ReviewReplicative senescence: a critical review
Section snippets
Introduction: the senescent phenotype
Cultures of diploid human fibroblasts can replicate only a finite number of times. During the proliferative lifespan of fibroblast cultures there is an initial phase of rapid proliferation followed by a period of declining replicative frequency; ultimately, cultures become senescent and are incapable of further proliferation. Replicative senescence is not specific to human fibroblasts; it has been described in cultures established from chickens as well as cell lines derived from numerous
Transduction of mitogenic signals at different stages of the replicative life history
Cellular responses to environmental cues are mediated via activation of complex signaling cascades that invariably induce changes in gene expression. For example, the first event in a cascade initiated by growth factors is the activation of their cognate receptors, followed by formation of multi-protein complexes, phospholipid turnover, calcium mobilization and activation of protein kinases, phosphatases and transcription factors. In response to mitogenic signals, the machinery of nuclear
Cellular stress and replicative senescence
With increasing replicative age, cells become more sensitive to environmental stressors, in part because of changes in gene expression. For example, the increased sensitivity of senescent fibroblasts to hyperthermic exposure can be attributed to their reduced expression of some heat shock proteins such as HSP 70, HSP 90 and HSP 28 (Luce and Cristofalo, 1992, Cristofalo et al., 1989a, Cristofalo et al., 1989b). Senescent fibroblasts also show a reduced response of the transcription factor NF-κB
Apoptosis and replicative senescence
Necrosis occurs when a cell loses control of its own ionic flow because of disruption in membrane integrity, loss of energy reserves, or others causes. Calcium then enters and precipitates the proteins, lactate accumulates and usually, because of osmotic changes, the cell lyses and releases its content to the extra-cellular environment (Trump and Berezesky, 1992).
Apoptosis, conversely, is a highly conserved process of programmed cell death which ensures that the entire content of a dying cell
Telomerase expression in normal and pathological conditions
Telomeres are nucleoprotein complexes at the ends of the chromosomes. In humans the telomeric DNA is composed of several kilo-bases of TTAGGG double-stranded repeats and of 5–400 bases of TTAGGG repeats in a 3′ single-stranded overhang (Hemann and Greider, 1999). When telomeric DNA is purified from its endogenously bound proteins, a fraction of the 3′ single-stranded overhang is found tucked back into the double-stranded telomeric tract forming a loop called the “T-loop” (Griffith et al., 1999,
Replicative senescence as a model of aging in vivo
The limited replicative lifespan of fibroblasts derived from various human tissues is commonly studied as a model of biological aging (Hayflick, 1965, Hayflick and Moorhead, 1961). There is little doubt that organismic failures in aging have a cellular basis. Replicative senescence in culture fits the description and definition of cell senescence; with subcultivation there is a gradual loss of proliferative capacity in the population until the culture can no longer be subcultivated. In vivo
References (338)
- et al.
Investigation of the role of g1/s cell cycle mediators in cellular senescence
Exp. Cell Res.
(1993) - et al.
Telomere reduction in human liver tissues with age and chronic inflammation
Exp. Cell Res.
(2000) - et al.
Development and age-associated differences in electron transport potential and consequences for oxidant generation
J. Biol. Chem.
(1997) - et al.
Oxidative stress and gene regulation
Free Radic. Biol. Med.
(2000) - et al.
Evidence for a critical telomere length in senescent human fibroblasts
Exp. Cell Res.
(1995) - et al.
Membrane targeting of the nucleotide exchange factor SOS is sufficient for activating the Ras signaling pathway
Cell
(1994) - et al.
Effects of establishing cell cultures and cell culture conditions on the proliferative life span of human fibroblasts isolated from different tissues and donors of different ages
Exp. Cell Res.
(2002) - et al.
Effects of ambient oxygen concentration on the growth and antioxidant defenses of human cell cultures established from fetal and postnatal skin
Free Radic. Biol. Med.
(2002) - et al.
