Targeted clearance of <i>p21</i>‐ but not <i>p16</i>‐positive senescent cells prevents radiation‐induced osteoporosis and increased marrow adiposity

Chandra, Abhishek; Lagnado, Anthony B.; Farr, Joshua N.; Doolittle, Madison L.; Tchkonia, Tamara; Kirkland, James L.; LeBrasseur, Nathan K.; Robbins, Paul D.; Niedernhofer, Laura J.; Ikeno, Yuji; Passos, João F.; Monroe, David G.; Pignolo, Robert J.; Khosla, Sundeep

doi:10.1111/acel.13602

Cited by 61 publications

(56 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surprisingly, p16INK4A- and p21-expressing cell populations seem to be different [ 212 ], which is contrasting with the lack of senescence in p16INK4A/p21 double knockout animals [ 251 ]. Also in the p21–ATTAC model, the clearance of p21- but not p16INK4A-positive senescent cells prevented radiation-induced osteoporosis and bone marrow adiposity [ 226 ], supporting the view that p16INK4A- and p21-dependent senescence comprise different and independent pathways [ 3 , 5 , 22 , 273 ]. A high number of p21- but not p16INK4A-expressing cells was detected in visceral adipose tissue of obese mice, mostly preadipocytes, endothelial cells, and macrophages [ 218 ].…”

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 87%

“…The second mouse strain is comparable to the p16INK4A-INK-ATTAC mouse model but uses a 3.2 kb p21 promoter fragment driving expression of the FKBP–Caspase-8 fusion suicide protein. The construct was inserted in the Rosa26 locus [ 226 ]. The p21-CreERT2 mice were crossed with a luciferase reporter, and luminescence was measured in vivo after doxorubicin treatment or a high-fat diet as known inducers of senescence.…”

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

See 1 more Smart Citation

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

View full text Add to dashboard Cite

It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.

show abstract

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 87%

Section: P16ink4a P14arf/p19arf and P21 In Homeostasismentioning

confidence: 99%

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

View full text Add to dashboard Cite

show abstract

“…Regarding senescence, the relative contributions of different senescence-inducing pathways to specific age-related diseases remain undetermined. A very recent study showed that radiation-induced osteoporosis in mice is mainly driven by p21 CIP1 SCs rather than SCs expressing p16 INK4 and that eliminating p21 + , but not p16 + , cells ameliorates this pathology (133). These comparative mouse models should be used by future research to associate specific senescence pathways with organ-specific aging outcomes, which will help rationalize the use of specific biomarkers over others.…”

Section: The Journal Of Clinical Investigationmentioning

confidence: 99%

The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence

Shafqat¹,

Chicas²,

Shafqat³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

Cancer survival times have increased annually owing to advances in early detection and treatment that prolong patient survival. However, increasing survivorship has underscored the observation that cancer survivors develop age-related diseases prematurely, which cause significant morbidity, health expenditures, and mortality. Many cancer survivors have been exposed to chemotherapy, radiotherapy, or both; despite eradicating cancer cells, these therapies also damage normal cells to accelerate biologic aging, such that a discrepancy exists between their biologic and chronologic age (1). Considerable data exist regarding the phenotypes of accelerated aging. However, mechanical and molecular uncertainties have limited the study of these manifestations in a clinical context. Our Review discusses accelerated aging phenotypes in cancer survivors and the cellular mechanisms underpinning these phenomena. We then discuss the translational evidence on how accelerated aging phenotypes, mainly related to senescence, are being targeted while highlighting areas of uncertainty for future research to address.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Recent reports show that cells expressing high levels of p21 in vivo express other markers of senescence and their numbers increase with age, in multiple murine organs [11]. In addition, elimination of p21 + senescent cells reduces frailty and attenuates insulin resistance in obese mice [12], while elimination of p21 + cells, but not p16 + cells, improves radiation-induced osteoporosis [13], suggesting that p21 is a good marker of senescent cells. Zebrafish have a homologue of the human p21 gene, known to increase with increased levels of p16-like expression and senescence associated beta-galactosidase [14].…”

Section: Introductionmentioning

confidence: 99%

A p21-GFP zebrafish model of senescence for rapid testing of senolyticsin vivo

Morsli

Henriques

Ellis

et al. 2022

Preprint

View full text Add to dashboard Cite

Senescence drives the onset and severity of multiple ageing-associated diseases as well as frailty. As a result, there has been an increased interest in mechanistic studies and in the search for compounds targeting senescent cells, known as senolytics. Mammalian models are commonly used to test senolytics and generate functional and toxicity data at the level of organs and systems, yet this is expensive and time consuming. Zebrafish share high homology in genes associated with human ageing and disease. They can be genetically-modified relatively easily. In larvae, most organs develop within 5 days of fertilisation and are transparent, which allows tracking of fluorescent cells in vivo in real time, testing drug off-target toxicity and assessment of cellular and phenotypic changes. Here, we have generated a transgenic zebrafish line that expresses green fluorescent protein (GFP) under the promoter of a key senescence marker, p21. We show an increase in p21:GFP+ cells in larvae following exposure to ionising radiation and with natural ageing. p21:GFP+ cells display other markers of senescence, including senescence-associated β-galactosidase and IL6 The observed increase in senescent cells following irradiation is associated with a reduction in the thickness of muscle fibres and mobility, two important ageing phenotypes. We also show that quercetin and dasatinib, two senolytics currently in clinical trials, reduce the number of p21:GFP+ cells, in a rapid 5-day assay. This model provides an important tool to study senescence in a living organism, allowing the rapid selection of senolytics before moving to more expensive and time-consuming mammalian systems.

show abstract

Targeted clearance of p21‐ but not p16‐positive senescent cells prevents radiation‐induced osteoporosis and increased marrow adiposity

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 61 publications

References 38 publications

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence

A p21-GFP zebrafish model of senescence for rapid testing of senolyticsin vivo

Contact Info

Product

Resources

About