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PubMed2002

Replicative senescence and senescence-like state induced in cancer-derived cells.

Studies on the replicative senescence and premature senescence induced by various stresses in normal somatic cells have provided important clues on the role of telomere shortening and mechanisms involved in aging processes and carcinogenesis. Recent work revealed that cancer cells also are induced to undergo replicative senescence state via telomere shortening as well as to enter a senescence-like state by the activation of cell cycle inhibitory pathways. Although less relevant in terms of aging physiology, studies on these phenomena in cancer cells have yielded important information on telomerase regulation and the roles of tumor suppressors in senescence and immortalization, and are expected to generate valuable anti-cancer strategies. Several features of the phenotypes specific for the senescent and senescence-like states induced in cancer cells are discussed.

Cell Division↗

PubMed1999

Overexpression of the p21 sdi1 gene induces senescence-like state in human cancer cells: implication for senescence-directed molecular therapy for cancer.

Normal cells in a culture enter a nondividing state after a finite number of population doubling, which is termed replicative senescence, whereas cancer cells have unlimited proliferative potential and are thought to exhibit an immmortal phenotype by escaping from senescence. The p21 gene (also known as sdi1), which encodes the cyclin-dependent kinase inhibitor, is expressed at high levels in senescent cells and contributes to the growth arrest. To examine if the p21sdi1 gene transfer could induce senescence in human cancer cells, we utilized an adenoviral vector-based expression system and four human cancer cell lines differing in their p53 status. Transient overexpression of p21sdi1 on cancer cells induced quiescence by arresting the cell cycle at the G1 phase and exhibited morphological changes, such as enlarged nuclei as well as a flattened cellular shape, specific to the senescence phenotype. We also showed that p21sdi1-transduced cancer cells expressed beta-galactosidase activity at pH 6.0, which is known to be a marker of senescence. Moreover, the polymerase chain reaction-based assay demonstrated that levels of telomerase activity were significantly lower in p21sdi1-expressing cells compared to parental cancer cells. These observations provide the evidence that p21sdi1 overexpression could induce a senescence-like state and reduce telomerase activity in human cancer cells, suggesting that these novel p21sdi1 functions may have important implications for anticancer therapy.

Adenoviridae↗

PubMed2003

Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation.

Normal human fibroblasts undergo a limited number of divisions in culture and progressively they reach a state of irreversible growth arrest, a process termed as replicative senescence. The proteasome is the major cellular proteolytic machinery, the function of which is impaired during replicative senescence. However, the exact causes of its malfunction in these conditions are unknown. Using WI38 fibroblasts as a model for cellular senescence we have observed reduced levels of proteasomal peptidase activities coupled with increased levels of both oxidized and ubiquitinated proteins in senescent cells. We have found the catalytic subunits of the 20 S complex and subunits of the 19 S regulatory complex to be down-regulated in senescent cells. This is accompanied by a decrease in the level of both 20 S and 26 S complexes. Partial inhibition of proteasomes in young cells caused by treatment with specific inhibitors induced a senescence-like phenotype, thus demonstrating the fundamental importance of the proteasome for retaining cellular maintenance and homeostasis. Stable overexpression of beta1 and beta5 subunits in WI38 established cell lines was shown to induce elevated expression levels of beta1 subunit in beta5 transfectants and vice versa. Transfectants possess increased proteasome activities and most importantly, increased capacity to cope better with various stresses. In summary these data demonstrate the central role of the proteasome during cellular senescence and survival as well as provide insights toward a better understanding of proteasome regulation.

Cell Division↗

PubMedDate not supplied

Senescence-accelerated mouse (SAM): a novel murine model of senescence.

The Senescence-Accelerated Mouse (SAM) has been under development by our research team at Kyoto University since 1970 through the selective inbreeding of the AKR/J strain of mice donated by the Jackson Laboratory in 1968, based on a graded score for senescence, life span, and pathologic phenotype. At present, there are 12 lines of SAM: nine senescence-prone inbred strains (SAMP) including SAMP1, SAMP2, SAMP3, SAMP6, SAMP7, SAMP8, SAMP9, SAMP10, and SAMP11; and three senescence-resistant inbred strains (SAMR) including SAMR1, SAMR4, and SAMR5. Data from survival curves, Gompertzian function, and grading score of senescence, together with growth patterns of body weight of these SAMP and SAMR, revealed that the characteristic feature of aging common to all SAMP mice is "accelerated senescence;" early onset and irreversible advance of senescence manifested by several signs and gross lesions such as the loss of normal behavior, various skin lesions, increased lordokyphosis, etc., after a period of normal development. In the course of SAM development, it became evident that SAMP strains manifest various pathologic phenotypes that are characteristic enough to differentiate the SAM strains. The genetic background and significance of SAM development are discussed.

