• BMB Reports
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• v.52 no.1
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• pp.35-41
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• 2019

Cellular senescence, a permanent state of cell cycle arrest, is believed to have originally evolved to limit the proliferation of old or damaged cells. However, it has been recently shown that cellular senescence is a physiological and pathological program contributing to embryogenesis, immune response, and wound repair, as well as aging and age-related diseases. Unlike replicative senescence associated with telomere attrition, premature senescence rapidly occurs in response to various intrinsic and extrinsic insults. Thus, cellular senescence has also been considered suppressive mechanism of tumorigenesis. Current studies have revealed that therapy-induced senescence (TIS), a type of senescence caused by traditional cancer therapy, could play a critical role in cancer treatment. In this review, we outline the key features and the molecular pathways of cellular senescence. Better understanding of cellular senescence will provide insights into the development of powerful strategies to control cellular senescence for therapeutic benefit. Lastly, we discuss existing strategies for the induction of cancer cell senescence to improve efficacy of anticancer therapy.

• Molecules and Cells
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• v.40 no.9
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• pp.607-612
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• 2017

When mammalian cells and animals face a variety of internal or external stresses, they need to make homeostatic changes so as to cope with various stresses. To this end, mammalian cells are equipped with two critical stress responses, autophagy and cellular senescence. Autophagy and cellular senescence share a number of stimuli including telomere shortening, DNA damage, oncogenic stress and oxidative stress, suggesting their intimate relationship. Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. These seemingly opposite roles of autophagy may reflect a complex picture of autophagic regulation on cellular senescence, including different types of autophagy or a unique spatiotemporal activation of autophagy. Thus, a better understanding of autophagy process will lead us to not only elucidate the conundrum how autophagy plays dual roles in the regulation of cellular senescence but also helps the development of new therapeutic strategies for many human diseases associated with cellular senescence. We address the pro-senescence and anti-senescence roles of autophagy while focusing on the potential mechanistic aspects of this complex relationship between autophagy and cellular senescence.

• BMB Reports
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• v.47 no.2
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• pp.51-59
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• 2014

Cellular senescence is a physiological process of irreversible cell-cycle arrest that contributes to various physiological and pathological processes of aging. Whereas replicative senescence is associated with telomere attrition after repeated cell division, stress-induced premature senescence occurs in response to aberrant oncogenic signaling, oxidative stress, and DNA damage which is independent of telomere dysfunction. Recent evidence indicates that cellular senescence provides a barrier to tumorigenesis and is a determinant of the outcome of cancer treatment. However, the senescence-associated secretory phenotype, which contributes to multiple facets of senescent cancer cells, may influence both cancer-inhibitory and cancer-promoting mechanisms of neighboring cells. Conventional treatments, such as chemo- and radiotherapies, preferentially induce premature senescence instead of apoptosis in the appropriate cellular context. In addition, treatment-induced premature senescence could compensate for resistance to apoptosis via alternative signaling pathways. Therefore, we believe that an intensive effort to understand cancer cell senescence could facilitate the development of novel therapeutic strategies for improving the efficacy of anticancer therapies. This review summarizes the current understanding of molecular mechanisms, functions, and clinical applications of cellular senescence for anticancer therapy.

• Biotechnology and Bioprocess Engineering:BBE
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• v.6 no.4
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• pp.231-236
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• 2001

How much do we know about the biology of aging from cell culture studies Most normal somatic cells have a finite potential to divide due to a process termed cellular or replicative senescence. A growing body evidence suggests that senescence evolved to protect higher eu-karyotes, particularly mammals, from developing cancer, We now know that telomere shortening due to the biochemistry of DNA replication, induces replicative senescence in human cells. How-ever in rodent cells, replicative senescence occurs despite very long telomeres. Recent findings suggest that replicative senescence is just the tip of the iceberg of a more general process termed cellular senescence. It appears that cellular senescence is a response to potentially oncogenic in-sults, including oxidative damage. In young orgainsms, growth arrest by cell senescence sup-presses tumor development, but later in life, due to the accumulation of senescent cells which se-cret factors that can disrupt tissues during aging, cellular senescence promotes tumorigenesis. Therefore, antagonistic pleiotropy may explain, if not in whole the apparently paradoxical effects of cellular senescence, though this still remains an open question.

• International Journal of Stem Cells
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• v.17 no.1
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• pp.80-90
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• 2024

Cellular senescence causes cell cycle arrest and promotes permanent cessation of proliferation. Since the senescence of mesenchymal stem cells (MSCs) reduces proliferation and multipotency and increases immunogenicity, aged MSCs are not suitable for cell therapy. Therefore, it is important to inhibit cellular senescence in MSCs. It has recently been reported that metabolites can control aging diseases. Therefore, we aimed to identify novel metabolites that regulate the replicative senescence in MSCs. Using a fecal metabolites library, we identified nervonic acid (NA) as a candidate metabolite for replicative senescence regulation. In replicative senescent MSCs, NA reduced senescence-associated 𝛽-galactosidase positive cells, the expression of senescence-related genes, as well as increased stemness and adipogenesis. Moreover, in non-senescent MSCs, NA treatment delayed senescence caused by sequential subculture and promoted proliferation. We confirmed, for the first time, that NA delayed and inhibited cellular senescence. Considering optimal concentration, duration, and timing of drug treatment, NA is a novel potential metabolite that can be used in the development of technologies that regulate cellular senescence.

