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Tocotrienol-rich fraction prevents cellular aging by modulating cell proliferation signaling pathways

Khor SC, Mohd Yusof YA, Wan Ngah WZ, Makpol S

Clin Ter, 2015;166(2):e81-90.
PMID: 25945449 DOI: 10.7417/CT.2015.1825

BACKGROUND AND OBJECTIVE: Vitamin E has been suggested as nutritional intervention for the prevention of degenerative and age-related diseases. In this study, we aimed to elucidate the underlying mechanism of tocotrienol-rich fraction (TRF) in delaying cellular aging by targeting the proliferation signaling pathways in human diploid fibroblasts (HDFs).
MATERIALS AND METHODS: Tocotrienol-rich fraction was used to treat different stages of cellular aging of primary human diploid fibroblasts viz. young (passage 6), pre-senescent (passage 15) and senescent (passage 30). Several selected targets involved in the downstream of PI3K/AKT and RAF/MEK/ERK pathways were compared in total RNA and protein.
RESULTS: Different transcriptional profiles were observed in young, pre-senescent and senescent HDFs, in which cellular aging increased AKT, FOXO3, CDKN1A and RSK1 mRNA expression level, but decreased ELK1, FOS and SIRT1 mRNA expression level. With tocotrienol-rich fraction treatment, gene expression of AKT, FOXO3, ERK and RSK1 mRNA was decreased in senescent cells, but not in young cells. The three down-regulated mRNA in cellular aging, ELK1, FOS and SIRT1, were increased with tocotrienol-rich fraction treatment. Expression of FOXO3 and P21Cip1 proteins showed up-regulation in senescent cells but tocotrienol-rich fraction only decreased P21Cip1 protein expression in senescent cells.
CONCLUSIONS: Tocotrienol-rich fraction exerts gene modulating properties that might be responsible in promoting cell cycle progression during cellular aging.

Matched MeSH terms: Cell Aging/drug effects*
Effect of Cell Age on Uptake and Toxicity of Nanoparticles: The Overlooked Factor at the Nanobio Interface

Foroozandeh P, Aziz AA, Mahmoudi M

ACS Appl Mater Interfaces, 2019 Oct 30;11(43):39672-39687.
PMID: 31633323 DOI: 10.1021/acsami.9b15533

Clinical translation of nanotechnologies has limited success, at least in part, due to the existence of several overlooked factors on the nature of the nanosystem (e.g., physicochemical properties of nanoparticles), nanobio interfaces (e.g., protein corona composition), and the cellular characteristics (e.g., cell type). In the past decade, several ignored factors including personalized and disease-specific protein corona (a layer of formed biomolecules at the surface of nanoparticles upon their entrance into a biological fluid), incubating temperature, local temperature gradient, cell shape, and cell sex has been introduced. Here, it was hypothesized and validated cell age as another overlooked factor in the field of nanomedicine. To test our hypothesis, cellular toxicity and uptake profiles of our model nanoparticles (i.e., PEGylated quantum dots, QDs) were probed in young and senescent cells (i.e., IMR90 fibroblast cells from human fetal lung and CCD841CoN epithelial cells from human fetal colon) and the outcomes revealed substantial dependency of cell-nanoparticles interactions to the cell age. For example, it was observed that the PEGylated QDs were acutely toxic to senescent IMR90 and CCD841CoN cells, leading to lysosomal membrane permeabilization which caused cell necrosis; in contrast, the young cells were resilient to the exact same amount of QDs and the same incubation time. It was also found that the formation of protein corona could delay the QDs' toxicity on senescent cells. These findings suggest that the cellular aging process have a capacity to cause deteriorative effects on their organelles and normal functions. The outcomes of this study suggest the proof-of-concept that cell age may have critical role in biosystem responses to nanoparticle technologies. Therefore, the effect of cell age should be carefully considered on the nanobio interactions and the information about cellular age (e.g., passage number and age of the cell donor) should be included in the nanomedicine papers to facilitate clinical translation of nanotechnologies and to help scientists to better design and produce safe and efficient diagnostic/therapeutic age-specific nanoparticles.