Aging↗

PubMed1979

Relation between leaf senescence and stomatal closure: Senescence in light.

Senescence of isolated oat seedling leaves, floating on water or solutions in white light, has been followed by the disappearance of chlorophyll and the liberation of free amino nitrogen. In parallel, measurements of stomatal aperture were made with a diffusion resistance porometer, and borne out also by changes in fresh weight. The stomata open as expected in the light but slowly begin to close after the first day; correspondingly, in the dark they close at once but gradually begin to open on successive days. Abscisic acid causes closure and this is accompanied by senescence. Phenylmercuric nitrate also causes closure and again the reaction is closely paralleled by senescence. Kinetin maintains stomatal opening even more than does light alone, and this is accompanied by complete prevention of chlorophyll loss for at least 5 days. Covering the leaf surface with a film of Vaseline, especially when detergents are added, accelerates senescence. Merely floating the leaf segments on hypertonic solutions of sucrose or mannitol suffices to bring the rate of senescence in light up to the rate in darkness. It is concluded that the effect of light in delaying senescence is primarily due to its effect on the stomatal aperture, and, more generally, that stomatal aperture is the principal controlling agent in leaf senescence.

Journal Article↗

PubMed2002

Leaf senescence induced by mild water deficit follows the same sequence of macroscopic, biochemical, and molecular events as monocarpic senescence in pea.

We have compared the time course of leaf senescence in pea (Pisum sativum L. cv Messire) plants subjected to a mild water deficit to that of monocarpic senescence in leaves of three different ages in well-watered plants and to that of plants in which leaf senescence was delayed by flower excision. The mild water deficit (with photosynthesis rate maintained at appreciable levels) sped up senescence by 15 d (200 degrees Cd), whereas flower excision delayed it by 17 d (270 degrees Cd) compared with leaves of the same age in well-watered plants. The range of life spans in leaves of different ages in control plants was 25 d (340 degrees Cd). In all cases, the first detected event was an increase in the mRNA encoding a cysteine-proteinase homologous to Arabidopsis SAG2. This happened while the photosynthesis rate and the chlorophyll and protein contents were still high. The 2-fold variability in life span of the studied leaves was closely linked to the duration from leaf unfolding to the beginning of accumulation of this mRNA. In contrast, the duration of the subsequent phases was essentially conserved in all studied cases, except in plants with excised flowers, where the degradation processes were slower. These results suggest that senescence in water-deficient plants was triggered by an early signal occurring while leaf photosynthesis was still active, followed by a program similar to that of monocarpic senescence. They also suggest that reproductive development plays a crucial role in the triggering of senescence.

Acclimatization↗

PubMed2005

Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.

In senescent cells, specialized domains of transcriptionally silent senescence-associated heterochromatic foci (SAHF), containing heterochromatin proteins such as HP1, are thought to repress expression of proliferation-promoting genes. We have investigated the composition and mode of assembly of SAHF and its contribution to cell cycle exit. SAHF is enriched in a transcription-silencing histone H2A variant, macroH2A. As cells approach senescence, a known chromatin regulator, HIRA, enters PML nuclear bodies, where it transiently colocalizes with HP1 proteins, prior to incorporation of HP1 proteins into SAHF. A physical complex containing HIRA and another chromatin regulator, ASF1a, is rate limiting for formation of SAHF and onset of senescence, and ASF1a is required for formation of SAHF and efficient senescence-associated cell cycle exit. These data indicate that HIRA and ASF1a drive formation of macroH2A-containing SAHF and senescence-associated cell cycle exit, via a pathway that appears to depend on flux of heterochromatic proteins through PML bodies.

Amino Acid Sequence↗

PubMed2003

TGF-beta cytokines increase senescence-associated beta-galactosidase activity in human prostate basal cells by supporting differentiation processes, but not cellular senescence.

