Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14ARF. Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.

Cellular senescence, a state of cell-cycle arrest accompanied by dramatic morphologic and metabolic changes, is a central means by which cells respond to physiologic stress and oncogene activity. Senescence is thought to play important roles in aging and in tumor suppression, yet the dynamics by which senescent cells are formed, their effects on tissue function and their eventual fate are poorly understood. To study cellular senescence within an adult tissue, we developed transgenic mice inducibly expressing p14 ARF (human ortholog of murine p19 ARF ), a central activator of senescence. Induction of p14 ARF in the epidermis rapidly led to widespread apoptosis and cellcycle arrest, a stage that was transient, and was followed by p53-dependent cellular senescence. The endogenous Cdkn2a products p19 ARF and p16 Ink4a were activated by the transgenic p14 ARF through p53, revealing a senescence-promoting feed-forward loop. Commitment of cells to senescence required continued p14 ARF expression, indicating that entry into this state depends on a persistent signal. However, once formed, senescent cells were retained in the epidermis, often for weeks after transgene silencing, indicating an absence of an efficient rapidly acting mechanism for their removal. Stem cells in the hair follicle bulge were largely protected from apoptosis upon p14 ARF induction, but irreversibly lost their ability to proliferate and initiate follicle growth.Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14 ARF induction. Our findings provide basic insights into the dynamics of cellular senescence, a central tumorsuppressive mechanism, and reveal the potential for prolonged retention of senescent cells within tissues. Cancer Res; 73(9); 2829-39. Ó2013 AACR.

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<div>Abstract<p>Cellular senescence, a state of cell-cycle arrest accompanied by dramatic morphologic and metabolic changes, is a central means by which cells respond to physiologic stress and oncogene activity. Senescence is thought to play important roles in aging and in tumor suppression, yet the dynamics by which senescent cells are formed, their effects on tissue function and their eventual fate are poorly understood. To study cellular senescence within an adult tissue, we developed transgenic mice inducibly expressing p14^ARF (human ortholog of murine p19^ARF), a central activator of senescence. Induction of p14^ARF in the epidermis rapidly led to widespread apoptosis and cell-cycle arrest, a stage that was transient, and was followed by p53-dependent cellular senescence. The endogenous <i>Cdkn2a</i> products <i>p19^ARF</i> and <i>p16^Ink4a</i> were activated by the transgenic p14^ARF through p53, revealing a senescence-promoting feed-forward loop. Commitment of cells to senescence required continued p14^ARF expression, indicating that entry into this state depends on a persistent signal. However, once formed, senescent cells were retained in the epidermis, often for weeks after transgene silencing, indicating an absence of an efficient rapidly acting mechanism for their removal. Stem cells in the hair follicle bulge were largely protected from apoptosis upon p14^ARF induction, but irreversibly lost their ability to proliferate and initiate follicle growth. Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14^ARF induction. Our findings provide basic insights into the dynamics of cellular senescence, a central tumor- suppressive mechanism, and reveal the potential for prolonged retention of senescent cells within tissues. <i>Cancer Res; 73(9); 2829–39. ©2013 AACR</i>.</p></div>

<div>Abstract<p>Cellular senescence, a state of cell-cycle arrest accompanied by dramatic morphologic and metabolic changes, is a central means by which cells respond to physiologic stress and oncogene activity. Senescence is thought to play important roles in aging and in tumor suppression, yet the dynamics by which senescent cells are formed, their effects on tissue function and their eventual fate are poorly understood. To study cellular senescence within an adult tissue, we developed transgenic mice inducibly expressing p14^ARF (human ortholog of murine p19^ARF), a central activator of senescence. Induction of p14^ARF in the epidermis rapidly led to widespread apoptosis and cell-cycle arrest, a stage that was transient, and was followed by p53-dependent cellular senescence. The endogenous <i>Cdkn2a</i> products <i>p19^ARF</i> and <i>p16^Ink4a</i> were activated by the transgenic p14^ARF through p53, revealing a senescence-promoting feed-forward loop. Commitment of cells to senescence required continued p14^ARF expression, indicating that entry into this state depends on a persistent signal. However, once formed, senescent cells were retained in the epidermis, often for weeks after transgene silencing, indicating an absence of an efficient rapidly acting mechanism for their removal. Stem cells in the hair follicle bulge were largely protected from apoptosis upon p14^ARF induction, but irreversibly lost their ability to proliferate and initiate follicle growth. Interestingly, induction of epidermal hyperplasia prevented the appearance of senescent cells upon p14^ARF induction. Our findings provide basic insights into the dynamics of cellular senescence, a central tumor- suppressive mechanism, and reveal the potential for prolonged retention of senescent cells within tissues. <i>Cancer Res; 73(9); 2829–39. ©2013 AACR</i>.</p></div>

<p>PDF file - 118K, Supplementary Figure S1. Species specificity of p14ARF and p19ARF antibodies. Supplementary Figure S2. Increase in SAβGal-positive cell numbers in control mice during early aging. Supplementary Figure S3. Rb and p130 dephosphorylation upon p14ARF induction. Supplementary Figure S4. Effects of p14ARF induction on skin histology. Supplementary Figure S5. p14ARF induces hair-follicle stem cell dysfunction through p53. Supplementary Figure S6. Senescence in TPA-treated mice.</p>

<p>PDF file - 90K</p>

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