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. 2024 Mar 18;36(3):135–144. doi: 10.5021/ad.23.156

Emerging Perspectives of YAP/TAZ in Human Skin Epidermal and Dermal Aging

Jun Young Kim 1,2, Taihao Quan 1,✉
PMCID: PMC11148314  PMID: 38816974

Abstract

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key downstream effectors of the Hippo signaling pathway, which plays a central role in tissue homeostasis, organ development, and regeneration. While the dysregulation of YAP/TAZ has been linked to various human diseases, their involvement in the aging of human skin has only recently begun to manifest. In the skin, the YAP/TAZ effectors emerge as central regulators in maintaining homeostasis of epidermal stem cells and dermal extracellular matrix, and thus intimately linked to skin aging processes. This review underscores recent molecular breakthroughs highlighting how age-related decline of YAP/TAZ activity impacts human epidermal and dermal aging. Gaining insight into the evolving roles of YAP/TAZ in human skin aging presents a promising avenue for the development of innovative therapeutic approaches aimed at enhancing skin health and addressing age-related skin conditions.

Keywords: Dermis, Extracellular matrix, Hippo signaling pathway, Skin aging, Stem cells

INTRODUCTION

The aging process is a complex and multifaceted phenomenon that affects various tissues and organs throughout the human body, with the skin being one of the most visibly impacted. As the largest organ, the skin undergoes significant structural and functional changes over time, influenced by both intrinsic and extrinsic factors1,2. While intrinsic skin aging is an inevitable, extrinsic skin aging is primarily driven by environmental factors such as ultraviolet (UV) radiation, pollution, and lifestyle.

The Hippo signaling pathway is an evolutionary conserved kinase cascade pathway that plays a fundamental role in regulating tissue growth, organ size, and organ homeostasis3,4. The core components of the Hippo signaling pathway include a series of protein kinases and transcriptional coactivators, with the primary regulatory pathway centering around the activity of the yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ)5,6. MST1/2 (Mammalian Ste20-like kinase 1/2) are serine/threonine kinases that function as the upstream components of the Hippo pathway. MST1/2 phosphorylates and activates LATS1/2, which subsequently phosphorylates YAP and TAZ. The phosphorylated YAP/TAZ is sequestered in the cytoplasm, preventing their nuclear localization and transcriptional coactivation. When the pathway is inactive, YAP and TAZ translocate into the nucleus, where they interact with transcription factors such as TEAD (TEA domain family member) to promote the transcription of genes involved in cell proliferation, survival, and tissue growth7. Furthermore, YAP/TAZ nuclear translocation/activity is regulated by cellular morphology and mechanical forces, independent of the Hippo pathway8,9,10.

Dysregulation of YAP/TAZ signaling pathway has been linked to diverse diseases, encompassing cancer and degenerative disorders11,12. In recent years, YAP/TAZ have emerged as key players in the regulation of skin homeostasis13,14,15,16 and aging17,18,19. In the subsequent sections of this review, we will navigate through the current state of knowledge regarding YAP/TAZ signaling in skin aging, emphasizing recent findings, challenges, and potential therapeutic avenues that may revolutionize our approach to maintaining skin health and combating the effects of aging.

YAP/TAZ AND EPIDERMAL AGING: MAINTAINING EPIDERMAL STEM CELL HOMEOSTASIS

The epidermis, composed mainly of keratinocytes, serves as a protective shield for the body against the external environment. The human epidermis is continuously self-renewed which relies on the skin stem cells. Epidermal aging is characterized by the noteworthy thinning of the epidermal layer, which is primarily attributed to the age-related decline in the regenerative capacity of epidermal stem cells. Stem cells possess the capacity to differentiate into a wide range of cell types and sustain their own renewal during development, maintaining homeostasis, and regeneration20,21.

