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

      Human and mouse skin accumulate senescent cells in both the epidermis and dermis during aging. When chronically present, senescent cells are thought to enhance the age-dependent deterioration of the skin during extrinsic and intrinsic aging. However, when transiently present, senescent cells promote optimal wound healing. Here, we review recent studies on how senescent cells and the senescence-associated secretory phenotype contribute to different physiological and pathophysiological conditions in the skin with a focus on some of the cell autonomous and non-autonomous functions of senescent cells in the context of skin aging and wound healing.

      Abbreviations

      MMP
      matrix metalloproteinase
      SASP
      senescence-associated secretory phenotype

      Introduction

      Cellular senescence is a complex stress response that renders cells incapable of cell division, even in the presence of growth stimuli (
      • Campisi J.
      Aging, cellular senescence, and cancer.
      ). Senescent cells are distinct from quiescent cells, which retain the ability to proliferate in response to appropriate stimuli. Senescent cells are also distinct from post-mitotic cells and terminally differentiated cells, which generally lose the ability to divide as a consequence of developmental, as opposed to stress-activated, programs.
      A senescence response is typically induced by cellular damage (often nuclear DNA damage or mitochondrial dysfunction;
      • von Zglinicki T.
      • Saretzki G.
      • Ladhoff J.
      • et al.
      Human cell senescence as a DNA damage response.
      ;
      • Ziegler D.V.
      • Wiley C.D.
      • Velarde M.C.
      Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging.
      ). As part of the senescence response, senescent cells express a number of non-exclusive markers, including the cell cycle inhibitor p16INK4A and elevated levels of a lysosomal enzyme, termed as senescence-associated β-galactosidase (
      • Rodier F.
      • Campisi J.
      Four faces of cellular senescence.
      ). Many senescent cells also secrete several cytokines, growth factors, and matrix metalloproteinases (MMPs), collectively termed as the senescence-associated secretory phenotype (SASP;
      • Coppe J.P.
      • Patil C.K.
      • Rodier F.
      • et al.
      Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
      ), which differ from those secreted by non-senescent quiescent, post-mitotic, and/or differentiated cells.
      Senescent cells can alter tissue homeostasis and promote age-related diseases, including degenerative pathologies and cancers (
      • Campisi J.
      Aging, cellular senescence, and cancer.
      ;
      • van Deursen J.M.
      The role of senescent cells in ageing.
      ). The inability of senescent cells to proliferate can impair tissue regeneration after injury, causing prolonged or permanent tissue damage with age. In addition, the SASP factors that are secreted by senescent cells can alter tissue microenvironments through their paracrine effects and promote age-related phenotypes (
      • Coppe J.P.
      • Patil C.K.
      • Rodier F.
      • et al.
      Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
      ). 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 D.J.
      • Wijshake T.
      • Tchkonia T.
      • et al.
      Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.
      ).
      Although cellular senescence is often viewed as a negative contributor to tissue function during the aging process, senescent cells, and particularly the SASP, can also have beneficial effects, such as the promotion of proper wound healing. This aspect of senescent cells could explain why cellular senescence evolved and has been preserved during evolution, even though it contributes to age-related phenotypes later in life. Here, we discuss how cellular senescence can be both beneficial and detrimental during skin aging and wound healing, and how the contrasting cell autonomous and non-cell autonomous effects of senescent cells can depend on the physiological context. On the one hand, senescent cells can accelerate aging phenotypes through the loss of tissue homeostasis by promoting chronic inflammation, persistent degradation of the extracellular matrix, and stem cell exhaustion. On the other hand, senescent cells can also have essential roles during wound healing by limiting excessive proliferation and fibrosis and promoting the formation of granulation tissue.

