe sun-protected skin biopsies and report that p16-positive epidermal cells were melanocytes; p16 is encoded by CDKN2A. They also report reduced HMGB1 in melanocytes from older donors and increased melanocyte TAF with age. The Discussion (page unavailable) describes melanocytes as the main population of p16-positive senescent epidermal cells. (LLM, conf=0.88)

  cites [213] Victorelli, S. et al. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J. 38, e101982 (2019). source

In the paper

“Moreover, several CCL and CXCL genes are expressed in immune cells of the postmenopausal human ovary, potentially reversing some of the detrimental effects of senescence246.”

What the sources say

• Supported

  The Results section (‘Ligand-receptor interactions between different cell types in the FT and ovary’) reports CCL and CXCL gene expression in ovarian immune cells and describes a potential, not demonstrated, reversal of deleterious senescence effects. The Discussion repeats this interpretation. The citing sentence preserves that uncertainty. (LLM, conf=0.94)

  cites [246] Lengyel, E. et al. A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA and ATAC sequencing. Cell Rep. 41, 111838 (2022). source

In the paper

“Apart from physiological ageing, treatments that accelerate reproductive ageing through genotoxic agents, such as the chemotherapeutics cisplatin242 and doxorubicin243, result in increased SA-β-gal242,243, CDKN2A (refs. 242,243) and CDKN1A (refs. 242,243) expression.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [242] Du, D. et al. Senotherapy protects against cisplatin-induced ovarian injury by removing senescent cells and alleviating DNA damage. Oxid. Med. Cell. Longev. 2022, 9144644 (2022).
• Supported

  Reference 243 is attached to doxorubicin, while reference 242 is attached to cisplatin. The Results section reports increased ovarian SA-β-gal positivity and significantly elevated Cdkn2a and Cdkn1a mRNA after doxorubicin treatment. The Introduction also describes doxorubicin-related ovarian injury, including early menopause. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [243] Gao, Y. et al. Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics. GeroScience 45, 1775–1790 (2023). source

In the paper

“Additionally, the BRAF oncogenic mutation found in more than half of all malignant cutaneous melanomas is commonly found also in non-malignant nevi, where it causes oncogene-induced senescence exemplified by high levels of CDKN2A and SA-β-gal expression225–227.”

What the sources say

• Partly supported

  The Abstract and main text report that BRAF V600E is frequent in benign naevi and that sustained expression induces senescence-like arrest with SA-β-Gal activity and increased p16INK4a, the CDKN2A protein. However, the paper does not establish the claimed ‘more than half’ frequency in cutaneous melanomas, and it describes p16INK4a expression in naevi as mosaic rather than uniformly high. (LLM, conf=0.87)

  cites [225] Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [226] Pollock, P. M. et al. High frequency of BRAF mutations in nevi. Nat. Genet. 33, 19–20 (2003). source
• Partly supported

  The introductory passage following the Abstract’s Conclusions says that nearly 50% of primary and metastatic melanomas harbour BRAF mutations, supporting their prevalence but not the claim’s ‘more than half’ figure. The paper does not address BRAF mutations in non-malignant nevi or senescence marked by CDKN2A and SA-β-gal expression. (LLM, conf=0.88)

  cites [227] Hugdahl, E., Kalvenes, M. B., Puntervoll, H. E., Ladstein, R. G. & Akslen, L. A. BRAF-V600E expression in primary nodular melanoma is associated with aggressive tumour features and reduced survival. Br. J. Cancer 114, 801–808 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Senescence in the skin is identified by expression of SA-β-gal, α-fucosidase, CDKN2A, CDKN1A and lipofuscin in both the epidermis and the dermis207,208, and of the histone variant H2AJ and γH2AX in human epidermis, especially in the stratum spinosum209.”

What the sources say

• Partly supported

  The Results identify Cdkn2a and Cdkn1a as classical senescence markers, but the mouse tissues studied were hypothalamus, heart, liver, and kidney—not epidermis or dermis. The cited paper does not establish the claimed skin-layer expression of those markers or address α-fucosidase and lipofuscin. The H2AJ and γH2AX clause is attached to a different citation (209) and is not judged here. (LLM, conf=0.86)

  cites [207] Hudgins, A. D. et al. Age- and tissue-specific expression of senescence biomarkers in mice. Front. Genet. 9, 59 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [208] Dimri, G. P. A biomarker that identifies senescenet human cells in culture and aging skin in vitro. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995). source
• Partly supported

  The Results section ('H2A.J is a biomarker of some senescent stem and skin cells'; page unavailable) reports that H2A.J-positive cells increase in aging human epidermis and suggests H2A.J as a biomarker of some senescent skin cells. It reports 53BP1 foci—not γH2AX—in human epidermis and does not identify the stratum spinosum as a particular site. The earlier markers are attached to citations 207 and 208, so they are not assessed against this source. (LLM, conf=0.87)

  cites [209] Contrepois, K. et al. Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nat. Commun. 8, 14995 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Additionally, the ovary exhibits age-dependent inflammation and fibrosis234–237; however, whether these are associated with senescence has not been conclusively established.”

What the sources say

• Supported

  The citation is attached to the age-dependent inflammation and fibrosis clause, not the subsequent statement about senescence. The Abstract and Results report increasing ovarian fibrosis and inflammatory markers with reproductive age in mice; the Discussion describes fibrosis coincident with increased inflammation. (LLM, conf=0.91)

  cites [234] Briley, S. M. et al. Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction 152, 245–260 (2016). source
• Partly supported

  The Discussion reports increased inflammatory markers in ageing mouse ovaries, and the Introduction cites an earlier study finding more stromal fibrosis in older mice. But this paper’s own Results (“Fibrosis does not change in the ageing mouse ovary”) found no significant change in fibrosis from 2 to 18 months, so it does not establish age-dependent fibrosis. (LLM, conf=0.88)

  cites [235] Lliberos, C. et al. Evaluation of inflammation and follicle depletion during ovarian ageing in mice. Sci. Rep. 11, 278 (2021). sourceExperimental — accuracy not yet measured
• Supported

  The Introduction states that the mammalian ovary becomes increasingly fibrotic with age. The Discussion describes an inflammatory response observed in ovaries of advanced reproductive age. The citation is attached to those age-dependent changes, not to the citing authors’ subsequent statement about senescence; page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [236] Amargant, F. et al. Ovarian stiffness increases with age in the mammalian ovary and depends on collagen and hyaluronan matrices. Aging Cell 19, e13259 (2020). source
• Supported

  The citation is attached to the statement that ovarian inflammation and fibrosis increase with age, not to the subsequent statement about senescence. The Introduction describes elevated inflammatory status and an extracellular-matrix profile implicating fibrosis in aged ovaries; the Abstract also reports findings consistent with increased ovarian stromal fibrosis with age. The paper concerns mouse ovaries. (LLM, conf=0.91)

  cites [237] Zhang, Z., Schlamp, F., Huang, L., Clark, H. & Brayboy, L. Inflammaging is associated with shifted macrophage ontogeny and polarization in the aging mouse ovary. Reproduction 159, 325–337 (2020). source

In the paper

“Several senescence markers have been reported to increase in the ageing mouse colon in homogenized tissue141.”

What the sources say

• Supported

  The section ‘Clearance by ATTAC is partial and tissue selective’ reports that p16Ink4a and multiple senescence markers increased with age across the tissues examined, explicitly including colon (Extended Data Fig. 3a). The Extended Data caption describes RT-PCR measurements in colon tissue, consistent with the claim’s tissue-level measurement rather than a cell-specific assay; the copy does not explicitly use the word ‘homogenized.’ (LLM, conf=0.93)

  cites [141] Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source

In the paper

“Moreover, mitochondria of syncytiotrophoblasts undergo morphological and functional changes, characterized by decreased size and diminished ATP production, leading to increased ROS production to adapt to changing oxygen tension in the placenta248,256.”

What the sources say

• ?Could not verify

  The Results and Discussion describe oxidative stress and senescence in syncytiotrophoblasts and placental explants after hypoxia-reoxygenation, but do not address the claimed mitochondrial changes. Searches for mitochondrial size, ATP production, ROS production, and adaptation to oxygen tension found no passage supporting that mechanism. (LLM, conf=0.73)

  cites [248] Cindrova-Davies, T., Fogarty, N. M. E., Jones, C. J. P., Kingdom, J. & Burton, G. J. Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas. Placenta 68, 15–22 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [256] Bartho, L. A., Fisher, J. J., Cuffe, J. S. M. & Perkins, A. V. Mitochondrial transformations in the aging human placenta. Am. J. Physiol. Endocrinol. Metab. 319, E981–E994 (2020). source

In the paper

“Telomeres from fetal growth restriction placentas are shorter and express higher levels of CDKN2A and CDKN1A protein and EEF1A1 RNA compared with placentas from normal growth fetuses265.”

