Expression of p16INK4a in peripheral blood T‐cells is a biomarker of human aging

Liu, Yan; Sanoff, Hanna K.; Cho, Hyunsoon; Burd, Christin E.; Torrice, Chad; Ibrahim, Joseph G.; Thomas, Nancy E.; Sharpless, Norman E.

doi:10.1111/j.1474-9726.2009.00489.x

Cited by 423 publications

(448 citation statements)

References 58 publications

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“…Studies have shown that the number of senescent cells increases with aging in multiple human tissues, including circulating T cells (Liu et al., 2009). Senescent cells are characterized by senescence‐associated secretory phenotype (SASP) that release inflammatory mediators, proteinases and other molecules in the surrounding niche, from where they are eventually released into circulation.…”

Section: Resultsmentioning

confidence: 99%

Plasma proteomic signature of age in healthy humans

Tanaka¹,

Biancotto²,

Moaddel³

et al. 2018

Aging Cell

404

396

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To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22–93 years old, who were disease‐ and treatment‐free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10−5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10−56). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.

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Section: Resultsmentioning

confidence: 99%

Plasma proteomic signature of age in healthy humans

Tanaka¹,

Biancotto²,

Moaddel³

et al. 2018

Aging Cell

404

396

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“…This has allowed p16 INK4a expression to serve as a biomarker of molecular aging, which can be used to measure the senescence burden and predict cellular function in some settings (Koppelstaetter et al., 2008; Liu et al., 2009; Wood et al., 2016). To determine this relationship in primary human chondrocytes, we analyzed whether the expression of p16 INK4a was associated with markers of chondrocyte dysfunction independent of chronological aging (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…The quantity of this subset increases during aging (thus the correlation of p16 INK4a to age) and p16 INK4a also serves as a biomarker that identifies chondrocytes with greater potential for secreting factors that drive tissue dysfunction (thus the correlation of p16 INK4a to SASP markers). The utility of p16 INK4a as a biomarker of molecular age in other cell types has been demonstrated by assessing the impact of lifestyle modifications such as smoking or exercise (Liu et al., 2009), predicting the risk for particular negative outcomes after chemotherapy (Demaria et al., 2017), and screening the quality of potential donor organs (Koppelstaetter et al., 2008). For chondrocytes, screening patients for low p16 INK4a expression may improve the outcomes of autologous chondrocyte implantation procedures, as the success of this procedure requires avoidance of senescence to ensure sufficient expansion and subsequent re‐differentiation of the chondrocytes (Ashraf et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

et al. 2018

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SummaryCellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro‐inflammatory molecules known as the senescence‐associated secretory phenotype (SASP). The senescence biomarker p16 INK 4a is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16 INK 4a identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16 INK 4a contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of p16 INK 4a in murine and human models of chondrocyte aging. We observed that p16 INK 4a mRNA expression was significantly upregulated with chronological aging in murine cartilage (~50‐fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (r 2 = .27, p < .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin‐dependent kinases 4 or 6 (CDK4/6), and proliferation was reduced in cells from older donors with increased p16 INK 4a expression. Moreover, increased chondrocyte p16 INK 4a expression correlated with several SASP transcripts. Despite the relationship between p16 INK 4a expression and these features of senescence, somatic inactivation of p16 INK 4a in chondrocytes of adult mice did not mitigate SASP expression and did not alter the rate of osteoarthritis (OA) with physiological aging or after destabilization of the medial meniscus. These results establish that p16 INK 4a expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on OA are more likely driven by production of SASP molecules than by loss of chondrocyte replicative function.

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“…Furthermore, the lack of effect of p16 deletion cannot be attributed to compensation by Arf, because HSCs from irradiated Arf and p16/Arf KO mice exhibited changes similar to those seen in the cells from WT mice after TBI. The finding that IR induced HSC senescence and residual BM suppression in a p16 and Arf-independent manner is intriguing, because upregulation of p16 and Arf has been implicated in mediating induction of HSC senescence in a variety of pathological conditions and during aging, 8,41,42 and it has been shown that IR induced senescence in BM stromal cells in a p16-and Arf-dependent manner. 32 Furthermore, early T-lymphoid progenitors are exquisitely dependent on CDK4/6 activity and, therefore, are very sensitive to p16 upregulation for induction of senescence during aging.…”

Section: Discussionmentioning

confidence: 99%

Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner

Shao

Wei

et al. 2014

Blood

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• Total body irradiation causes long-term bone marrow suppression by selectively inducing HSC senescence.• The induction of HSC senescence is independent of telomere shortening and p16 Ink4a and Arf.Exposure to total body irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term or residual bone marrow (BM) injury. This residual BM injury is mainly attributed to permanent damage to hematopoietic stem cells (HSCs), including impaired self-renewal, decreased long-term repopulating capacity, and myeloid skewing. These HSC defects were associated with significant increases in production of reactive oxygen species (ROS), expression of p16 Ink4a (p16) and Arf mRNA, and senescenceassociated b-galacotosidase (SA-b-gal) activity, but not with telomere shortening or increased apoptosis, suggesting that TBI induces residual BM injury via induction of HSC premature senescence. This suggestion is supported by the finding that SA-b-gal 1 HSCenriched LSK cells showed more pronounced defects in clonogenic activity in vitro and long-term engraftment after transplantation than SA-b-gal -LSK cells isolated from irradiated mice. However, genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression and HSC senescence, because HSCs from irradiated p16 and/or Arf knockout (KO) mice exhibited changes similar to those seen in HSCs from wild-type mice after exposure to TBI. These findings provide important new insights into the mechanism by which TBI causes long-term BM suppression (eg, via induction of premature senescence of HSCs in a p16-Arf-independent manner). (Blood. 2014;123(20):3105-3115)

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Expression of p16^INK4a in peripheral blood T‐cells is a biomarker of human aging

Cited by 423 publications

References 58 publications

Plasma proteomic signature of age in healthy humans

Plasma proteomic signature of age in healthy humans

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner

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Expression of p16INK4a in peripheral blood T‐cells is a biomarker of human aging

Cited by 423 publications

References 58 publications

Plasma proteomic signature of age in healthy humans

Plasma proteomic signature of age in healthy humans

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner

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Expression of p16^INK4a in peripheral blood T‐cells is a biomarker of human aging

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis