Cellular Senescence: Defining a Path Forward

Gorgoulis, Vassilis G.; Adams, Peter D.; Alimonti, Andrea; Bennett, Dorothy C.; Bischof, Oliver; Bishop, Cleo L.; Campisi, Judith; Collado, Manuel; Evangelou, Konstantinos; Ferbeyre, Gerardo; Gil, Jesús; Hara, Eiji; Krizhanovsky, Valery; Jurk, Diana; Maier, Andrea B.; Narita, Masashi; Niedernhofer, Laura J.; Passos, João F.; Robbins, Paul D.; Schmitt, Clemens A.; Sedivy, John M.; Vougas, Konstantinos; Zglinicki, Thomas von; Zhou, Daohong; Serrano, Manuel; Demaria, Marco

doi:10.1016/j.cell.2019.10.005

Cited by 1,629 publications

(1,653 citation statements)

References 158 publications

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“…Prior studies using a related but distinct flow cytometry readout of β-galactosidase activity revealed enhanced sensitivity as compared to the more widely used cytochemical method 34 . Although full characterization of the senescent state incorporates numerous orthogonal biomarkers 35 , the quantitative analysis of SA-β-gal was effective for distinguishing the cellular response to the applied culture conditions used in this study.…”

Section: Discussionmentioning

confidence: 99%

The combination of mitogenic stimulation and cell cycle arrest induces senescence in equine and human cartilage explants

Gagliardi

et al. 2020

Preprint

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Objective: Cellular senescence is a phenotypic state characterized by stable cell-cycle arrest, enhanced lysosomal activity, and the secretion of inflammatory molecules and matrix degrading enzymes. Senescence has been implicated in osteoarthritis (OA) pathophysiology; however, the mechanisms that drive senescence induction in cartilage and other joint tissues are unknown. While numerous physiological signals are capable of initiating the senescence phenotype, one emerging theme is that growth-arrested cells convert to senescence in response to sustained mitogenic stimulation. The goal of this study was to develop an in vitro articular cartilage explant model to investigate the mechanisms of senescence induction.Design: This study utilized healthy articular cartilage derived from cadaveric equine stifles and human ankles.Explants were irradiated or treated with palbociclib to initiate cell cycle arrest, and mitogenic stimulation was provided by serum-containing medium (horse) and the inclusion of growth factors (human). The primary readout of senescence was a quantitative flow cytometry assay to detect senescence-associated ꞵ galactosidase activity (SA-ꞵ-gal).Results: Irradiation of equine explants caused 25.39% of cells to express high levels of SA-ꞵ-gal, as compared to 3.82% in control explants (p=0.0031). For human cartilage, explants that received both mitogenic stimulation and cell cycle arrest showed increased rates of senescence induction as compared to baseline control (7.16% vs. 2.34% SA-ꞵ-gal high, p=0.0007).Conclusions: Treatment of cartilage explants with mitogenic stimuli in the context of cell-cycle arrest reliably induces high levels of SA-β gal activity, which provides a physiologically relevant model system to investigate the mechanisms of senescence induction. Introduction:Osteoarthritis (OA) is a disease characterized by joint pain and progressive degradation of articular cartilage and other tissues of the joint 1,2 . As the most common chronic disease of the articular joint, OA produces a substantial burden on society and the economy 3,4 . Despite increasing knowledge about factors contributing to the progression of OA, there are no approved disease-modifying therapies 5 , leading to high rates of total joint replacement 6 . Risk factors for OA include obesity, joint injury, and genetic predisposition, with the most dominant risk factor being aging 7,8 . Cellular senescence has been described as a key phenotype associated with aging 9 , and there is mounting evidence that the accumulation of senescent cells in the joint during both aging and in response to injury contributes to the development of OA 10-14 . Senescent chondrocytes likely contribute to tissue degradation by producing pro-inflammatory and matrix-degrading molecules known collectively as the senescence-associated secretory phenotype (SASP) 15,16 . Significant advances have begun to unravel the role of senescence in OA and the therapeutic implications of such findings, including the potential for senolytic therapy as a potential di...