The family of transforming growth factors betas (TGF-betas) comprises molecules involved in growth inhibition, stress-induced premature senescence, epithelial mesenchymal transition and differentiation processes. The aim of this study was to clarify the effect of long term exposure of human prostate basal cells to TGF-betas, which are found in high concentrations in prostatic fluid and areas of benign prostatic hyperplasia (BPH). Basal cell cultures established from prostate explants (n=3) were either grown into cellular senescence, or stimulated with TGF-beta1, beta2 and beta3. Similar to cellular senescence, TGF-beta stimulation resulted in an increase of SA-beta galactosidase (SA-beta-gal) activity, flattened and enlarged cell morphology, and down-regulation of the inhibitor of differentiation Id-1. TGF-beta-treated prostate epithelial cells neither showed terminal growth arrest nor induction of important senescence-relevant genes, such as p16(INK4A), IFI-6-16, IGFBP-3 or Dkk-3. Cells stained positive for cytokeratins 8/18, but did not express other lumenal markers, such as prostate-specific antigen and androgen-receptors. TGF-betas increased also the expression of the mesenchymal marker vimentin, indicating that basal epithelial cells underwent differentiation with lumenal and mesenchymal features. In contrast, in vitro-differentiated neuroendocrine-like cells from prostate organoide cultures, expressing chromogranin A and cytokeratin 18, strongly stained positive for SA-beta-gal. Thus, SA-beta-gal activity is not only a marker for senescence, but also for differentiation of human prostate epithelial cells. With regard to the in vivo situation, in addition to cellular senescence, TGF-beta could contribute to the increased number of SA-beta-gal positive epithelial cells in BPH.

Aged↗

PubMed2005

Senescence-associated decline in the intranuclear accumulation of hOGG1-alpha and impaired 8-oxo-dG repair activity in senescing normal human oral keratinocytes in vivo.

We determined the mitochondrial membrane status, presence of reactive oxygen species (ROS), and oxidative DNA adduct formation in normal human oral keratinocytes (NHOK) during senescence. The senescent cells showed accumulation of intracellular ROS and 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG), a major oxidative DNA adduct. Exposure of cells to H2O2 induced 8-oxo-dG accumulation in cellular DNA, which was rapidly removed in replicating NHOK. However, the 8-oxo-dG removal activity was almost completely abolished in the senescing culture. Both replicating and senescing NHOK expressed readily detectable 8-oxo-dG DNA glycosylase (hOGG1), the enzyme responsible for glycosidic cleavage of 8-oxo-dG. After exposure to H2O2, however, the intranuclear level of the hOGG1-alpha isoform was decreased in senescing but not in replicating NHOK. These results indicated that senescing NHOK accumulated oxidative DNA lesions in part due to increased level of endogenous ROS and impaired intranuclear translocation of hOGG1 enzyme upon exposure to oxidative stress.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2001

Histone deacetylases in replicative senescence: evidence for a senescence-specific form of HDAC-2.

To analyze mechanisms of senescence-associated gene expression, we have investigated histone deacetylases (HDACs) in human fibroblasts undergoing replicative senescence. We found that the overall acetylation pattern of histones does not vary detectably with replicative senescence. By Northern blot and Western blot, we found a significant decrease in the abundance of HDAC-1 in senescent cells. Biochemical analysis of deacetylase activities in extracts from old and young cells revealed a striking difference. While by anion exchange chromatography we found a single peak of activity in extracts from young cells, which coincided with the elution of both HDAC-1 and HDAC-2, in senescent cells a second peak of activity was found. This second peak of activity is associated with HDAC-2 but does not contain HDAC-1. These results suggest that HDAC-2 is present in at least two distinct forms, one of which is specific for senescent cells. Further biochemical characterization of the enzyme activity revealed that addition of nicotinamide adenine dinucleotide (NAD) did not detectably influence the activity of any fraction, suggesting that NAD is not an essential co-factor for the analyzed HDACs from diploid human fibroblasts.

Blotting, Western↗

PubMed2002

Telomerase positive human diploid fibroblasts are resistant to replicative senescence but not premature senescence induced by chemical reagents.

Human diploid fibroblasts in tissue culture undergo replicative senescence after a finite number of divisions that is characterized by a permanent loss of their dividing potential. However, senescence-like phenotypes, including growth cessation, morphological changes, and appearance of senescence-associated beta-galactosidae (SA-gal) activity, can be induced by treating early passage cells with C(6)-ceramide, H(2)O(2), LY294002, or trichostatin A. While there is convincing evidence that telomere shortening is causally related to replicative senescence, the role of telomere shortening in the chemical-induced premature senescence is unclear. Here we employed a normal human BJ cell strain and its telomerase-transfected counterpart, termed BJ-T cells, to examine whether active telomerase in BJ-T can block or delay the premature senescence induced by various chemicals and, if not, whether telomere shortening still occurs. We found that, although all four chemicals tested could induce growth arrest, and in some cases SA-gal activity, in both BJ and BJ-T cells, only H(2)O(2) clearly caused an irreversible loss of dividing potential. H(2)O(2) treatment did not inhibit the cellular telomerase activity, nor did it cause any appreciable telomere shortening in BJ-T cells. These results suggest that oxidative stress and other chemical reagents can target at sites unrelated to the telomere-associated clocking mechanism. Alternatively these chemicals may bypass the telomere length maintenance machinery and target at its downstream sites.