Matched MeSH terms: Cell Aging/drug effects*
Effect of kidney ischemia/reperfusion injury on proliferation, apoptosis, and cellular senescence in acute kidney injury in mice

Sari FT, Sari FT, Sari FT, Arfian N, Sari DCR

Med J Malaysia, 2020 05;75(Suppl 1):20-23.
PMID: 32471965

INTRODUCTION: Kidney ischemia/reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). Kidney IRI demonstrated apoptosis of epithelial cells in acute phase followed by proliferation of interstitial cells in chronic episode, and cellular senescence may contribute to development of AKI, however, its occurrence within acute or chronic episodes is still not completely understood.
METHODS: Kidney IRI was performed with bilateral pediculus clamping in Swiss Background mice (3 months, 30-40g). Mice were euthanised on day one (I/R1, n=6), day eight (I/R8, n=6), and day twelve (I/R12, n=6) to exam acute and chronic episodes. Sham operation procedure was performed in the control. Tubular injury was assessed based on periodic acid- Schift (PAS) staining. Reverse transcriptase PCR (RT-PCR) was done to quantify mRNA expression of Bax, Bcl-2, and p16. Immunohistostaining (IHC) was performed to examine localisation of apoptosis (p53) and proliferation (Bcl-2).
RESULTS: RT-PCR analysis showed upregulation of mRNA expression of Bcl-2, Bax, and p16 (p<0.05). The data showed that ischemia/reperfusion induces upregulation of Bax (p=0.20), Bcl-2 (p=0.45), p16 (p=0.18). Apoptosis and proliferation occurred in the epithelial cells in acute episodes, but occurred in interstitial areas in chronic episodes.
CONCLUSIONS: Ischemia/reperfusion injury induces upregulation proliferation, apoptosis, and cellular senescence in acute kidney injury. Apoptosis reached its peak on day 1, proliferation on day 8, and cellular senescence on day 12.

Matched MeSH terms: Cell Aging*
Fulltext Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts

Durani LW, Khor SC, Tan JK, Chua KH, Mohd Yusof YA, Makpol S

Biomed Res Int, 2017;2017:6894026.
PMID: 28596968 DOI: 10.1155/2017/6894026

Piper betle
(PB) is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs) was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%), presenescent (127.3%), and senescent (157.3%) HDFs. Increased expressions ofPRDX6,TP53,CDKN2A,PAK2, andMAPK14were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions ofSOD1increased, whereasGPX1,PRDX6,TP53,CDKN2A,PAK2, andMAPK14were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways.

Matched MeSH terms: Cell Aging/drug effects*
Targeting the genetic landscape of oral potentially malignant disorders has the potential as a preventative strategy in oral cancer

Prime SS, Cirillo N, Cheong SC, Prime MS, Parkinson EK

Cancer Lett, 2021 10 10;518:102-114.
PMID: 34139286 DOI: 10.1016/j.canlet.2021.05.025

This study reviews the molecular landscape of oral potentially malignant disorders (OPMD). We examine the impact of tumour heterogeneity, the spectrum of driver mutations (TP53, CDKN2A, TERT, NOTCH1, AJUBA, PIK3CA, CASP8) and gene transcription on tumour progression. We comment on how some of these mutations impact cellular senescence, field cancerization and cancer stem cells. We propose that OPMD can be monitored more closely and more dynamically through the use of liquid biopsies using an appropriate biomarker of transformation. We describe new gene interactions through the use of a systems biology approach and we highlight some of the first studies to identify functional genes using CRISPR-Cas9 technology. We believe that this information has translational implications for the use of re-purposed existing drugs and/or new drug development. Further, we argue that the use of digital technology encompassing clinical and laboratory-based data will create relevant datasets for machine learning/artificial intelligence. We believe that therapeutic intervention at an early molecular premalignant stage should be an important preventative strategy to inhibit the development of oral squamous cell carcinoma and that this approach is applicable to other aerodigestive tract cancers.

