Cell Autonomous and Non-Autonomous Effects of Senescent Cells in the Skin

“Senescent cells increase with age in both the epidermis and dermis, as determined by elevated levels of senescenceassociated β-galactosidase activity and p16 expression (Dimri et al., 1995; Krishnamurthy et al., 2004; Ressler et al., 2006; Waaijer et al., 2012).”

“The proliferative phase begins with the formation of granulation tissue and collagen deposition, and the wound closes by epithelialization and the contraction of differentiated myofibroblasts, which are specialized contractile fibroblasts (Guo and Dipietro, 2010).”

“Because wound healing and cancer share several molecular and cellular events (Dvorak, 1986; Feng et al., 2010), senescent cells may have an essential role in promoting wound healing while preventing cancer initiation.”

“Wound contraction is important for wound closure during the proliferative phase (Midwood et al., 2004) and proceeds through the formation of newly synthesized granulation tissue and the activation of contraction in myofibroblasts (Tomasek et al., 2002).”

“Indeed, removal of senescent cells in a premature aging mouse model reduced selected age-related pathologies, such as sarcopenia, cataracts, and loss of subdermal adipose tissue (Baker et al., 2011).”

“Because chronic wounds fail to progress through the different stages of the wound-healing process (Sen et al., 2009), an excessive number of senescent cells may restrict cell proliferation and disrupt paracrine signaling cascades, thereby retarding the ability of wounds to resolve after injury.”

“Cellular senescence is a complex stress response that renders cells incapable of cell division, even in the presence of growth stimuli (Campisi, 2013).”

“Senescent cells can alter tissue homeostasis and promote age-related diseases, including degenerative pathologies and cancers (Campisi, 2013; van Deursen, 2014).”

“As part of the senescence response, senescent cells express a number of non-exclusive markers, including the cell cycle inhibitor p16 and elevated levels of a lysosomal enzyme, termed as senescence-associated β-galactosidase (Rodier and Campisi, 2011).”

“Indeed, failure to induce senescence during wound healing causes fibrosis in the skin and liver (Jun and Lau, 2010; Kim et al., 2013; Krizhanovsky et al., 2008).”

“Before the inflammatory phase ends, fibroblasts are recruited to the wound site and endothelial cells mature from progenitor cells to reestablish vascularization (Chen et al., 2008; Postlethwaite et al., 1987; Table 1.”

“Senescent cells increase with age in both the epidermis and dermis, as determined by elevated levels of senescenceassociated β-galactosidase activity and p16 expression (Dimri et al., 1995; Krishnamurthy et al., 2004; Ressler et al., 2006; Waaijer et al., 2012).”

“…MMP10, MMP12, and MMP13 Coppe et al., 2010; Freund et al., 2011 Wound healing Temporal upregulation of MMP1, MMP2, MMP9, MMP3, MMP10, MMP14, MMP8, MMP12, MMP13, MMP19, MMP26, MMP28 Martins et al., 2013 Abbreviation: MMP, matrix metalloproteinase. www.jidonline.org 1723 Sunderkotter et al., 1994).”

“, 2008) and can degrade excess collagen and maintain tissue homeostasis during wound healing (Jun and Lau, 2010).”

“Wound contraction is important for wound closure during the proliferative phase (Midwood et al., 2004) and proceeds through the formation of newly synthesized granulation tissue and the activation of contraction in myofibroblasts (Tomasek et al., 2002).”

“Hence, increased expression and activity of MMPs during aging can decrease the amount of collagen in the skin (Varani et al., 2004), diminish fibroblast-collagen interactions, and reduce mechanical tension, explaining the wrinkling phenotype observed in aged skin (Varani et al., 2006).”

“Before the inflammatory phase ends, fibroblasts are recruited to the wound site and endothelial cells mature from progenitor cells to reestablish vascularization (Chen et al., 2008; Postlethwaite et al., 1987; Table 1.”