Base Sequence↗

PubMed1999

Senescence-associated gene expression during ozone-induced leaf senescence in Arabidopsis.

The expression patterns of senescence-related genes were determined during ozone (O(3)) exposure in Arabidopsis. Rosettes were treated with 0.15 microL L(-1) O(3) for 6 h d(-1) for 14 d. O(3)-treated leaves began to yellow after 10 d of exposure, whereas yellowing was not apparent in control leaves until d 14. Transcript levels for eight of 12 senescence related genes characterized showed induction by O(3). SAG13 (senescence-associated gene), SAG21, ERD1 (early responsive to dehydration), and BCB (blue copper-binding protein) were induced within 2 to 4 d of O(3) treatment; SAG18, SAG20, and ACS6 (ACC synthase) were induced within 4 to 6 d; and CCH (copper chaperone) was induced within 6 to 8 d. In contrast, levels of photosynthetic gene transcripts, rbcS (small subunit of Rubisco) and cab (chlorophyll a/b-binding protein), declined after 6 d. Other markers of natural senescence, SAG12, SAG19, MT1 (metallothionein), and Atgsr2 (glutamine synthetase), did not show enhanced transcript accumulation. When SAG12 promoter-GUS (beta-glucuronidase) and SAG13 promoter-GUS transgenic plants were treated with O(3), GUS activity was induced in SAG13-GUS plants after 2 d but was not detected in SAG12-GUS plants. SAG13 promoter-driven GUS activity was located throughout O(3)-treated leaves, whereas control leaves generally showed activity along the margins. The acceleration of leaf senescence induced by O(3) is a regulated event involving many genes associated with natural senescence.

Alcohol Dehydrogenase↗

PubMed1996

A senescence-associated gene of Arabidopsis thaliana is distinctively regulated during natural and artificially induced leaf senescence.

We have characterized the structure and expression of a senescence-associated gene (sen1) of Arabidopsis thaliana. The protein-coding region of the gene consists of 5 exons encoding 182 amino acids. The encoded peptide shows noticeable similarity to the bacterial sulfide dehydrogenase and 81% identity to the peptide encoded by the radish din1 gene. The 5'-upstream region contains sequence motifs resembling the heat-shock- and ABA-responsive elements and the TCA motif conserved among stress-inducible genes. Examination of the expression patterns of the sen1 gene under various senescing conditions along with measurements of photochemical efficiency and of chlorophyll content revealed that the sen1 gene expression is associated with Arabidopsis leaf senescence. During the normal growth phase, the gene is strongly induced in leaves at 25 days after germination when inflorescence stems are 2-3 cm high, and then the mRNA level is maintained at a comparable level in naturally senescing leaves. In addition, dark-induced senescence of detached leaves or of leaves in planta resulted in a high-level induction of the gene. Expression of the sen1 gene was also strongly induced in leaves subjected to senescence by 0.1mM abscisic acid or 1 mM ethephon treatment. The induced expression of the gene by dark treatment was not significantly repressed by treatment with 0.1 mM cytokinin or 50 mM CaCl2 which delayed loss of chlorophyll but not that of photochemical efficiency.

Aging↗

PubMed1984

Grading score system: a method for evaluation of the degree of senescence in senescence accelerated mouse (SAM).

For evaluation of the degree of senescence in SAM-P, accelerated senescence prone mouse, formerly called SAM or prone series or P-series, consisting of SAM-P/1, SAM-P/2, SAM-P/3 and SAM-P/4 corresponding to P-1, P-2, P-3 and P-4 series, respectively, in the previous reports, and in SAM-R, accelerated senescence resistant mouse, formerly called resistant series or R-series, consisting of SAM-R/1, SAM-R/2 and SAM-R/3 corresponding to R-1, R-2 and R-3 series, respectively, in the previous reports, the grading score system was adopted. The items to be examined in this system include 11 categories selected from the clinical signs and gross lesions considered to be associated with the aging process. The degree of the senescence in each category was graded from 0 to 4 according to the detailed criteria devised in our laboratory. After 8 months of age each mouse was examined every 4 months, and some of the mice were examined after 2 months of age. In almost all categories, the grading score and incidence began to increase from 4 or 6 months of age and continued to increase with advancing age in both SAM-P and SAM-R. The increase, however, was more marked in SAM-P than in SAM-R. The slow but steady increase in the SAM-R levelled out at 24 months of age and was comparable to that at 12 months of age in SAM-P. In both SAM-P/1 at 8 months of age and SAM-R/2 at 12 months of age, there was a significant reverse correlation between total score of this grading score system and length of residual life after examination. Systematic and extensive studies using the grading score system showed that if the validity of the system is, based on "irreversibility" and "universality" of the changes in each category with advancing age, most categories are valid for evaluation of the degree of senescence. This grading score system is a unique, useful and convenient method for evaluation of the degree of senescence in mice.

