PerspectiveCellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes
Section snippets
Free radicals, ageing, and replicative senescence
The free radical theory of ageing (Harman et al., 1998) proposes that normal ageing results from random deleterious damage to tissue by oxidative stress caused by reactive oxygen species (ROS). Aged animals contain defective mitochondria and can produce higher levels of ROS than their young counterparts. Ischemia-reperfusion and inflammation produce ROS, as well as many xenobiotics do. Tissues from aged individuals or aged experimental animals accumulate oxidative damage in their DNA, proteins
Induction of premature senescence by oxidative stress
From an experimental point of view, oxidative stress is probably the most often used inducer of SIPS. Common pathways with other triggers will be discussed below. In accordance with theoretical studies based on the criteria of stability of cellular systems (Toussaint et al., 1991), numerous experimental studies demonstrated that sublethal oxidative stresses induce premature replicative senescence. Both chronic and acute oxidative stress protocols were used to induce cellular senescence. In the
Morphological studies
HDFs exposed to repeated sublethal stress under t-BHP display the morphological phenotype of senescence. The first studies were based on the description of the successive HDF morphotypes observed during in vitro ageing: three successive mitotic morphotypes followed by three successive post-mitotic morphotypes and eventually a degenerative state of short existence, all of these states observed at very low density allowing spreading of cells (Rodemann et al., 1989, Toussaint et al., 1992). Using
Telomeres and SIPS
There are different causes of telomere shortening with replicative age. The inability of DNA polymerases to replicate a linear DNA template to its very end (the so-called end-replication problem) has been known for a long time (Olovnikov, 1973). The contribution of the end-replication problem to the actual telomere shortening might be as small as very few nucleotides per CPD, though. The action of a C strand-specific exonuclease has been suggested to contribute to the shortening of telomeres (
SIPS: interaction between metabolic and signalling pathways
Antioxidants are not the only ones which may slow down the rate of oxidative stress-induced premature senescence (SIPS). A thermodynamic model of ageing was proposed that predicts not only that sublethal stress may induce SIPS, but also that the level of global metabolic activity may protect the cells against SIPS and against cell death caused by lethal stress (Remacle et al., 1995, Toussaint et al., 1995a). Under stress, additional energy utilisation is required for the induction of defence
Premature senescence in human melanocytes
Melanocytes are pigment cells that are located in the basal layer of the epidermis. They produce the pigment melanin, which is synthesised in melanosomes, a lysosomal-like organelle. Melanin pigments play a key protective role against the carcinogenic effect of solar irradiation in vivo. In melanocytes, senescence is associated with increased binding of p16INK4a to CDK4 and loss of binding activity, and protein expression of transcription factors of the E2F family. Intriguingly, melanocytes
Conclusions
Ageing is the result of an complicated interplay of deterministic and stochastic processes. Random damage is prominent among the stochastic processes, leading to concepts like “critical threshold of error accumulation” (Remacle et al., 1992) or “failure of maintenance” (Holliday, 1988). These concepts encompass the notion that the kinetics of the accumulation of damage must not only be attributed to the extent of damage but also to the efficiency of the systems for elimination and/or repair of
Acknowledgements
O. Toussaint is a Research Assistant of the FNRS, Belgium. He also thanks the FRIA and the French Community of Belgium, the European Union Biomed & Health Research Programme, Shared-Cost Action Programme ‘Genage’ (BMH2 CT98) and the Fulbright programme. E.E. Medrano was supported by a grant AG3663 from the National Institute of Health (EEM). T. von Zglinicki thanks the Deutsche Forschungsgemeinschaft and the VERUM Foundation for support.
References (106)
- et al.
Different mechanisms of tert-butyl hydroperoxide-induced lethal injury in normal and tumor thymocytes
Arch. Biochem. Biophys.
(1994) - et al.
DNA repair and transcription in human premature aging disorders
J. Invest. Dermatol. Symp. Proc.
(1998) - et al.
tert-Butyl hydroperoxide induced [Ca2+]i increase in thymus and thymoma cells
Biochem. Biophys. Res. Commun.
(1993) - et al.
Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast
Free Radical Biol. Med.
(2000) - et al.
Quantification of wild-type mitochondrial DNA and its 4,8 kb deletion in rat organs
Biochem. Biophys. Res. Commun.