• BMB Reports
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• v.52 no.1
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• pp.3-4
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• 2019

Cellular senescence is defined as a state of stable cell cycle exit in response to various stimuli, which include both cytotoxic stress and physiological cues. In addition to the core non-proliferative aspect, senescence is associated with diverse functionalities, which contribute to the role of senescence in a wide range of pathological and physiological processes. Such functionality is often mediated by the capability of senescent cells to communicate with their surroundings. Emerging evidence suggests that senescence is not a single entity, but a dynamic and heterogeneous collective phenotype. Understanding the diverse nature of senescence should provide insights into the complexity of tissue homeostasis and its disruption, such as in aging and tumorigenesis.

• BMB Reports
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• v.56 no.12
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• pp.651-656
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• 2023

Senescence, a cellular process through which damaged or dysfunctional cells suppress the cell cycle, contributes to aging or age-related functional decline. Cell metabolism has been closely correlated with aging processes, and it has been widely recognized that metabolic changes underlie the cellular alterations that occur with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We found that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, increased formation of autophagosomes following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we found that inhibition of autophagy or enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence.

• Korean Journal of Plant Tissue Culture
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• v.27 no.4
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• pp.259-268
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• 2000

Senescence is a sequence of biochemical and physiological events that lead to death of a cell, organ, or whole organism. Senescence is now clearly regarded as a genetically determined and evolutionarilly acquired developmental process comprising the final stage of development. However, in spite of the biological and practical importance, genetic mechanism of senescence has been very limited. Through forward and reverse genetic approaches, we are trying to reveal the molecular and genetic mechanism of senescence in plants, employing leaf organs of Arabidopsis as a model system. Using forward genetic approach, we have initially isolated several delayed senescence mutants either from T-DNA insertional lines or chemical-mutagenized lines. In the case of ore 4 and ore 9 mutants, the mutated genes were identified. The recent progress on characterization of mutants and identification of the mutated genes will be reported. We are also screening mutations from other various sources of mutant pools, such as activation tagging lines and promoter trap lines. Two dominant senescence-delayed mutants were isolated from the activation tagging pool. Cloning of the genes responsible for this phenotype is in progress. For reverse genetic approach, the genes that induced during leaf senescence were first isolated by differential screening method. We are currently using PCR-based suppression subtractive hybridization, designed to enrich a cDNA library for rare differentially expressed transcripts. Using this method, we have identified over 35 new sequences that are upregulated at leaf senescence stage. We are investigating the function of these novel genes by systemically generating antisense lines.

• Toxicological Research
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• v.19 no.3
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• pp.161-172
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• 2003

Explanted mammalian cells perform a limited number of cell division in vitro and than are arrested in a state known as replicative senescence. Such cells are irreversibly blocked, mostly in the G1 phase of cell cycle, and are no longer sensitive to growth factor stimulation. Thus replicative senescence is defined as a permanent and irreversible loss of replicative potential of cells. For this characteristic, replicative senescence seems to evolve to protect mammalian organism from cancer. However, senescence also contributes to aging. It seems to decrease with age of the cell donor and, as a form of cell senescence, is thought to underlie the aging process. Extensive evidence supports the idea that progressive telomere loss contributes to the phenomenon of cell senescence. Telomeres are repetitive structures of the sequence (TTAGGG)n at the ends of linear chromosomes. It has been shown that the average length of telomere repeats in human somatic cells decreases by 30∼200 bp with each cell division. It is generally believed that when telomeres reach a critical length, a signal is activated to initiate the senescent program. This has given rise to the hypothesis that telomeres act as mitotic clocks to regulate lifespan. One proposes that cumulative oxidative stress, mainly reactive oxygen species generated from mitochondria, may mainly cause telomere shortening, accelerating aging. Here, the biological importance and mechanism of replicative senescence were briefly reviewed. Also it was summarized that how oxidative stress affects replicative senescence and telomere shortening.

• Korea Journal of Cosmetic Science
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• v.1 no.1
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• pp.1-9
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• 2019

The identification of compounds with anti-senescence activity in cell culture system is a first step in aging research. Given that pyruvate can be used energy source by conversion to acetyl-CoA in mitochondria, and protects cultured cell from various stress-induced cell damage and cell death, synthetic media (e.g., DMEM) often includes 1 mM pyruvate, which is very higher than the pyruvate concentration in human blood (approximately 30 ��M). However, the use of medium containing high concentration of pyruvate is not suitable for screening anti-senescence compounds, because pyruvate also protects against the cellular senescence of primary human dermal fibroblasts (NHDFs) through NAD+ generated during conversion to lactate. In this study, four extracts, i.e., Sprouted seed and fruit complex, Poncirus trifoliata fruit extract, Jaum balancing complex, and Prunus mume extract were used for evaluation of different anti-senescence effect in the absence or presence of 0.1 mM pyruvate, similar to the physiological pyruvate concentration. The senescence in NHDFs cultured with DMEM in the presence of 0.1 mM pyruvate (approximately the physiological concentration in human blood) is accelerated, as observed in pyruvate deprivation conditions. The cytotoxicity of the Poncirus trifoliata fruit extract was protected by pyruvate, and Jaum balancing complex and Prunus mume extract had anti-senescence activity in the presence of 0.1 mM pyruvate, but not in the absence of pyruvate. Given that pyruvate is a powerful protector against both cytotoxicity and cellular senescence, the screening of candidate agents for anti-senescence in high pyruvate conditions using an in vitro cell culture system is not valid. Therefore, we recommend the use of a low concentration of pyruvate to evaluate the anti-senescence effects of candidates, which is more similar to in vivo aging conditions than excessive stress-induced senescence models, to exclude the effect of excessive pyruvate in vitro.