Aging↗

PubMed2001

Leaf senescence in rice plants: cloning and characterization of senescence up-regulated genes.

To identify senescence-associated genes (SAGs) in rice leaves, senescence was induced by transferring rice seedlings into darkness. Senescence up-regulated cDNAs were obtained by PCR-based subtractive hybridization. Among 14 SAG clones characterized, 11 were found to be associated with both dark-induced and natural leaf senescence. Three clones were associated only with dark-induced leaf senescence. The possible physiological roles of these SAGs during rice leaf senescence are discussed.

Cloning, Molecular↗

PubMed1977

Metabolism of Oat Leaves during Senescence: V. Senescence in Light.

A comparison has been made of the progress of senescence in the first leaf of 7-day-old oat plants (Avena sativa cv. Victory) in darkness and in white light. Light delays the senescence, and intensities not over 100 to 200 ft-c (1000-2000 lux) suffice for the maximum effect. In such intensities, chlorophyll loss and amino acid liberation still go on in detached leaves at one-third to one-half the rate observed in darkness; however, when the leaves are attached to the plant, the loss of chlorophyll in 5 days is barely detectable. Transfer of the leaves from 1 or 2 days in the low intensity light to darkness, or vice versa, shows no carryover of the effects of the preceding exposure, so that such treatment affords no evidence for the photoproduction of a stable substance, such as cytokinin, inhibiting senescence. Light causes a large increase in invertaselabile sugar and a smaller increase in glucose, and application of 100 to 300 mm glucose or sucrose in the dark maintains the chlorophyll, at least partially. Correspondingly, short exposure to high light intensity, which increased the sugar content, had a moderate effect in maintaining the chlorophyll. However, 3-(3,4-dichlorphenyl)-1,1-dimethylurea (DCMU) completely prevents the increases in sugars and yet does not prevent the effect of light on senescence, whether determined by chlorophyll loss or by protein hydrolysis. Light causes a 300% increase in the respiration of detached oat leaves, and kinetin lowers that only partly, but unlike the increased respiration associated with senescence in the dark, the increase in the light is fully sensitive to dinitrophenol, and therefore cannot be ascribed to respiratory uncoupling. The increased respiration in light is prevented by DCMU, parallel with the prevention of sugar formation. It is therefore ascribed to the accumulation of soluble sugars, acting as respirable substrate. Also, l-serine does not antagonize the light effect. For all of these reasons, it is concluded that the action of light is not mediated by photosynthetic sugar formation, nor by photoproduction of a cytokinin. Instead, we propose that light exerts its effect by photoproduction of ATP. The action of sugars is ascribed to the same mechanism but by way of respiratory ATP. This hypothesis unifies most of the observed phenomena of the senescence process in oat leaves, and helps to explain some of the divergent findings of earlier workers.

Journal Article↗

PubMed2025

Senescent-like microglia limit remyelination through the senescence associated secretory phenotype.

The capacity to regenerate myelin in the central nervous system diminishes with age. This decline is particularly evident in multiple sclerosis (MS), a chronic demyelinating disease. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells accumulate within demyelinated lesions after injury, and treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice. In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination. However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination. Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice, which is found to inhibit oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

Animals↗

PubMed2001

Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis.

Human ageing is characterized by a progressive loss of physiological functions, increased tissue damage and defects in various tissue renewal systems. Age-related decreases of the cellular replicative capacity can be reproduced by in vitro assays of cellular ageing. When diploid human fibroblasts reach their finite lifespan, they enter an irreversible G1 growth arrest status referred to as replicative senescence. While deregulation of programmed cell death (apoptosis) is a key feature of age-related pathology in several tissues, this is not reflected in the standard in vitro senescence model of human fibroblasts, and the role of apoptosis during cellular ageing remains unclear. We have analyzed replicative senescence of human umbilical vein endothelial cells (HUVEC) in vitro and found that senescent HUVEC also arrest in the G1 phase of the cell cycle but, unlike fibroblasts, accumulate with a 4N DNA content, indicative of polyploidization. In contrast to human fibroblasts, senescent endothelial cells display a considerable increase in spontaneous apoptosis. The data imply that age-dependent apoptosis is a regular feature of human endothelial cells and suggest cell type specific differences in human ageing.

Apoptosis↗