      Cellular senescence and skin aging

      Skin aging is caused by both intrinsic and extrinsic factors. Intrinsic aging, sometimes termed as chronologic aging, refers mainly to sun-protected areas of the skin. Intrinsic aging is associated with morphological changes primarily in the epidermal layer, manifest as marked thinning and loss of undulation (flattening of the dermo–epidermal junction;
      • Makrantonaki E.
      • Zouboulis C.C.
      Molecular mechanisms of skin aging: state of the art.
      ). Intrinsic aging also reduces subcutaneous fat and dermal thickness with an accompanying loss of cellularity and vascularity (
      • Farage M.A.
      • Miller K.W.
      • Elsner P.
      • et al.
      Characteristics of the aging skin.
      ). 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 T.
      • He T.
      • Kang S.
      • et al.
      Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling.
      ,
      • Quan T.
      • Shao Y.
      • He T.
      • et al.
      Reduced expression of connective tissue growth factor (CTGF/CCN2) mediates collagen loss in chronologically aged human skin.
      ). There is also accumulation of abnormal elastic tissues (
      • Bernstein E.F.
      • Chen Y.Q.
      • Tamai K.
      • et al.
      Enhanced elastin and fibrillin gene expression in chronically photodamaged skin.
      ;
      • Mitchell R.E.
      Chronic solar dermatosis: a light and electron microscopic study of the dermis.
      ), which are due to formation of structurally different elastic fibers (
      • Watson R.E.
      • Craven N.M.
      • Kang S.
      • et al.
      A short-term screening protocol, using fibrillin-1 as a reporter molecule, for photoaging repair agents.
      ).
      Senescent cells increase with age in both the epidermis and dermis, as determined by elevated levels of senescence-associated β-galactosidase activity and p16INK4A expression (
      • Dimri G.P.
      • Lee X.
      • Basile G.
      • et al.
      A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
      ;
      • Krishnamurthy J.
      • Torrice C.
      • Ramsey M.R.
      • et al.
      Ink4a/Arf expression is a biomarker of aging.
      ;
      • Ressler S.
      • Bartkova J.
      • Niederegger H.
      • et al.
      p16INK4A is a robust in vivo biomarker of cellular aging in human skin.
      ;
      • Waaijer M.E.
      • Parish W.E.
      • Strongitharm B.H.
      • et al.
      The number of p16INK4a positive cells in human skin reflects biological age.
      ). Because senescent cells cannot proliferate, their presence in aged skin can potentially impair tissue homeostasis, regeneration, and youthful tissue structure/function (
      • Campisi J.
      Aging, cellular senescence, and cancer.
      ;
      • Signer R.A.
      • Morrison S.J.
      Mechanisms that regulate stem cell aging and life span.
      ). For example, in a three-dimensional organotypic culture model using neonatal dermal fibroblasts and epidermal keratinocytes from human donors of varying ages, increasing the expression of p16INK4A in keratinocytes isolated from young (30–40 years) donors yielded a thin epidermal layer similar to that formed by keratinocytes from elderly (53–66 years) donors; decreasing the expression of p16INK4A in keratinocytes from elderly donors transformed the aged skin phenotype of a thin epidermal layer into a thicker epidermis, similar to that formed by keratinocytes from young donors (
      • Adamus J.
      • Aho S.
      • Meldrum H.
      • et al.
      p16INK4A influences the aging phenotype in the living skin equivalent.
      ).
      Aside from the cell autonomous effects of non-proliferating senescent cells on skin homeostasis, SASP factors secreted by senescent cells are also thought to contribute to skin aging phenotypes in a cell non-autonomous manner. SASP factors, especially the MMPs, become elevated with age and can alter the tissue microenvironment and accelerate skin aging phenotypes (Table 1). MMPs can degrade collagens, including type I collagen, which is the most abundant protein in the dermal extracellular matrix. Loss of collagen is associated with several clinical manifestations of aging skin, including wrinkles, sagging, and laxity (
      • Jariashvili K.
      • Madhan B.
      • Brodsky B.
      • et al.
      UV damage of collagen: insights from model collagen peptides.
      ;
      • Quan T.
      • Shao Y.
      • He T.
      • et al.
      Reduced expression of connective tissue growth factor (CTGF/CCN2) mediates collagen loss in chronologically aged human skin.
      ;
      • Shuster S.
      • Black M.M.
      • McVitie E.
      The influence of age and sex on skin thickness, skin collagen and density.
      ). Hence, increased expression and activity of MMPs during aging can decrease the amount of collagen in the skin (
      • Varani J.
      • Schuger L.
      • Dame M.K.
      • et al.
      Reduced fibroblast interaction with intact collagen as a mechanism for depressed collagen synthesis in photodamaged skin.
      ), diminish fibroblast-collagen interactions, and reduce mechanical tension, explaining the wrinkling phenotype observed in aged skin (
      • Varani J.
      • Dame M.K.
      • Rittie L.
      • et al.
      Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation.
      ). 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 G.
      Mechanism of UVB-induced wrinkling of the skin: paracrine cytokine linkage between keratinocytes and fibroblasts leading to the stimulation of elastase.
      ). The role of cellular senescence in promoting changes in the elastic tissue has not been addressed yet but represents an important avenue for future clinical approaches.
      Table 1List of MMPs involved in skin aging, cellular senescence, and wound healing
      MMP expressionReferences
      Skin agingElevated expression of MMP1, MMP3, and MMP9
      • Quan T.
      • Qin Z.
      • Xia W.
      • et al.
      Matrix-degrading metalloproteinases in photoaging.
      Cellular senescenceElevated expression of MMP1, MMP3, MMP8, MMP10, MMP12, and MMP13
      • Coppe J.P.
      • Patil C.K.
      • Rodier F.
      • et al.
      A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.
      ;
      • Freund A.
      • Patil C.K.
      • Campisi J.
      p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.
      Wound healingTemporal upregulation of MMP1, MMP2, MMP9, MMP3, MMP10, MMP14, MMP8, MMP12, MMP13, MMP19, MMP26, MMP28
      • Martins V.L.
      • Caley M.
      • O'Toole E.A.
      Matrix metalloproteinases and epidermal wound repair.
      Abbreviation: MMP, matrix metalloproteinase.
      Although it is still unclear which specific stimuli are responsible for inducing cellular senescence during aging, both intrinsic and extrinsic aging have been linked to the age-related increase in the number of senescent cells in the skin. For example, the hereditary disorders, the Werner syndrome, xeroderma 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 T.
      • Wyllie F.S.
      • Rokicki M.J.
      • et al.
      The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging.
      ;
      • Harada Y.N.
      • Shiomi N.
      • Koike M.
      • et al.
      Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene.
      ;
      • Liu Y.
      • Rusinol A.
      • Sinensky M.
      • et al.
      DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A.
      ). 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 J.
      • Kim J.H.
      • Kim E.K.
      Repeated exposure of human fibroblasts to UVR induces secretion of stem cell factor and senescence.
      ;
      • Velarde M.C.
      • Flynn J.M.
      • Day N.U.
      • et al.
      Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin.
      ;
      • Yang G.Y.
      • Zhang C.L.
      • Liu X.C.
      • et al.
      Effects of cigarette smoke extracts on the growth and senescence of skin fibroblasts in vitro.
      ).
      UV light can induce photoaging via direct damage to extracellular matrix components, such as collagen and fibrillin fibers (
      • Jariashvili K.
      • Madhan B.
      • Brodsky B.
      • et al.
      UV damage of collagen: insights from model collagen peptides.
      ;
      • Menter J.M.
      • Patta A.M.
      • Sayre R.M.
      • et al.
      Effect of UV irradiation on type I collagen fibril formation in neutral collagen solutions.
      ;
      • Sherratt M.J.
      • Bayley C.P.
      • Reilly S.M.
      • et al.
      Low-dose ultraviolet radiation selectively degrades chromophore-rich extracellular matrix components.
      ), or indirect damage through mitochondrial dysfunction. 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 J.
      • Schroeder P.
      Role of mitochondria in photoaging of human skin: the defective powerhouse model.
      ). UV radiation–induced photoaging of human skin is associated with large-scale deletions in mitochondrial genomes (mitochondrial DNA (mtDNA);
      • Berneburg M.
      • Gattermann N.
      • Stege H.
      • et al.
      Chronically ultraviolet-exposed human skin shows a higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hematopoietic system.
      ;
      • Birch-Machin M.A.
      • Tindall M.
      • Turner R.
      • et al.
      Mitochondrial DNA deletions in human skin reflect photo- rather than chronologic aging.
      ). Intra-individual studies have revealed that the frequency of a 4,977 bp deletion, also defined as “common deletion”, is increased up to 10-fold in photoaged skin compared with sun-protected skin (
      • Berneburg M.
      • Gattermann N.
      • Stege H.
      • et al.
      Chronically ultraviolet-exposed human skin shows a higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hematopoietic system.
      ). The majority of these deletions are detectable in the dermis of human skin exposed to physiological doses of UVA (
      • Berneburg M.
      • Gremmel T.
      • Kurten V.
      • et al.
      Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences.
      ). UV radiation also induces this common deletion in cultured skin fibroblasts and decreases mitochondrial function (
      • Berneburg M.
      • Gremmel T.
      • Kurten V.
      • et al.
      Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences.
      ). Because mitochondrial damage and dysfunction induces cellular senescence in culture and in vivo (
      • Passos J.F.
      • von Zglinicki T.
      • Saretzki G.
      Mitochondrial dysfunction and cell senescence: cause or consequence?.
      ;
      • Velarde M.C.
      • Flynn J.M.
      • Day N.U.
      • et al.
      Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin.
      ), 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 mitochondrial dysfunction–associated senescence.

      Cellular senescence and wound healing

      Wound healing is a complex process by which the skin repairs itself after injury. This process is classically divided into four distinct but overlapping phases (
      • Singer A.J.
      • Clark R.A.
      Cutaneous wound healing.
      ): (i) hemostasis, (ii) inflammation, (iii) proliferation, and (iv) remodeling. 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 B.
      • Brook G.J.
      • Aviram M.
      Activated platelets secrete a protein-like factor that stimulates oxidized-LDL receptor activity in macrophages.
      ;
      • Kim M.H.
      • Liu W.
      • Borjesson D.L.
      • et al.
      Dynamics of neutrophil infiltration during cutaneous wound healing and infection using fluorescence imaging.
      ;
      • Shallo H.
      • Plackett T.P.
      • Heinrich S.A.
      • et al.
      Monocyte chemoattractant protein-1 (MCP-1) and macrophage infiltration into the skin after burn injury in aged mice.
      ). Before the inflammatory phase ends, fibroblasts are recruited to the wound site and endothelial cells mature from progenitor cells to reestablish vascularization (
      • Chen L.
      • Tredget E.E.
      • Wu P.Y.
      • et al.
      Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing.
      ;
      • Postlethwaite A.E.
      • Keski-Oja J.
      • Moses H.L.
      • et al.
      Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta.
      ;
      • Sunderkotter C.
      • Steinbrink K.
      • Goebeler M.
      • et al.
      Macrophages and angiogenesis.
      ). 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 S.
      • Dipietro L.A.
      Factors affecting wound healing.
      ). The final remodeling phase initiates when a stable ratio of collagen production and degradation is reached and ends when the tissue acquires a mature organization and tensile strength after replacing transiently expressed collagen III with collagen I (
      • Madden J.W.
      • Peacock Jr., E.E.
      Studies on the biology of collagen during wound healing. 3. Dynamic metabolism of scar collagen and remodeling of dermal wounds.
      ;
      • Tomasek J.J.
      • Gabbiani G.
      • Hinz B.
      • et al.
      Myofibroblasts and mechano-regulation of connective tissue remodelling.
      ).
      Recent findings using mouse models show that senescent cells are transiently induced in the granulation tissue during the proliferative phase of wound healing and are efficiently removed during the transition to the remodeling phase (
      • Demaria M.
      • Ohtani N.
      • Youssef S.A.
      • et al.
      An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.
      ). Wound contraction is important for wound closure during the proliferative phase (
      • Midwood K.S.
      • Williams L.V.
      • Schwarzbauer J.E.
      Tissue repair and the dynamics of the extracellular matrix.
      ) and proceeds through the formation of newly synthesized granulation tissue and the activation of contraction in myofibroblasts (
      • Tomasek J.J.
      • Gabbiani G.
      • Hinz B.
      • et al.
      Myofibroblasts and mechano-regulation of connective tissue remodelling.
      ). Thus, the presence of senescent cells within this window may be essential for proper wound healing. Indeed, the elimination of senescent cells in young mice bearing cutaneous wounds leads to poor formation of granulation tissue and a marked reduction in the number of myofibroblasts, with consequent delayed wound closure (
      • Demaria M.
      • Ohtani N.
      • Youssef S.A.
      • et al.
      An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.
      ). 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. Senescence-free wounds were also more fibrotic during the remodeling phase, but topical platelet-derived growth factor AA was unable to limit this excessive fibrosis. These findings illustrate the complex and diverse roles played by senescent cells during wound healing and suggest that other SASP factors in addition to platelet-derived growth factor AA are important for optimal wound healing.
      As indicated above, another important contribution of senescent fibroblasts during tissue repair is to limit fibrosis, which is commonly observed in chronic wounds and is characterized by excessive collagen deposition (
      • Telgenhoff D.
      • Shroot B.
      Cellular senescence mechanisms in chronic wound healing.
      ). Several MMPs, including MMP2, MMP3, and MMP9, are part of the SASP (Table 1;
      • Coppe J.P.
      • Patil C.K.
      • Rodier F.
      • et al.
      A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.
      ;
      • Coppe J.P.
      • Patil C.K.
      • Rodier F.
      • et al.
      Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
      ) and can degrade excess collagen and maintain tissue homeostasis during wound healing (
      • Jun J.I.
      • Lau L.F.
      The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing.
      ). Indeed, failure to induce senescence during wound healing causes fibrosis in the skin and liver (
      • Jun J.I.
      • Lau L.F.
      The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing.
      ;
      • Kim K.H.
      • Chen C.C.
      • Monzon R.I.
      • et al.
      Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts.
      ;
      • Krizhanovsky V.
      • Yon M.
      • Dickins R.A.
      • et al.
      Senescence of activated stellate cells limits liver fibrosis.
      ). Overall, these results indicate that senescent cells can promote tissue repair through cell non-autonomous mechanisms.
      The irreversible growth arrest of senescent cells may restrict proliferation during wound healing as a means to protect against aberrant cell proliferation. This cell autonomous effect of senescent cells is in keeping with a fundamental role for cellular senescence in tumor suppression (
      • Campisi J.
      Cellular senescence as a tumor-suppressor mechanism.
      ). Cells from mice lacking the p16INK4a and p21WAF1/CIP1 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 S.
      • Takahashi A.
      • Motoi N.
      • et al.
      Intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo.
      ). Hence, the absence of cellular senescence may transform a wound into a hyperplastic or premalignant phenotype characterized by unregulated cell proliferation. Because wound healing and cancer share several molecular and cellular events (
      • Dvorak H.F.
      Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
      ;
      • Feng Y.
      • Santoriello C.
      • Mione M.
      • et al.
      Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation.
      ), senescent cells may have an essential role in promoting wound healing while preventing cancer initiation.
      Although a lack of senescent cells impairs wound healing and can promote tumorigenesis, the persistent presence of senescent cells may exacerbate pathological diseases in the skin. For example, chronic wounds are characterized by the persistent presence of senescent cells in the wound areas (
      • Mendez M.V.
      • Stanley A.
      • Park H.Y.
      • et al.
      Fibroblasts cultured from venous ulcers display cellular characteristics of senescence.
      ;
      • Vande Berg J.S.
      • Robson M.C.
      Arresting cell cycles and the effect on wound healing.
      ;
      • Vande Berg J.S.
      • Rose M.A.
      • Haywood-Reid P.L.
      • et al.
      Cultured pressure ulcer fibroblasts show replicative senescence with elevated production of plasmin, plasminogen activator inhibitor-1, and transforming growth factor-beta1.
      ). Because chronic wounds fail to progress through the different stages of the wound-healing process (
      • Sen C.K.
      • Gordillo G.M.
      • Roy S.
      • et al.
      Human skin wounds: a major and snowballing threat to public health and the economy.
      ), 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. Moreover, some of the SASP factors that are important for wound healing seem to also promote cancer progression through cell non-autonomous mechanisms. For example, certain MMPs that are anti-fibrotic in wounds can also promote tumor cell invasion during the progression of skin cancers (
      • Woenne E.C.
      • Lederle W.
      • Zwick S.
      • et al.
      MMP inhibition blocks fibroblast-dependent skin cancer invasion, reduces vascularization and alters VEGF-A and PDGF-BB expression.
      ).