Matched MeSH terms: Cell Aging/genetics
Fulltext Disruptive chemicals, senescence and immortality

Carnero A, Blanco-Aparicio C, Kondoh H, Lleonart ME, Martinez-Leal JF, Mondello C, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1(Suppl 1):S19-37.
PMID: 26106138 DOI: 10.1093/carcin/bgv029

Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.

Matched MeSH terms: Cell Aging/drug effects*
In vitro modulation of extracellular matrix genes by stingless bee honey in cellular aging of human dermal fibroblast cells

Abdul Malik N, Mohamed M, Mustafa MZ, Zainuddin A

J Food Biochem, 2020 01;44(1):e13098.
PMID: 31746481 DOI: 10.1111/jfbc.13098

This study determined the antiaging effect of stingless bee honey on the expression of extracellular matrix genes. MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay was performed for determination of optimum concentration and incubation time of stingless bee honey. Gene expression of matrix metalloproteinase-1 (MMP-1) and collagen type Ⅰ (COL1A1) were analyzed using real time reverse transcriptase polymerase chain reaction technique. Incubation with stingless bee honey at concentration of 0.02% for 72 hr showed significant increase in the viability of human fibroblast cells. Stingless bee honey significantly downregulates metalloproteinase-1 gene expression in both pre-senescence and senescence fibroblast cells and upregulates collagen type Ⅰ gene expression in senescence fibroblast cells. In conclusion, stingless bee honey potentially delayed skin aging through modulation of extracellular matrix genes. PRACTICAL APPLICATIONS: Changes of the extracellular matrix regulation promote skin aging. Stingless bee honey is a good source of natural antioxidant which potentially delays skin aging. This study demonstrated that stingless bee honey beneficially increases collagen type Ⅰ expression and decreases MMP-1 expression during cellular aging of human dermal fibroblast cells.

Matched MeSH terms: Cell Aging
Bisphenol A exposure modulates reproductive and endocrine system, mitochondrial function and cellular senescence in female adult rats: A hallmarks of polycystic ovarian syndrome phenotype

Prabhu NB, Adiga D, Kabekkodu SP, Bhat SK, Satyamoorthy K, Rai PS

Environ Toxicol Pharmacol, 2022 Nov;96:104010.
PMID: 36334871 DOI: 10.1016/j.etap.2022.104010

Bisphenol A (BPA) mimics estrogen and consequently suspected to be detrimental to female reproductive system. Biomonitoring confirms the BPA burden in body leading to a complex condition called polycystic ovarian syndrome (PCOS) which is frequently attributed to female infertility. Due to unclear precise molecular pathomechanisms of BPA in PCOS, we intend to examine the molecular mechanisms of the reproductive, endocrine, mitochondrial features, and cellular senescence in BPA-treated rats. We analyzed vaginal smears and ovarian follicles using microscope, assessed sex hormones by ELISA, analyzed BPA target gene expression by semi-quantitative RT-PCR, assessed senescence induction by β-galactosidase staining and immunofluorescence in BPA-treated rats. Our data showed hormonal imbalance, impaired folliculogenesis, abnormal expression patterns of target genes, CDKN2A overexpression and enhanced ROS levels in BPA-treated rats. This study provides insights on the effects of BPA exposure on ovulatory, hormonal, mitochondrial dysfunction, and senescence that benefit in better understanding of PCOS induced by BPA.