What the sources say

• Partly supported

  The Results and discussion section reports shorter telomeres and higher expression of p16, p21, and EF-1α in FGR placentas than in controls. But it measured expression of all three markers by RT-PCR; it does not establish higher CDKN2A or CDKN1A protein levels. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites [265] Davy, P., Nagata, M., Bullard, P., Fogelson, N. S. & Allsopp, R. Fetal growth restriction is associated with accelerated telomere shortening and increased expression of cell senescence markers in the placenta. Placenta 30, 539–542 (2009). sourceExperimental — accuracy not yet measured

In the paper

“In addition to trophoblast senescence, which is a physiological phenomenon that progresses with gestation and peaks at term, senescence is also extensively described in maternal decidual cells and fetoplacental membranes, where it has a pivotal role in the promotion of parturition and detachment of the placenta from the uterus at term257–262.”

What the sources say

• Partly supported

  The sections on fetal membrane structure and biologic aging describe physiological membrane senescence during pregnancy and at term; the latter says signals from senescent membranes could trigger parturition. The copy does not establish the claimed gestational trajectory of trophoblast senescence, senescence in maternal decidual cells, or a role in placental detachment. It also presents the membrane contribution to labor as possible, rather than pivotal. (LLM, conf=0.88)

  cites [257] Menon, R. Human fetal membranes at term: dead tissue or signalers of parturition? Placenta 44, 1–5 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page not provided) reports that fetal-membrane senescence progresses through mouse gestation, while placental and decidual senescence is minimal and detectable only near its end. The Conclusions say fetal-membrane senescence may contribute to parturition at term. The paper does not establish progressive senescence specifically in trophoblasts or a role for senescence in placental detachment, and the claim states the parturition role more definitively than the source does. (LLM, conf=0.88)

  cites [258] Bonney, E. A. et al. Differential senescence in feto-maternal tissues during mouse pregnancy. Placenta 43, 26–34 (2016). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [259] Cox, L. S. & Redman, C. The role of cellular senescence in ageing of the placenta. Placenta 52, 139–145 (2017). source
• ?Not checked — no full text of the sourcecites [260] Wijaya, J. C., Khanabdali, R., Georgiou, H. M. & Kalionis, B. Ageing in human parturition: impetus of the gestation clock in the deciduadagger. Biol. Reprod. 103, 695–710 (2020). source
• Partly supported

  The Results section (page unavailable) reports increased senescence markers in fetal amnion and chorion membranes at term labor, and the Introduction proposes that membrane-cell senescence may promote parturition. The paper does not establish senescence in trophoblasts or maternal decidual cells, a gestation-long progression peaking at term, or a role in placental detachment. It also treats promotion of labor as a hypothesis rather than a proven causal role. (LLM, conf=0.87)

  cites [261] Menon, R. et al. Placental membrane aging and HMGB1 signaling associated with human parturition. Aging 8, 216–230 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The section on CD158d activation reports a senescence signature in decidual NK cells during weeks 6–12 of pregnancy, and the paper proposes a reproductive role through vascular remodeling in early pregnancy. It does not establish senescence of trophoblasts or fetoplacental membranes, progression or a peak at term, or a role in parturition or placental detachment. (LLM, conf=0.84)

  cites [262] Rajagopalan, S. & Long, E. O. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc. Natl Acad. Sci. USA 109, 20596–20601 (2012). sourceExperimental — accuracy not yet measured

In the paper

“The Biomarkers Working Group within SenNet has observed a recurring issue within the scientific literature regarding cellular senescence in various tissues in the context of ageing and age-related conditions, namely a tendency towards oversimplification of cell-state annotation, exacerbated by the absence of a universally accepted definition of cellular senescence.”

In the paper

“Importantly, a considerable portion of the literature heavily relies on analyses of homogenized tissue samples, which disregards the unique attributes of distinct cell types.”

In the paper

“The database contains information from 224 peer-reviewed papers and 328 markers, covering a total of 14 mouse and human tissues, along with circulating markers.”

In the paper

“Table 1 features senescence markers documented in our database in three or more tissues.”

In the paper

“Collectively, these markers represent six of the nine senescence hallmarks, with the SASP being most represented.”

In the paper

“H2AX is the most utilized marker for assessing the DDR across tissues, followed by telomere length and TAF.”

In the paper

“nuclear changes evidenced by the loss of LMNB1 and nuclear HMGB1 have been documented in 5 and 7 tissues, respectively.”

In the paper

“By contrast, in tissues, these cells are relatively rare and difficult to characterize”

In the paper

“Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest.”

In the paper

“Therefore, the presence of multiple hallmarks is required to identify senescent cells.”

In the paper

“Additionally, our selection criteria focused on publications that evaluated multiple senescence-associated markers.”

In the paper

“it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype”

In the paper

“A key challenge is the lack of a specific marker of cellular senescence, as virtually all markers that have been proposed can be absent from senescent cells in specific contexts (for example, cell types, senescence type), or they can be present in non-senescent cells.”