YAP/TAZ has been critically linked to the self-renewal and differentiation of epidermal stem cells4,16,22. YAP/TAZ activity gradually decreases with age, concomitant with a decline in the proliferative potential of epidermal progenitors23. Deletion of YAP/TAZ in epidermal keratinocytes in adult mice results in a swift reduction in the proliferation of basal epidermal stem cells and a noticeable loss of hair in the skin22. Consistently, epidermal keratinocyte-specific deletion of YAP/TAZ impairs epidermal regeneration and delays wound healing14,22.

Conversely, overexpression activated YAP mutant in the basal epidermis of transgenic mice caused marked expansion of epidermal stem/progenitor cell populations16. Furthermore, forced YAP expression in the skin leads to the development of squamous cell carcinoma and basal cell carcinoma24,25,26. Likewise, deletion of YAP/TAZ in the stem cell compartment of the murine skin epidermis prevents DMBA/TPA-induced carcinogenesis22,27. These results highlight the critical requirement for precise control of YAP/TAZ activity in maintaining the homeostasis cutaneous stem cells and keratinocytes proliferation.

Recent articles have intriguingly proposed that YAP can directly interact with the promoter region of COL17A1 to regulate its expression28. COL17A1, a structural protein in the dermal-epidermal basement membrane29, is crucial for maintaining skin stem cell homeostasis1,30,31. The expression of COL17A1 is significantly diminished in both intrinsic and extrinsic photoaging, as well as following acute UV exposure in human skin32,33. This reduction is primarily attributed to the increased activity of matrix-degrading proteases associated with aging. The decrease in COL17A1 levels impairs stem cells attachment to the basement membrane, leading to their elimination from the skin epidermal basal layer, results in decreased rates of keratinocyte renewal and the development of thinner epidermal layers32,34. COL17A1 deficiency also plays a significant role in hair aging, which is an inevitable part of the natural aging process30,35. These findings suggest that age-related decline of YAP/TAZ activity induces age-related skin stem cell exhaustion through downregulation of COL17A1 expression. Conversely, recent studies suggest that YAP activation takes place in basal stem cells when they contact the basement membrane, aided by integrin-SRC signaling22. It is possible that age-related decline in COL17A1 expression disrupts the connection between basal stem cells and the basement membrane, leading to the inactivation of YAP, consequently initiating the aging of epidermal stem cells. As such, the decrease in COL17A1 with age could contribute to the depletion of stem cells by hindering the activity of YAP/TAZ. Considering these findings, we propose the existence of a self-perpetuating positive feedback loop involving COL17A1 and YAP/TAZ in epidermal aging (Fig. 1). In this loop, the age-related decline in COL17A1 impairs YAP/TAZ activity, and the diminished YAP/TAZ activity, in turn, further reduces COL17A1, ultimately promoting the aging of the epidermis.

Fig. 1. Proposed model of epidermal aging: COL17A1 (Collagen type XVII alpha 1) is expressed in dermal-epidermal basement membrane and serves as a niche for epidermal stem cells. During the skin aging process, COL17A1 undergoes degradation through proteolysis facilitated by various proteases, including MMPs. The diminished expression of COL17A1 in the niches of epidermal stem cells leads to weakened adhesion of stem cells to the basement membrane. Consequently, this weakening results in the loss of YAP/TAZ activity and a decline in the stem cell population. The reduction in stem cells contributes to the flattening of the ret ridge and the thinning of the epidermis, which are distinctive features of aging skin.

Fig. 1

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YAP: yes-associated protein, TAZ: transcriptional coactivator with PDZ-binding motif.

YAP/TAZ can crosstalk with several signaling pathways, including Wnt, Notch, and BMP (bone morphogenetic protein), which are important in regulating stem cell fate in the epidermis6,36,37. The interplay between these pathways can influence the balance between epidermal stem cell self-renewal and differentiation. Given that skin epidermal stem cell depletion is a fundamental contributor to epidermal aging, the activity of YAP and TAZ becomes indispensable in maintaining the homeostasis of epidermal stem cell populations.

