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Stress induced premature senescence - SIPS

We proposed that exposures of cells to sublethal stress may trigger the appearance of biomarkers of senescence. This prediction was based on the thermodynamics of open systems and considered stress as fluctuations threatening the stability of biological systems (Toussaint et al., Mech. Ageing Dev., 61, 1991). We demonstrated that stress with tert-butylhydroperoxide (t-BHP) and ethanol at sublethal concentrations, repeated (at each cumulative population doubling or every two days) or not, triggered the appearance of the typical morphology of senescence in human diploid fibroblasts (Toussaint et al., Mech. Ageing Dev., 64, 1992). These findings were confirmed by later studies which were extended to other biomarkers of senescence. Indeed fibroblasts treated with t-BHP or H2O2 display many morphological changes, growth arrest in G1/S phase of the cell cycle, long-term p21waf-1 overexpression and pRb hypophosphorylation, senescence-associated ß galactosidase activity at pH 6.0, senescence-associated changes in gene expression, and the common 4,977 kb deletion in the mitochondrial DNA after t-BHP treatment and in senescent fibroblasts (Toussaint et al., Exp. Gerontol, 30, 1995, Dumont et al., Free Radic. Biol. Med, 28, 2000, Dumont et al., Ann.NY Acad. Sci., 2000). We have also shown that repeated exposures of fibroblasts to cytokines (IL-1a, TNF-a, TGF-ß1) also triggers the appearance of biomarkers of senescence (Dumont et al., J. Anat., in press).

Proteome analysis allowed to identify several tenths of proteins which expression is shared by senescent cells and by cells in SÌPS. However proteins have been found which expression is shared by senescent cells only or by cells in SÌPS caused by t-BHP or ethanol.

These results suggest there is a mechanism whereby sublethal stresses lead cells to a state close to replicative senescence which could be differently regulated since proteins are specific to SÌPS.

Research Units involved

Terminated projects (10)

PHDs (5)