Disease relevance of Aging

• To determine the importance of mitochondrial reactive oxygen species toxicity in aging and senescence, we analyzed changes in mitochondrial function with age in mice with partial or complete deficiencies in the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) [1].
• Oncogenic stimuli are thought to induce senescence in normal cells in order to protect against transformation and to induce proliferation in cells with altered p53 and/or retinoblastoma (Rb) pathways [2].
• Manganese superoxide dismutase induces p53-dependent senescence in colorectal cancer cells [3].
• Cells arrested and subsequently released from histone deacetylase inhibitors display markers of senescence and exhibit a persistent G1 block but remain competent to initiate a round of DNA synthesis in response to simian virus 40 T antigen [4].
• Early-passage rat kidney cells were immortalized or rescued from senescence with three different oncogenes: viral promoter-driven c-myc, H-ras (Val-12), and adenovirus type 5 E1a [5].

Psychiatry related information on Aging

• Using this P1 phage clone as a probe, the PK428 gene was located on 1q41-42, a possible location for a human senescence gene, a gene associated with Rippling muscle disease, as well as a region associated with genetically acquired mental retardation [6].
• The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain [7].
• The relationship between voluntary alcohol consumption and brain monoamine levels was studied in the inbred strains of C57BL/6N, C57BL/6J, A/J, BALB/cA, CBA/N, C3H/He and DBA/2cr mice; the congeneric mouse strain, B10.Br/Sg, and the senescence accelerated mouse (SAM P1, SAM P2) [8].
• Sulpiride and tiapride are often used in the treatment of depression, schizophrenia and psychopathology of senescence, gastric or duodenal ulcers and are also partly excreted by kidney [9].
• 2. Changes in DA, NA and 5-HT uptake during aging are suggested to be neurochemical correlates of cognition and memory deficits that develops in senescence [10].

High impact information on Aging

• At the cellular level, p53 induces apoptosis, cell cycle arrest and senescence [11].
• A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy [12].
• We identified bes1, a semidominant suppressor of bri1, which exhibits constitutive BR response phenotypes including long and bending petioles, curly leaves, accelerated senescence, and constitutive expression of BR-response genes [13].
• Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers [14].
• In addition, expression of mutant forms of TRF2 induced a growth arrest with characteristics of senescence [15].

Chemical compound and disease context of Aging

• Src expression increased drug survival in HT1080 fibrosarcoma cells, as measured by the colony formation assay, and strongly inhibited Adriamycin-induced senescence [16].
• These concentrations of ceramide also induced retinoblastoma dephosphorylation and inhibited serum-induced AP-1 activation in young HDF, thus recapitulating basic biochemical and molecular changes of senescence [17].
• Expression of ipt, a cytokinin biosynthetic gene from Agrobacterium tumefaciens, under the control of the promoter from a senescence-associated gene (SAG12) has been one approach used to delay senescence [18].
• METHODS: Several different chronic conditions were studied in rats: senescence, hypertension, chronic hypoxia, and administration of thyroid hormone [19].
• The results suggest that both ABA and cytokinins are involved in controlling plant senescence, and an enhanced carbon remobilization is attributed to an elevated ABA level in rice plants subjected to water stress [20].

Biological context of Aging

• In yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senescence in higher eukaryotic cells [21].
• The gene age-1 is required for non-dauer development and normal senescence. age-1 encodes a homologue of mammalian phosphatidylinositol-3-OH kinase (PI(3)K) catalytic subunits [22].
• Disruption of the S. pombe gene resulted in telomere shortening and senescence, and expression of mRNA from the human gene correlated with telomerase activity in cell lines [23].
• The tumor suppressor p53, a sensor of multiple forms of cellular stress, is regulated by post-translational mechanisms to induce cell-cycle arrest, senescence, or apoptosis [24].
• Smurf2 up-regulation activates telomere-dependent senescence [25].

Anatomical context of Aging

• These data suggest that human endothelial cell senescence in vitro is a dynamic process regulated by the potential intracellular activity of IL-1 alpha [26].
• Activation of Raf-1 in nonimmortalized human lung fibroblasts (IMR-90) led to the prompt and irreversible arrest of cellular proliferation and the premature onset of senescence [27].
• Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways [28].
• Either a deficiency of p16(INK4a) and p19(ARF) or an increase in Cdk4 allows cultured astrocytes to grow without senescence [29].
• CONCLUSION: Normal mouse melanocyte senescence and associated pigmentation require both copies of Ink4a-Arf and appear to depend more on p16 than on Arf function [30].

Associations of Aging with chemical compounds

• Ethylene regulates a multitude of plant processes, ranging from seed germination to organ senescence [31].
• Inhibition of leaf senescence by autoregulated production of cytokinin [32].
• Brain acetylcholine synthesis declines with senescence [33].
• Lysine acetylation of the tumor suppressor protein p53 in response to a wide variety of cellular stress signals is required for its activation as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis [34].
• Both p53 and ceramide have been implicated in the regulation of growth suppression. p53 has been proposed as the "guardian of the genome" and ceramide has been suggested as a "tumor suppressor lipid. " Both molecules appear to regulate cell cycle arrest, senescence, and apoptosis [35].

Gene context of Aging

• Thus, Cdk4 deficiency causes senescence in a unique Arf/p53-independent manner, which accounts for the loss of transformation potential [36].
• A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling [37].
• We made a large library containing random mutations in the amino terminus of the EST2 gene, which encodes the Saccharomyces cerevisiae TERT, and selected functional alleles by their ability to rescue senescence of telomerase-negative cells [38].
• Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform [39].
• WS fibroblasts display defects associated with telomere dysfunction, including accelerated telomere erosion and premature senescence [40].

Analytical, diagnostic and therapeutic context of Aging

• These findings suggest that mac25 may be a downstream effector of retinoid chemoprevention in breast epithelial cells and that its tumor-suppressive role may involve a senescence pathway [41].
• Western blot analyses indicated that DHS protein also increases at the onset of senescence [42].
• Whereas salt treatment had no effect on xanthine dehydrogenase activities, cold stress caused a decrease, but desiccation and senescence caused a strong increase of activities in leaves [43].
• Our data suggest that repression of CDK2 activity by p27(Kip1) is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered cell cycle arrest after treatment with LY294002 [44].
• Molecular cloning and nucleotide sequence of cDNA for murine senile amyloid protein: nucleotide substitutions found in apolipoprotein A-II cDNA of senescence accelerated mouse (SAM) [45].

References