Telomere Dysfunction Initiates p53Dependent Replicative Senescence

Primary human cells have a limited replicative potential due to progressive telomere shortening, eventually resulting in the onset of replicative senescence, a state of permanent cell cycle arrest in which cells remain metabolically active, exhibit characteristic morphological changes, and stain for senescence-associated ß-galactosidase (SA-ß-gal) activity (Hayflick 1961, Harley et al. 1990, Allsopp et al. 1992, Wright and Shay 1992, Dimri et al. 1995; see also Allsopp, this volume). Replicative senescence has been shown to be due to dysfunctional telomeres engaging the p53 and pRb-dependent DDR (reviewed in Campisi 2005). In response to genotoxic stress, p53 initiates cell-cycle arrest, cellular senescence, or apoptosis to eliminate genomically unstable cells and suppress tumorigenesis (Schmitt 2003). Senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks (reviewed in Jackson 2003). These markers include the DNA damage response proteins phosphorylated yH2AX, 53BP1, NBS1, and the DNA damage checkpoint kinase CHK2 (d'Adda di Fagagna et al. 2003, Taki et al. 2003). Many of these proteins localize directly to dysfunctional telomeres, and their inactivation in senescent cells restores cell cycle progression into S-phase (d'Adda di Fagagna et al. 2003). These results suggest that dysfunctional tel-omeres are recognized by the DNA damage machinery as double-strand DNA breaks, which signal entry into replicative senescence. DNA damage response proteins may therefore be excellent biochemical markers for the detection of replicative senescence in vivo, a hypothesis that can be tested in premature aging mouse models and in human progeric syndromes.

Although a definitive connection between telomere dynamics and normal aging in humans has yet to be established, accumulating evidence has strengthened the view that accelerated telomere attrition contributes directly to acquired and inherited degenerative conditions and premature aging syndromes such as Werner Syndrome (see below and also Davis and Kipling, this volume). In support of this notion, analysis of telomere lengths in cells derived from peripheral blood of humans over age 60 revealed that individuals possessing shorter telomeres than age-matched controls had significantly poorer survival rates, which was attributed in part to an elevated mortality rate from heart and infectious diseases (Cawthon et al. 2003). Increased telomere shortening also correlates with increased incidence of coronary heart disease and elevated mortality (Brouilette et al. 2007). While it is somewhat surprising that the function of a postmitotic tissue such as the heart might be adversely impacted upon by dysfunctional telomeres, it is possible that cardiac stem cells with long telomeres are required to confer long-term cardiac protection.

It is postulated that senescent cells accumulate with normal aging and may contribute to age-related pathologies by inhibiting tissue regenerative capacities (Krtolica and Campisi 2002, Itahana et al. 2001). Increasing evidence suggests that senescent cells do accumulate in aging human tissues. For example, SA-P-gal-positive senescent cells have been identified in aged liver, atherosclerotic plaques, and skin (Dimri et al. 1995, Vasile et al. 2001). Perhaps the best evidence that senescent cells exist in vivo comes from studies of aging baboon skin: ~15% of aged baboon skin fibroblasts possess prominent foci of DNA damage markers, including y-H2AX, 53-BP1, and phosphorylated ATM kinase that co-localize with telomeres, indicating that telomeres are dysfunctional in aging skin (Herbig et al. 2006). These results suggest that in old primates, telomere dysfunction activates the ATM-dependent DNA-damage signaling pathway to initiate cellular senescence in tissues, likely negatively impacting upon tissue physiology and function.

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