In the paper

“As features of the SASP overlap with those of immune cells, it is imperative to identify marker(s) that can distinguish between activated resident immune cells and bona fide senescent cells.”

In the paper

“Importantly, the complex heterogeneity of senescence in the ageing mouse and human brain warrants cell type-specific and region-specific characterization.”

In the paper

“CDKN2A, CDKN1B, CDK4, MMP1 and HSPA5 mRNA levels increase in the cortex and nuclear staining of CDKN2A is observed predominantly in distal tubules and collecting ducts, but also in glomerular parietal epithelium and podocytes151.”

What the sources say

• ?Not checked — no full text of the sourcecites [151] Melk, A. et al. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 65, 510–520 (2004). source

In the paper

“Telomeres are shorter in the cortex but not in the medulla153.”

What the sources say

• ?Not checked — no full text of the sourcecites [153] Melk, A. et al. Telomere shortening in kidneys with age. J. Am. Soc. Nephrol. 11, 444–453 (2000). source

In the paper

“CDKN2A protein expression in cortical interstitial cells and TECs correlates with age; by contrast, expression of CDKN1B protein correlates with age only in cortical tubular cells152.”

What the sources say

• ?Not checked — no full text of the sourcecites [152] Chkhotua, A. B. et al. Increased expression of p16INK4a and p27Kip1 cyclin-dependent kinase inhibitor genes in aging human kidney and chronic allograft nephropathy. Am. J. Kidney Dis. 41, 1303–1313 (2003). source

In the paper

“Furthermore, the nuclear CDKN2A level increases in glomerular and interstitial cells in individuals with glomerular disease145, and in tubules and podocytes in individuals with diabetic nephropathy147.”

What the sources say

• ?Not checked — no full text of the sourcecites [145] Sis, B. et al. Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int. 71, 218–226 (2007). source
• ?Not checked — no full text of the sourcecites [147] Verzola, D. et al. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 295, F1563–F1573 (2008). source

In the paper

“In a study of the post-mortem pancreas of 140 individuals without pancreatic disease, 114 (81%) exhibited ductal lesions such as mucous cell hyperplasia, typically associated with KRAS activating mutations; the ductal lesions show an increasing trend after the age of 40 years195.”

What the sources say

• ?Not checked — no full text of the sourcecites [195] Luttges, J. et al. Duct changes and K-ras mutations in the disease-free pancreas: analysis of type, age relation and spatial distribution. Virchows Arch. 435, 461–468 (1999). source

In the paper

“These findings suggest that senescence is induced in early neoplastic stages and may have a role in preventing the progression of malignancy.”

What the sources say

• ?Not checked — no full text of the sourcecites [197] Miyasaka, Y. et al. Senescence in intraductal papillary mucinous neoplasm of the pancreas. Hum. Pathol. 42, 2010–2017 (2011). source

In the paper

“Developmental senescence is a programmed transient cellular senescence that has a crucial role in mammalian embryonic development, occurring not only in the embryo but also in the placenta.”

In the paper

“Our primary objective here was to establish a foundation for the informed development of spatial mapping panels based on the existing evidence of senescence markers in tissues.”

In the paper

“The database associated with this Expert Recommendation will serve as a dynamic document that SenNet will regularly update, incorporating novel findings from within the consortium and beyond.”

In the paper

“We anticipate that the results generated by SenNet, as well as by the broader cellular senescence research community using spatial mapping techniques, will considerably advance our comprehension of the diversity of senescence in various cell types and its functional implications in ageing and disease.”

In the paper

“Recently, highly specific syncytiotrophoblast genes were identified to be induced in physiologically aged fibroblasts, as well as during replicative senescence or stress-induced cellular senescence in non-trophoblast cell lineages263.”

What the sources say

• ?Not checked — no full text of the sourcecites [263] Liu, Z. et al. Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging. Dev. Cell 57, 1347–1368.e12 (2022). source

In the paper

“The multimodal efforts of SenNet are designed to pinpoint novel and specific markers of senescence, enabling us to differentiate them from other types of cellular change that may occur during ageing.”

In the paper

“Specifically, we have focused our discussion on senescence markers applied to the identification of senescent cells in individual tissues.”

In the paper

“Furthermore, innovative machine learning and artificial intelligence techniques are under development to distinguish senescent from non-senescent cells based on their morphological differences (Box 3).”

In the paper

“To achieve this goal, high-content and high-throughput single-cell and spatial omics technologies are deployed, which accelerate the discovery of crucial senescence biomarkers required for progress in the study of ageing and disease (Box 5).”