Cellular Senescence

Stable Identifier
R-HSA-2559583
Type
Pathway
Species
Homo sapiens
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Summation

Cellular senescence involves irreversible growth arrest accompanied by phenotypic changes such as enlarged morphology, reorganization of chromatin through formation of senescence-associated heterochromatic foci (SAHF), and changes in gene expression that result in secretion of a number of proteins that alter local tissue environment, known as senescence-associated secretory phenotype (SASP).

Senescence is considered to be a cancer protective mechanism and is also involved in aging. Senescent cells accumulate in aged tissues (reviewed by Campisi 1997 and Lopez-Otin 2013), which may be due to an increased senescence rate and/or decrease in the rate of clearance of senescent cells. In a mouse model of accelerated aging, clearance of senescent cells delays the onset of age-related phenotypes (Baker et al. 2011).

Cellular senescence can be triggered by the aberrant activation of oncogenes or loss-of-function of tumor suppressor genes, and this type of senescence is known as the oncogene-induced senescence, with RAS signaling-induced senescence being the best studied. Oxidative stress, which may or may not be caused by oncogenic RAS signaling, can also trigger senescence. Finally, the cellular senescence program can be initiated by DNA damage, which may be caused by reactive oxygen species (ROS) during oxidative stress, and by telomere shortening caused by replicative exhaustion which may be due to oncogenic signaling. The senescent phenotype was first reported by Hayflick and Moorhead in 1961, when they proposed replicative senescence as a mechanism responsible for the cessation of mitotic activity and morphological changes that occur in human somatic diploid cell strains as a consequence of serial passaging, preventing the continuous culture of untransformed cells-the Hayflick limit (Hayflick and Moorhead 1961).

Secreted proteins that constitute the senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS), include inflammatory and immune-modulatory cytokines, growth factors, shed cell surface molecules and survival factors. The SASP profile is not significantly affected by the type of senescence trigger or the cell type (Coppe et al. 2008), but the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008).

Senescent cells may remain viable for years, such as senescent melanocytes of moles and nevi, or they can be removed by phagocytic cells. The standard marker for immunohistochemical detection of senescent cells is senescence-associated beta-galactosidase (SA-beta-Gal), a lysosomal enzyme that is not required for senescence.

For reviews of this topic, please refer to Collado et al. 2007, Adams 2009, Kuilman et al. 2010. For a review of differential gene expression between senescent and immortalized cells, please refer to Fridman and Tainsky 2008.

Literature References
PubMed ID Title Journal Year
18555777 Chemokine signaling via the CXCR2 receptor reinforces senescence

Acosta, JC, O'Loghlen, A, Banito, A, Guijarro, MV, Augert, A, Raguz, S, Fumagalli, M, Da Costa, M, Brown, C, Popov, N, Takatsu, Y, Melamed, J, d'Adda di Fagagna, F, Bernard, D, Hernando, E, Gil, J

Cell 2008
17667954 Cellular senescence: when bad things happen to good cells

Campisi, J, d'Adda di Fagagna, F

Nat. Rev. Mol. Cell Biol. 2007
21078816 The essence of senescence

Kuilman, T, Michaloglou, C, Mooi, WJ, Peeper, DS

Genes Dev. 2010
18711403 Critical pathways in cellular senescence and immortalization revealed by gene expression profiling

Fridman, AL, Tainsky, MA

Oncogene 2008
17662938 Cellular senescence in cancer and aging

Collado, M, Blasco, MA, Serrano, M

Cell 2007
22048312 Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

Baker, DJ, Wijshake, T, Tchkonia, T, LeBrasseur, NK, Childs, BG, van De Sluis, B, Kirkland, JL, van Deursen, JM

Nature 2011
19818705 Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence

Adams, PD

Mol. Cell 2009
19053174 Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor

Coppé, JP, Patil, CK, Rodier, F, Sun, Y, Muñoz, DP, Goldstein, J, Nelson, PS, Desprez, PY, Campisi, J

PLoS Biol. 2008
19597488 Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion

Rodier, F, Coppé, JP, Patil, CK, Hoeijmakers, WA, Muñoz, DP, Raza, SR, Freund, A, Campeau, E, Davalos, AR, Campisi, J

Nat. Cell Biol. 2009
13905658 The serial cultivation of human diploid cell strains

HAYFLICK, L, MOORHEAD, PS

Exp. Cell Res. 1961
18555778 Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network

Kuilman, T, Michaloglou, C, Vredeveld, LC, Douma, S, van Doorn, R, Desmet, CJ, Aarden, LA, Mooi, WJ, Peeper, DS

Cell 2008
9282108 The biology of replicative senescence

Campisi, J

Eur. J. Cancer 1997
23746838 The hallmarks of aging

López-Otín, C, Blasco, MA, Partridge, L, Serrano, M, Kroemer, G

Cell 2013
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