Disease relevance of Cell Aging

• To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV- donors [1].
• Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers [2].
• Conditional overexpression of p21 in a fibrosarcoma cell line was shown previously to inhibit the expression of multiple proliferation-associated genes and to induce the expression of genes associated with various aspects of cell senescence and organism aging [3].
• Moreover, this replicative senescence was not reversed by treating cultured hepatocytes with agents (i.e., betaine or leptin) that improve liver disease in intact ethanol-fed or leptin-deficient mice [4].
• Loss of the hSNF5 gene concomitantly inactivates p21CIP/WAF1 and p16INK4a activity associated with replicative senescence in A204 rhabdoid tumor cells [5].

Psychiatry related information on Cell Aging

• Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro [6].
• We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres [7].

High impact information on Cell Aging

• This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism [8].
• Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence [9].
• Erosion of the telomeric single-strand overhang at replicative senescence [10].
• The ectopic expression of telomerase in normal human cells results in an extended lifespan, indicating that telomere shortening regulates the timing of cellular senescence [11].
• Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a [12].

Chemical compound and disease context of Cell Aging

• L-Tyrosine promotes a dramatic increase in melanogenesis and an apparent replicative senescence in B16 melanoma (M. Strasberg-Rieber and M. Rieber, Cancer Res., 53:2469-2471, 1993) [13].
• In three different models of acute renal failure (ischemia, ureteral obstruction, and cisplatin administration), the p21WAF1/CIP1/SDI1 gene, the protein product of which is associated with cell-cycle interruption, terminal differentiation, and cellular senescence, was activated in murine kidney cells [14].

Biological context of Cell Aging

• The tumour suppressor p53 induces cellular senescence in response to oncogenic signals. p53 activity is modulated by protein stability and post-translational modification, including phosphorylation and acetylation [15].
• The p53 tumor suppressor exerts anti-proliferative effects, including growth arrest, apoptosis and cell senescence, in response to various types of stress [16].
• We propose that WRN up-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence [17].
• Thus, the HPV16 E7 gene led to HUC immortalization by a pathway that blocked cellular senescence, but did not disrupt genome stability [18].
• Loss-of-function mutations in WRN lead to genomic instability, an elevated cancer risk, and premature cellular senescence [17].

Anatomical context of Cell Aging

• Arf and Mdm2 co-localize in the nucleolus in response to activation of the oncoprotein Myc and as mouse fibroblasts undergo replicative senescence [19].
• In a genetic screen for cDNAs bypassing replicative senescence of normal human prostate epithelial cells (HPrEC), we identified CBX7, a gene that encodes a Polycomb protein, as shown by sequence homology, its interaction with Ring1 and its localization to nuclear Polycomb bodies [20].
• Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death [21].
• This was true whether quiescence was induced by contact inhibition (NIH 3T3 mouse cells), growth factor removal (bromodeoxyuridine-blocked mouse myoblasts), reexpression of cellular senescence (the reversibly immortalized IDH4 cells), or irreversible cell differentiation (HL60 promyelocytic leukemia cells and C2C12 mouse myoblasts) [22].
• Absence of Ku80 results in increased sensitivity to ionizing radiation, defective lymphocyte development, early onset of an age-related phenotype, and premature replicative senescence [23].

Associations of Cell Aging with chemical compounds

• Treatment with 6-anilino-5,8-quinolinequinone (LY83583, referred to as LY hereafter), a previously described inhibitor of guanylate cyclase, induced cellular senescence [24].
• First, we show that the flattened RA-treated SH-F expresses markers of cells undergoing replicative senescence [25].
• These findings may help elucidate the mechanisms of hormonal control of telomerase activity and aid understanding of the roles of sex steroids in cellular senescence and aging as well as estrogen-induced carcinogenesis [26].
• However, replicative senescence was induced by progesterone only in cells expressing PRA [27].
• We find that a specific PI-3 kinase inhibitor (LY294002) causes growth arrest in these cells accompanied by changes in gene expression that are similar to those seen during cellular senescence [28].

Gene context of Cell Aging

• The ability to reconstitute telomerase permits further analysis of its biochemical and biological roles in cell aging and carcinogenesis [29].
• Werner syndrome protein limits MYC-induced cellular senescence [17].
• These observations provide the first in vivo evidence that links cell senescence to aging due to impaired function of Brca1 at the expense of tumorigenesis [30].
• CBX7 expression is downregulated during replicative senescence and its ablation by short-hairpin RNA (shRNA) treatment inhibited growth of normal cells though induction of the Ink4a/Arf locus [20].
• The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture [31].

Analytical, diagnostic and therapeutic context of Cell Aging

• Moreover, small amounts of p38, which is induced by oxidative stress and mediates cellular senescence, were found in beta cells from the high-fat diet group, but not in beta cells from the control group [32].
• Using quantitative RT-PCR, we have monitored mRNA expression levels of c-fos, c-jun, JunB, c-myc, p53, H-ras, and histone H4 during the replicative senescence of human fibroblasts [33].
• Because cellular senescence is critically influenced by telomerase, which elongates telomeres, we measured telomerase activity using a polymerase chain reaction (PCR)-enzyme-linked immunosorbent assay (ELISA) technique [34].
• In this paper we have used a new method which allows the simultaneous extraction and HPLC determination of ATP, ADP, AMP, NADP, NADPH, NAD and NADH to evaluate the changes in concentration of these compounds during maturation of rabbit reticulocytes and cell aging [35].
• Long-Term Corneal Keratocyte Deficits After PRK and LASIK: In Vivo Evidence of Stress-Induced Premature Cellular Senescence [36].

References