(1997) - et al.
Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress
Life Sci.
(1998) - et al.
Senescence of cultured human fibroblasts: mitotic versus metabolic time
Exp. Cell Res.
(1974) - et al.
Mammalian telomeres end in a large duplex loop
Cell
(1999) - et al.
Activation of a cAMP pathway and induction of melanogenesis correlate with association of p16(INK4) and p27(KIP1) to CDKs, loss of E2F-binding activity, and premature senescence of human melanocytes
Exp. Cell Res.
(1999) Telomere loss: mitotic clock or genetic time bomb?
Mutat. Res.
(1991)
The serial cultivation of human diploid cell strains
Exp. Cell Res.
Shortening of the in vitro lifespan of human diploid fibroblasts exposed to hyperbaric oxygen
Exp. Gerontol.
Effect of oxygen on the growth of human epidermal keratinocytes
J. Invest. Dermatol.
Intramitotic variation in proliferative potential: stochastic events in cellular aging
Mech. Ageing Dev.
Increased cytotoxicity of chronic hypoxic cells by molecular inhibition of GRP78 induction
Int. J. Radiat. Oncol. Biol. Phys.
Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species
J. Biol. Chem.
Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening
Cell
Accumulation of short telomeres in human fibroblasts prior to replicative senescence
Exp. Cell Res.
Slowing down ageing of cultured embryonal chick chondrocytes by maintenance under lowered oxygen tension
Mech. Ageing Dev.
A set of endoplasmic reticulum proteins possessing properties of molecular chaperones includes Ca(2+)-binding proteins and members of the thioredoxin superfamily
J. Biol. Chem.
A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon
J. Theor. Biol.
Human skin mitochondrial DNA deletions associated with light exposure
Arch. Biochem. Biophys.
Preferential accumulation of single-stranded regions in telomeres of human fibroblasts
Exp. Cell Res.
Low levels of reactive oxygen species as modulators of cell function
Mutat. Res.
Differential degradation of intracellular proteins in human skin fibroblasts of mitotic and mitomicyn-C (MMC)-induced postmitotic differentiation states in vitro
Differentiation
Selective enrichment and biochemical characterization of seven human skin fibroblasts cell types in vitro
Exp. Cell Res.
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Cell
Is beta-galactosidase staining a marker of senescence in vitro and in vivo?
Exp. Cell Res.
Microarray analysis of replicative senescence
Curr. Biol.
Accelerated telomere shortening in fibroblasts after extended periods of confluency
Free Radical Biol. Med.
Different kinetics of senescence in human fibroblasts and peritoneal mesothelial cells
Exp. Cell Res.
Aging as a multi-step process characterized by a lowering of entropy production leading the cell to a sequence of defined stages. II. Testing some predictions on aging human fibroblasts in culture
Mech. Ageing Dev.
Effects of modulations of the energetic metabolism on the mortality of cultured cells
Biochim. Biophys. Acta
Cellular aging and the importance of energetic factors
Exp. Gerontol.
Aging as a multi-step process characterized by a lowering of entropy production leading the cell to a sequence of defined stages
Mech. Ageing Dev.
From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging
Exp. Gerontol.
Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts
Free Radical Biol. Med.
Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts
Proc. Natl. Acad. Sci. USA
UVB induces atypical melanocytic lesions and melanoma in human skin
Am. J. Pathol.
Oxygen modulates growth of human cells at physiologic partial pressures
J. Exp. Med.
Melanin accumulation accelerates melanocyte senescence by a mechanism involving p16INK4a/CDK4/pRB and E2F1
Ann. N.Y. Acad. Sci.
Comparison of the responses of human melanocytes with different melanin contents to ultraviolet B irradiation
Cancer Res.
Identification of a gene that reverses the immortal phenotype of a subset of cells and is a member of a novel family of transcription factor-like genes
Mol. Cell Biol.
Extension of life-span by introduction of telomerase into normal human cells
Science
Molecular and cellular gerontology
EMBO J.
The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit
Hum. Mol. Genet.
Replicative senescence and immortalization
Cancer, aging and cellular senescence
In Vivo
Control of replicative senescence
Defending genome integrity during DNA replication: a proposed role for RecQ family helicases
Bioessays
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The authors contributed equally to this perspective.