Matched MeSH terms: Cell Aging
Fulltext Over-expression of Nicotinamide phosphoribosyltransferase in mouse cells confers protective effect against oxidative and ER stress-induced premature senescence

Nuriliani A, Nakahata Y, Ahmed R, Khaidizar FD, Matsui T, Bessho Y

Genes Cells, 2020 Aug;25(8):593-602.
PMID: 32533606 DOI: 10.1111/gtc.12794

A main feature of aged organisms is the accumulation of senescent cells. Accumulated senescent cells, especially stress-induced premature senescent cells, in aged organisms lead to the decline of the regenerative potential and function of tissues. We recently reported that the over-expression of NAMPT, which is the rate-limiting enzyme in mammalian NAD+ salvage pathway, delays replicative senescence in vitro. However, whether Nampt-overexpressing cells are tolerant of stress-induced premature senescence remains unknown. Here, we show that primary mouse embryonic fibroblasts derived from Nampt-overexpressing transgenic mice (Nampt Tg-MEF cells) possess resistance against stress-induced premature senescence in vitro. We found that higher oxidative or endoplasmic reticulum (ER) stress is required to induce premature senescence in Nampt Tg-MEF cells compared to wild-type cells. Moreover, we found that Nampt Tg-MEF cells show acute expression of unfolded protein response (UPR)-related genes, which in turn would have helped to restore proteostasis and avoid cellular senescence. Our results demonstrate that NAMPT/NAD+ axis functions to protect cells not only from replicative senescence, but also from stress-induced premature senescence in vitro. We anticipate that in vivo activation of NAMPT activity or increment of NAD+ would protect tissues from the accumulation of premature senescent cells, thereby maintaining healthy aging.

Matched MeSH terms: Cell Aging/genetics; Cell Aging/physiology*
Alpha-tocopherol modulates hydrogen peroxide-induced DNA damage and telomere shortening of human skin fibroblasts derived from differently aged individuals

Makpol S, Zainuddin A, Rahim NA, Yusof YA, Ngah WZ

Planta Med, 2010 Jun;76(9):869-75.
PMID: 20112180 DOI: 10.1055/s-0029-1240812

Antioxidants such as vitamin E may act differently on skin cells depending on the age of the skin and the level of oxidative damage induced. The effects of alpha-tocopherol (ATF) on H(2)O(2)-induced DNA damage and telomere shortening of normal human skin fibroblast cells derived from young and old individual donors were determined. Fibroblasts were divided into five groups; untreated control, H(2)O(2)-induced oxidative stress, alpha-tocopherol treatment, and pre- and post-treatment with alpha-tocopherol for H(2)O(2)-induced oxidative stress. Our results showed that H(2)O(2)-induced oxidative stress increased DNA damage, shortened the telomere length and reduced the telomerase activity (p < 0.05) in fibroblasts obtained from young and old donors. Pre- and post-treatment with alpha-tocopherol protected against H(2)O(2)-induced DNA damage in fibroblasts obtained from young individuals (p = 0.005; p = 0.01, respectively). However, in fibroblasts obtained from old individuals, similar protective effects were only seen in cells pretreated with alpha-tocopherol (p = 0.05) but not in the post-treated cells. Protection against H(2)O(2)-induced telomere shortening was observed in fibroblasts obtained from both young and old donors which were pre-treated with alpha-tocopherol (p = 0.009; p = 0.008, respectively). However, similar protective effects against telomere shortening in fibroblasts obtained from both young and old donors were not observed in the post-treated fibroblasts. Protection against H(2)O(2)-induced telomerase activity loss was observed only in fibroblasts obtained from old donors which were pretreated with alpha-tocopherol (p = 0.04) but not in fibroblasts obtained from young donors. Similar protective effects against telomerase activity loss in fibroblasts obtained from both young and old donors were not observed in the post-treated fibroblasts. In conclusion, alpha-tocopherol protected against H(2)O(2)-induced telomere shortening by restoring the telomerase activity. It also modulated H(2)O(2)-induced DNA damage and this modulation was affected by donor age.

Matched MeSH terms: Cell Aging/drug effects*; Cell Aging/genetics
Autophagy and senescence: A new insight in selected human diseases

Rajendran P, Alzahrani AM, Hanieh HN, Kumar SA, Ben Ammar R, Rengarajan T, et al.

J Cell Physiol, 2019 12;234(12):21485-21492.
PMID: 31144309 DOI: 10.1002/jcp.28895

Senescence and autophagy play important roles in homeostasis. Cellular senescence and autophagy commonly cause several degenerative processes, including oxidative stress, DNA damage, telomere shortening, and oncogenic stress; hence, both events are known to be interrelated. Autophagy is well known for its disruptive effect on human diseases, and it is currently proposed to have a direct effect on triggering senescence and quiescence. However, it is yet to be proven whether autophagy has a positive or negative impact on senescence. It is known that elevated levels of autophagy induce cell death, whereas inadequate autophagy can trigger cellular senescence. Both have important roles in human diseases such as aging, renal degeneration, neurodegenerative disorders, and cancer. Therefore, this review aims to highlight the relevance of senescence and autophagy in selected human ailments through a summary of recent findings on the connection and effects of autophagy and senescence in these diseases.

Matched MeSH terms: Cell Aging/genetics; Cell Aging/physiology*
MicroRNAs-associated with FOXO3 in cellular senescence and other stress responses

Khor YS, Wong PF

Biogerontology, 2024 Feb;25(1):23-51.
PMID: 37646881 DOI: 10.1007/s10522-023-10059-6

FOXO3 is a member of the FOXO transcription factor family and is known for regulating cellular survival in response to stress caused by various external and biological stimuli. FOXO3 decides cell fate by modulating cellular senescence, apoptosis and autophagy by transcriptional regulation of genes involved in DNA damage response and oxidative stress resistance. These cellular processes are tightly regulated physiologically, with FOXO3 acting as the hub that integrates signalling networks controlling them. The activity of FOXO3 is influenced by post-translational modifications, altering its subcellular localisation. In addition, FOXO3 can also be regulated directly or indirectly by microRNAs (miRNAs) or vice versa. This review discusses the involvement of various miRNAs in FOXO3-driven cellular responses such as senescence, apoptosis, autophagy, redox and inflammation defence. Given that these responses are linked and influence cell fate, a thorough understanding of the complex regulation by miRNAs would provide key information for developing therapeutic strategy and avoid unintended consequences caused by off-site targeting of FOXO3.

Matched MeSH terms: Cell Aging
Fulltext The Molecular Floodgates of Stress-Induced Senescence Reveal Translation, Signalling and Protein Activity Central to the Post-Mortem Proteome

Wasinger VC, Curnoe D, Boel C, Machin N, Goh HM

Int J Mol Sci, 2020 Sep 03;21(17).
PMID: 32899302 DOI: 10.3390/ijms21176422

The transitioning of cells during the systemic demise of an organism is poorly understood. Here, we present evidence that organismal death is accompanied by a common and sequential molecular flood of stress-induced events that propagate the senescence phenotype, and this phenotype is preserved in the proteome after death. We demonstrate activation of "death" pathways involvement in diseases of ageing, with biochemical mechanisms mapping onto neurological damage, embryonic development, the inflammatory response, cardiac disease and ultimately cancer with increased significance. There is sufficient bioavailability of the building blocks required to support the continued translation, energy, and functional catalytic activity of proteins. Significant abundance changes occur in 1258 proteins across 1 to 720 h post-mortem of the 12-week-old mouse mandible. Protein abundance increases concord with enzyme activity, while mitochondrial dysfunction is evident with metabolic reprogramming. This study reveals differences in protein abundances which are akin to states of stress-induced premature senescence (SIPS). The control of these pathways is significant for a large number of biological scenarios. Understanding how these pathways function during the process of cellular death holds promise in generating novel solutions capable of overcoming disease complications, maintaining organ transplant viability and could influence the findings of proteomics through "deep-time" of individuals with no historically recorded cause of death.

Matched MeSH terms: Cell Aging*
Retention of Somatic Memory Associated with Cell Identity, Age and Metabolism in Induced Pluripotent Stem (iPS) Cells Reprogramming

Khoo TS, Jamal R, Abdul Ghani NA, Alauddin H, Hussin NH, Abdul Murad NA

Stem Cell Rev Rep, 2020 04;16(2):251-261.
PMID: 32016780 DOI: 10.1007/s12015-020-09956-x

The discovery of induced pluripotent stem (iPS) cells in 2006 marked a major breakthrough in regenerative medicine, enabling reversal of terminally differentiated somatic cells into pluripotent stem cells. The embryonic stem (ES) cells-like pluripotency and unlimited self-renewal capability of iPS cells have granted them enormous potential in many applications, particularly regenerative therapy. Unlike ES cells, however, iPS cells exhibit somatic memories which were carried over from the tissue of origin thus limited its translation in clinical applications. This review provides an updated overview of the retention of various somatic memories associated with the cellular identity, age and metabolism of tissue of origin in iPS cells. The influence of cell types, stage of maturation, age and various other factors on the retention of somatic memory has been discussed. Recent evidence of somatic memory in the form of epigenetic, transcriptomic, metabolic signatures and its functional manifestations in both in vitro and in vivo settings also have been reviewed. The increasing number of studies which had adopted isogenic cell lines for comparisons in recent years had facilitated the identification of genuine somatic memories. These memories functionally affect iPS cells and its derivatives and are potentially tumorigenic thus, raising concerns on their safety in clinical application. Various approaches for memory erasure had since being reported and their efficacies were highlighted in this review.

Matched MeSH terms: Cell Aging*
The roles of MTOR and miRNAs in endothelial cell senescence

Khor ES, Wong PF

Biogerontology, 2020 10;21(5):517-530.
PMID: 32246301 DOI: 10.1007/s10522-020-09876-w

Accumulation of senescent cells in vascular endothelium is known to contribute to vascular aging and increases the risk of developing cardiovascular diseases. The involvement of classical pathways such as p53/p21 and p16/pRB in cellular senescence are well described but there are emerging evidence supporting the increasingly important role of mammalian target of rapamycin (MTOR) as driver of cellular senescence via these pathways or other effector molecules. MicroRNAs (miRNAs) are a highly conserved group of small non-coding RNAs (18-25 nucleotides), instrumental in modulating the expression of target genes associated with various biological and cellular processes including cellular senescence. The inhibition of MTOR activity is predominantly linked to cellular senescence blunting and prolonged lifespan in model organisms. To date, known miRNAs regulating MTOR in endothelial cell senescence remain limited. Herein, this review discusses the roles of MTOR and MTOR-associated miRNAs in regulating endothelial cell senescence, including the crosstalk between MTOR Complex 1 (MTORC1) and cell cycle pathways and the emerging role of MTORC2 in cellular senescence. New insights on how MTOR and miRNAs coordinate underlying molecular mechanisms of endothelial senescence will provide deeper understanding and clarity to the complexity of the regulation of cellular senescence.

Matched MeSH terms: Cell Aging*
Potential role of ergothioneine rich mushroom as anti-aging candidate through elimination of neuronal senescent cells

Apparoo Y, Wei Phan C, Rani Kuppusamy U, Chan EWC

Brain Res, 2024 Feb 01;1824:148693.
PMID: 38036238 DOI: 10.1016/j.brainres.2023.148693

Oxidative stress can upset the antioxidant balance and cause accelerated aging including neurodegenerative diseases and decline in physiological function. Therefore, an antioxidant-rich diet plays a crucial role in healthy aging. This study aimed to identify and quantify mushrooms with the highest ergothioneine content through HPLC analysis and evaluate their anti-aging potential as a natural antioxidant and antisenescence in HT22 cells. Among the 14 evaluated mushroom species, Lentinula edodes (LE), shiitake mushroom contains the highest ergothioneine content and hence was used for the in-vitro studies. The cells were preincubated with ethanolic extract of ergothioneine-rich mushroom and the equimolar concentration of EGT on t-BHP-induced senescence HT22 cells. The extract was analyzed for its free radical scavenging properties using DPPH and ABTS methods. Then, the neuroprotective effect was conducted by measuring the cell viability using MTT. Senescence-associated markers and ROS staining were also analyzed. Our results revealed that a low dose of t-BHP reduces cell viability and induces senescence in HT22 cells as determined through β-galactosidase staining and expressions of P16INK4a, P21CIPL which are the markers of cellular senescence. However, the pretreatment with ethanolic extract of LE for 8 h significantly improved the cell viability, reversed the t-BHP-induced cellular senescence in the neuronal cells, and reduced the reactive oxygen species visualized through DCFH-DA staining. These results suggest that ergothioneine-rich mushroom is a potential candidate for anti-aging exploration through the elimination of senescent cells.

Matched MeSH terms: Cell Aging
Senotherapeutics for mesenchymal stem cell senescence and rejuvenation

Wong PF, Dharmani M, Ramasamy TS

Drug Discov Today, 2023 Jan;28(1):103424.
PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424

Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.

Matched MeSH terms: Cell Aging/genetics
Senolytics: Opening avenues in drug discovery to find novel therapeutics for Parkinson's Disease

Kakoty V, Kalarikkal Chandran S, Gulati M, Goh BH, Dua K, Kumar Singh S

Drug Discov Today, 2023 Jun;28(6):103582.
PMID: 37023942 DOI: 10.1016/j.drudis.2023.103582

Aging is one of the major risk factors for most neurodegenerative disorders including Parkinson's disease (PD). More than 10 million people are affected with PD worldwide. One of the predominant factors accountable for progression of PD pathology could be enhanced accumulation of senescent cells in the brain with the progress of age. Recent investigations have highlighted that senescent cells can ignite PD pathology via increased oxidative stress and neuroinflammation. Senolytics are agents that kill senescent cells. This review mainly focuses on understanding the pathological connection between senescence and PD, with emphasis on some of the recent advances made in the area of senolytics and their evolution to potential clinical candidates for future pharmaceuticals against PD.

Matched MeSH terms: Cell Aging
Aging of the cells: Insight into cellular senescence and detection Methods

Mohamad Kamal NS, Safuan S, Shamsuddin S, Foroozandeh P

Eur J Cell Biol, 2020 Aug;99(6):151108.
PMID: 32800277 DOI: 10.1016/j.ejcb.2020.151108

Cellular theory of aging states that human aging is the result of cellular aging, in which an increasing proportion of cells reach senescence. Senescence, from the Latin word senex, means "growing old," is an irreversible growth arrest which occurs in response to damaging stimuli, such as DNA damage, telomere shortening, telomere dysfunction and oncogenic stress leading to suppression of potentially dysfunctional, transformed, or aged cells. Cellular senescence is characterized by irreversible cell cycle arrest, flattened and enlarged morphology, resistance to apoptosis, alteration in gene expression and chromatin structure, expression of senescence associated- β-galactosidase (SA-β-gal) and acquisition of senescence associated secretory phenotype (SASP). In this review paper, different types of cellular senescence including replicative senescence (RS) which occurs due to telomere shortening and stress induced premature senescence (SIPS) which occurs in response to different types of stress in cells, are discussed. Biomarkers of cellular senescence and senescent assays including BrdU incorporation assay, senescence associated- β-galactosidase (SA-β-gal) and senescence-associated heterochromatin foci assays to detect senescent cells are also addressed.

Matched MeSH terms: Cell Aging/physiology*

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