      The balance between cell autonomous and non-autonomous effects in skin homeostasis

      The complex role of senescent cells in the skin includes cell autonomous and non-autonomous functions, which may be beneficial during wound healing but deleterious during aging (Figure 1). What determines the phenotype of senescent cells, and whether their effects on the tissue microenvironment are positive or negative? One hypothesis is that both the cell autonomous and non-autonomous properties of senescent cells are highly dependent on age and time. First, the induction of an irreversible growth arrest might be an essential mechanism during wound healing that limits the number of highly proliferative cells, which are at risk for acquiring premalignant or malignant mutations. However, with time and age, this mechanism can exhaust the pool of proliferation-competent stem or progenitor cells, which contribute to tissue turnover and regeneration. Second, the slow accumulation of senescent cells in the skin due to increased number and/or defective clearance might create chronic inflammation and promote age-associated skin pathologies––for example, through the chronic production of MMPs. Third, the SASP may be a malleable phenotype and change over time and with age. Thus, harmful cytokines, chemokines, and other inflammatory factors may be secreted by senescent cells only when they are persistently present in the skin.
      Figure thumbnail gr1
      Figure 1Senescent cells act in the skin via both cell autonomous and non-autonomous mechanisms. The transient induction of cellular senescence during wound healing promotes granulation tissue formation and tissue remodeling, whereas it prevents the hyperproliferation of potentially premalignant or malignant lesions. In contrast, the accumulation of senescent cells with age causes poor tissue regeneration and loss of homeostasis in the skin. The chronic presence of senescent cells further creates a tissue environment with chronic inflammation promoting collagen degradation, both of which can lead to aging phenotypes in the skin. SASP, senescence-associated secretory phenotype.

      Conclusion

      The elimination of senescent cells is an attractive avenue for developing new interventions to treat age-related pathologies, and several laboratories are searching for small molecules that might be of potential interest for future clinical studies (see
      • Dorr J.R.
      • Yu Y.
      • Milanovic M.
      • et al.
      Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.
      , for an example). In the skin, the different roles of senescent cells in promoting both physiological and pathophysiological conditions are still in early phases of discovery. More experiments need to be conducted to determine how senescent cells can tip the balance between efficient and chronic wound healing. It also remains to be proven whether the presence of long-lived versus short-lived senescent cells has a major contributory factor to this difference. Thus, whether and how an anti-senescence approach will help maintain healthy skin awaits future experimentation. Although the elimination of senescent cells might reduce age-related chronic inflammation and collagen degradation, this strategy could fail to restore youthful skin phenotypes that depend on adequate stem cell numbers. Finding ways to replenish these stem cells may be necessary in order to rescue age-related skin defects after the elimination of senescent cells. Furthermore, the continuous removal of senescent cells in the skin, particularly in the elderly, could impede wound healing and increase tissue scarring, which are of bigger concerns than having a youthful looking skin. Hence, a better understanding of the complexity of the cell autonomous and non-autonomous functions of senescent cells, and the mechanisms that lead to their induction, will be essential in order to develop specific therapeutic approaches with minimal side effects to treat age-related skin phenotypes and pathologies.
      The authors are supported by National Institutes of Health grants R37-AG009909, P01- AG017242, P01-AG041122, R21-CA166347, and K99-AG041221.

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