“…MMPs involved in skin aging, cellular senescence, and wound healing MMP expression References Skin aging Elevated expression of MMP1, MMP3, and MMP9 Quan et al., 2009 Cellular senescence Elevated expression of MMP1, MMP3, MMP8, MMP10, MMP12, and MMP13 Coppe et al., 2010; Freund et al., 2011 Wound…”

“Loss of collagen is associated with several clinical manifestations of aging skin, including wrinkles, sagging, and laxity (Jariashvili et al., 2012; Quan et al., 2010; Shuster et al., 1975).”

“Senescent cells increase with age in both the epidermis and dermis, as determined by elevated levels of senescenceassociated β-galactosidase activity and p16 expression (Dimri et al., 1995; Krishnamurthy et al., 2004; Ressler et al., 2006; Waaijer et al., 2012).”

“Intrinsic aging also reduces subcutaneous fat and dermal thickness with an accompanying loss of cellularity and vascularity (Farage et al., 2013).”

“Notably, this phenotype can be rescued in senescence-free mice by topical application of the SASP factor platelet-derived growth factor AA, which promotes the differentiation and maturation of myofibroblasts.”

“A senescence response is typically induced by cellular damage (often nuclear DNA damage or mitochondrial dysfunction; von Zglinicki et al., 2005; Ziegler et al., 2015).”

“In contrast, extrinsic aging, particularly photoaging (sun exposure), markedly affects both the epidermal and dermal layers, with the latter showing a striking loss of collagen and extracellular matrix (Quan et al., 2004, 2010).”

“This cell autonomous effect of senescent cells is in keeping with a fundamental role for cellular senescence in tumor suppression (Campisi, 2001).”

“A senescence response is typically induced by cellular damage (often nuclear DNA damage or mitochondrial dysfunction; von Zglinicki et al., 2005; Ziegler et al., 2015).”

“Notably, this phenotype can be rescued in senescence-free mice by topical application of the SASP factor platelet-derived growth factor AA, which promotes the differentiation and maturation of myofibroblasts.”

“Because mitochondrial damage and dysfunction induces cellular senescence in culture and in vivo (Passos et al., 2006; Velarde et al., 2012), and UV light also promotes mitochondrial damage and cellular senescence, it would be interesting to test whether the UV-induced common deletion contributes to skin aging through…”

“…MMP10, MMP12, and MMP13 Coppe et al., 2010; Freund et al., 2011 Wound healing Temporal upregulation of MMP1, MMP2, MMP9, MMP3, MMP10, MMP14, MMP8, MMP12, MMP13, MMP19, MMP26, MMP28 Martins et al., 2013 Abbreviation: MMP, matrix metalloproteinase. www.jidonline.org 1723 Sunderkotter et al., 1994).”

“Indeed, failure to induce senescence during wound healing causes fibrosis in the skin and liver (Jun and Lau, 2010; Kim et al., 2013; Krizhanovsky et al., 2008).”

“In contrast, extrinsic aging, particularly photoaging (sun exposure), markedly affects both the epidermal and dermal layers, with the latter showing a striking loss of collagen and extracellular matrix (Quan et al., 2004, 2010).”

“There is also accumulation of abnormal elastic tissues (Bernstein et al., 1994; Mitchell, 1967), which are due to formation of structurally different elastic fibers (Watson et al.”

“Because wound healing and cancer share several molecular and cellular events (Dvorak, 1986; Feng et al., 2010), senescent cells may have an essential role in promoting wound healing while preventing cancer initiation.”

“For example, chronic wounds are characterized by the persistent presence of senescent cells in the wound areas (Mendez et al., 1998; Vande Berg and Robson, 2003; Vande Berg et al., 2005).”

“Indeed, mitochondrial dysfunction is suggested to have a role in both intrinsic and extrinsic aging and may potentially serve as a common link between the two (Krutmann and Schroeder, 2009).”