Identification of a candidate tumor-suppressor gene specifically activated during ras-induced senescence
Exp. Cell Res.
(2002) Switching and signaling at the telomere
Cell
(2001)
Ultrastructural and cytochemical changes in cultured human lung cells
J. Ultrastruct. Res.
Tumor suppressors and oncogenes in cellular senescence
Exp. Gerontol.
A signaling pathway to translational control
Cell
Telomere dynamics and telomerase activity in in vitro immortalised human cells
Eur. J. Cancer
Age-related alterations of proteasome structure and function in aging epidermis
Exp. Gerontol.
Age-dependent declines in proteasome activity in the heart
Arch. Biochem. Biophys.
Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes
Exp. Gerontol.
Impairment of proteasome structure and function in aging
Int. J. Biochem. Cell Biol.
Association between telomere length in blood and mortality in people aged 60 years or older
Lancet
Beginning to understand the end of the chromosome
Cell
Telomeres, telomerase, and myc. An update
Mutat. Res.
Decline of protein kinase c activation in response to growth stimulation during senescence of IMR-90 human diploid fibroblasts
Biochem. Biophys. Res. Commun.
Fibroblast cultures from healthy centenarians have an active proteasome
Exp. Gerontol.
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
J. Biol. Chem.
Decline of signal transduction by phospholipase c gamma 1 in imr 90 human diploid fibroblasts at high population doubling levels
FEBS Lett.
Receptor for epidermal growth factor retains normal structure and function in aging cells
Mech. Ageing Dev.
Mechanisms of ubiquitin-mediated, limited processing of the NF-kappaB1 precursor protein p105
Biochimie
Electron microscopy of human fibroblasts in tissue culture during logarithmic and confluent stages of growth
Exp. Cell Res.
Growth factors as probes of cell aging
Exp. Gerontol.
Lysosomal enzymes and aging in vitro: subcellular enzyme distribution and effect of hydrocortisone on cell life-span
Mech. Ageing Dev.
Cellular senescence and DNA synthesis. Thymidine incorporation as a measure of population age in human diploid cells
Exp. Cell Res.
Age-related decline in chaperone-mediated autophagy
J. Biol. Chem.
When lysosomes get old
Exp. Gerontol.
Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element
Cell
Effects of the tumor promoting agent phorbol 12-myristate 13-acetate (PMA) on the proliferation of young and senescent WI-38 human diploid fibroblasts
Exp. Cell Res.
Induction of apoptosis in human replicative senescent fibroblasts
Exp. Cell Res.
Stress-induced premature senescence and replicative senescence are different phenotypes, proteomic evidence
Biochem. Pharmacol.
Overexpression of the two-chain form of cathepsin (in senescent WI-38 cells
Exp. Cell Res.
Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast
Free. Radic. Biol. Med.
Identification of telomere-dependent “senescence-like” arrest in mouse embryonic fibroblasts
Exp. Cell Res.
New developments in phospholipase d
J. Biol. Chem.
Redox regulation of NF-kappa B activation
Free. Radic. Biol. Med.
Cell cycle regulation in H2O2 induced premature senescence of human diploid fibroblasts and regulatory control exerted by the papilloma virus E6 and E7 proteins
Exp. Gerontol.
Hyperoxia inhibits proliferation of cultured rat tracheal smooth muscle cells
Am. J. Physiol.
Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts
Proc. Natl. Acad. Sci. U.S.A.
Oxidative stress and superoxide dismutase in development, aging and gene regulation
Age
Effects of oxygen on the antioxidant responses of normal and transformed cells
Exp. Cell Res.
Expression and regulation of SOD activity in human skin fibroblasts from donors of different ages
J. Cell. Physiol.
Telomere length predicts replicative capacity of human fibroblasts
Proc. Natl. Acad. Sci. U.S.A.
Effect of n-3 fatty acid supplementation on lipid peroxidation and protein aggregation in rat erythrocyte membranes
Lipids
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