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Section: Discussionmentioning

confidence: 99%

The combination of mitogenic stimulation and cell cycle arrest induces senescence in equine and human cartilage explants

Gagliardi

et al. 2020

Preprint

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“…SASP is an energy-dependent process in which senescent cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases [7,8,28,48,49]. IL6 and IL1 are major secretory interleukins present in SASP, and are associated with the pro-inflammatory environment that occurs during aging [1,3,8,50].…”

Section: Senescent Cells Are Metabolically Hyperactive and Display Amentioning

confidence: 99%

“…Cellular senescence in the main feature manifested in tissues of the aging organism [1,[5][6][7][8]. It is characterized by permanent cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype [5].…”

Section: Introductionmentioning

confidence: 99%

“…It is characterized by permanent cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype [5]. Under pathological stress conditions, excessive accumulation of senescence cells in affected tissues adversely affects the tissue's regenerative ability and creates a proinflammatory environment that can resemble various age-related disorders such as Alzheimer's disease, cancer, arthritis, cataracts, osteoporosis, atherosclerosis, hypertension, cardiovascular disease, Type 2 diabetes, and chronic liver disorders [3,5,7,[9][10][11][12]. Targeting senescent cells has the potential to delay age-associated disorders and/or reverse pathological metabolic phenotypes [3,[13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Development of an in vitro senescent hepatic cell model for metabolic studies in aging

Singh

Tripathi

Yen

et al. 2020

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Although in vitro senescence models have been developed using primary fibroblasts, they may not be applicable for the study of metabolically active organs such as the liver. We thus developed an in vitro protocol to induce senescence in AML12 nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha. Sequential oxidative stress with hydrogen peroxide induced premature senescence in these cells as they exhibited molecular and metabolic signatures, had increased SA-Gal and H2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled the livers from aged mice.Metabolic phenotyping showed fuel switching towards more glycolysis, mitochondrial glutamine oxidation, and impaired energy production that also was similar to the livers from aged mice. Additionally, Senescence Activated Secretory Proteins (SASPs) sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated an in vitro senescent AML12 cell model that not only show the molecular hallmarks of aging, but also recapitulates the aberrant metabolic phenotype found in aged liver. As such, they represent a novel and useful model to study nutritional, pharmacological, or genetic factors on hepatic metabolism during aging.

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“…18,19 Notably, SA-β-gal in diverse types of senescent cells is one widely used marker for identifying senescence in vitro and in vivo, which is linked to the increased content of lysosomes. [20][21][22][23] Therefore, we hypothesized that lysosomal β-gal could be utilized for the design of a galactosemodified prodrug to target senescent cells in a broader spectrum. This prodrug could be processed into a cytotoxic compound by β-gal and subsequently delete senescent cells in a specific manner, a strategy that could overcome the limitations of current senolytic drugs.…”

Section: Introductionmentioning

confidence: 99%

Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

et al. 2020

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Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives age-related phenotypes. The clearance of senescent cells is expected to decrease chronic, low-grade inflammation and improve tissue repair capacity, thus attenuating the decline of physical function in aged organisms. However, selective and effective clearance of senescent cells of different cell types has proven challenging. Herein, we developed a prodrug strategy to design a new compound based on the increased activity of lysosomal β-galactosidase (β-gal), a primary characteristic of senescent cells. Our prodrug SSK1 is specifically activated by β-gal and eliminates mouse and human senescent cells independently of senescence inducers and cell types. In aged mice, our compound effectively cleared senescent cells in different tissues, decreased the senescence-and age-associated gene signatures, attenuated low-grade local and systemic inflammation, and restored physical function. Our results demonstrate that lysosomal β-gal can be effectively leveraged to selectively eliminate senescent cells, providing a novel strategy to develop anti-aging interventions.Cell Research (2020) 0:1-16; https://doi.

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Cellular Senescence: Defining a Path Forward

Cited by 1,629 publications

References 158 publications

The combination of mitogenic stimulation and cell cycle arrest induces senescence in equine and human cartilage explants

The combination of mitogenic stimulation and cell cycle arrest induces senescence in equine and human cartilage explants

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

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