“Hence, increased expression and activity of MMPs during aging can decrease the amount of collagen in the skin (Varani et al., 2004), diminish fibroblast-collagen interactions, and reduce mechanical tension, explaining the wrinkling phenotype observed in aged skin (Varani et al., 2006).”

“Journal of Investigative Dermatology (2015) 135, 1722–1726; doi:10.1038/jid.2015.108; published online 9 April 2015”

“UV radiation–induced photoaging of human skin is associated with large-scale deletions in mitochondrial genomes (mitochondrial DNA (mtDNA); Berneburg et al., 1997; Birch-Machin et al., 1998).”

“Cells from mice lacking the p16 and p21 genes are incapable of undergoing cellular senescence and highly susceptible to skin carcinogenesis upon 7,12-dimethylbenz[a] anthracene/12-O-tetradecanoylphorbol-13-acetate treatment due to their inability to arrest cell proliferation (Takeuchi et al., 2010).”

“…pigmentosum, and the Hutchinson–Gilford progeria syndrome, which are due to defects in DNA damage repair or nuclear organization, are associated with increased cellular senescence and accelerated age-related phenotypes in the skin (Davis et al., 2007; Harada et al., 1999; Liu et al., 2006).”

“UV light can induce photoaging via direct damage to extracellular matrix components, such as collagen and fibrillin fibers (Jariashvili et al., 2012; Menter et al., 2001; Sherratt et al., 2010), or indirect damage through mitochondrial dysfunction.”

“The majority of these deletions are detectable in the dermis of human skin exposed to physiological doses of UVA (Berneburg et al., 2005).”

“Another hypothesis for facial wrinkling is the enhanced elastase activity upon UVB stimuli, which is associated with a reduction in the elastic properties of the skin (Imokawa, 2009).”

“, 1994; Mitchell, 1967), which are due to formation of structurally different elastic fibers (Watson et al., 2001).”

“For example, chronic wounds are characterized by the persistent presence of senescent cells in the wound areas (Mendez et al., 1998; Vande Berg and Robson, 2003; Vande Berg et al., 2005).”

“UV light can induce photoaging via direct damage to extracellular matrix components, such as collagen and fibrillin fibers (Jariashvili et al., 2012; Menter et al., 2001; Sherratt et al., 2010), or indirect damage through mitochondrial dysfunction.”

“…pigmentosum, and the Hutchinson–Gilford progeria syndrome, which are due to defects in DNA damage repair or nuclear organization, are associated with increased cellular senescence and accelerated age-related phenotypes in the skin (Davis et al., 2007; Harada et al., 1999; Liu et al., 2006).”

“During the first two phases, platelets promote coagulation and begin an inflammatory cascade by secreting a variety of cytokines and chemokines to attract macrophages and neutrophils (Fuhrman et al., 1991; Kim et al., 2008; Shallo et al., 2003).”

“Extrinsic factors, such as X-rays, UV light, and cigarette smoke, also can induce cellular senescence, as well as age-related phenotypes in the skin (Shin et al., 2012; Velarde et al., 2012; Yang et al., 2013).”

“Extrinsic factors, such as X-rays, UV light, and cigarette smoke, also can induce cellular senescence, as well as age-related phenotypes in the skin (Shin et al., 2012; Velarde et al., 2012; Yang et al., 2013).”

“Because mitochondrial damage and dysfunction induces cellular senescence in culture and in vivo (Passos et al., 2006; Velarde et al., 2012), and UV light also promotes mitochondrial damage and cellular senescence, it would be interesting to test whether the UV-induced common deletion contributes to skin aging through…”

“For example, chronic wounds are characterized by the persistent presence of senescent cells in the wound areas (Mendez et al., 1998; Vande Berg and Robson, 2003; Vande Berg et al., 2005).”

“We and others have suggested that the secretory phenotype associated with senescent cells (SASP) can serve several biological functions, either beneficial or deleterious (29).”