YAP/TAZ AND DERMAL AGING: MAINTAINING DERMAL FIBROBLASTS HOMEOSTASIS

Collagen serves as the primary structural protein in the skin, mainly produced by dermal fibroblasts. During the process of skin dermal aging, the structural integrity of the dermal collagen diminishes, primarily due to the alterations of collagen fibrils, which include fragmentation, glycation, crosslinking, and reduced production1,38,39. These modifications ultimately lead to alterations in the physical, mechanical, and architectural characteristics of the dermis38,40. Structural alteration of dermal collagenous extracellular matrix (ECM) creates a tissue microenvironment that is conducive to various skin disorders, such as increased fragility41, compromised vascular support42, delayed wound healing43,44, and an increased susceptibility to cancer development45,46,47.

YAP/TAZ have been demonstrated to exert influence over collagen production by regulating the activity of fibroblasts14,18, and age-related decline of YAP/TAZ activity in dermal fibroblasts has been reported in both human skin17,18,48 and mouse skin19. Age-related loss of YAP/TAZ activity in skin dermal fibroblasts leads to an impairment of collagen homeostasis18,19. Mechanistically, age-related loss of YAP/TAZ activity leads to the upregulation of MMP-1 (matrix metalloproteinase-1) by activation of AP-1 and downregulation of collagen by inhibition of transforming growth factor (TGF)-β signaling49. Consequently, the age-related decline in YAP/TAZ activity in dermal fibroblasts can lead to an imbalance between collagen production and degradation, ultimately contributing to dermal aging (Fig. 2). Interestingly, recent research has shed light on the loss of YAP/TAZ, due to the age-related mechano-defective ECM, is a driving force for dermal aging19. Single-cell RNA-seq identified a notable reduction in the YAP/TAZ signature gene set as the primary characteristic in aged mouse dermal fibroblasts. Furthermore, targeted deletion of YAP/TAZ in dermal fibroblasts in young mice accelerated dermal aging. Significantly, the restoration of YAP/TAZ activity in dermal fibroblasts through constitutively active YAPS127A was sufficient to rescue the normal aging of the skin in fibroblast-specific YAP/TAZ knockout mice. These findings provide compelling evidence that the decrease in YAP/TAZ activity in dermal fibroblasts plays a pivotal role in dermal aging, underscoring the substantial importance of YAP/TAZ in the skin dermal aging process.

Fig. 2. Dermal aging: Collagen fragmentation due to age-related MMPs (Matrix metalloproteinases) is the hallmark of the dermal aging. Fragmented collagen fibrils create mechano-defective ECM microenvironment and impairs fibroblast-collagen interaction result in loss of YAP/TAZ activity. The age-related decline in YAP/TAZ activity within aged dermal fibroblasts plays a pivotal role in disrupting collagen homeostasis by impairing TGF-β/Smad signaling and triggering MMP-1 induction, ultimately contributing to the thin and damaged dermis, the characteristic feature of the dermal aging.

Fig. 2

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ECM: extracellular matrix, YAP: yes-associated protein, TAZ: transcriptional coactivator with PDZ-binding motif, TGF: transforming growth factor.

YAP/TAZ CONTRIBUTES TO SKIN AGING THROUGH THEIR TARGET GENES CCN1/CYR61 AND CCN2/CTGF

The proteins CCN1/Cyr61 and CCN2/CTGF are members of the matricellular protein family known as CCN50,51,52. This family encompasses extracellular signaling proteins that engage with cell surface receptors and ECM proteins to influence and regulate cellular activities. CCN family proteins are pivotal in a wide array of cellular functions, including cell adhesion, migration, proliferation, differentiation, and tissue remodeling proteases51,53,54. Both CCN1/Cyr61 and CCN2/CTGF are well-recognized as established downstream target genes of YAP/TAZ; instead, they often serve as a simple readout of YAP/TAZ activity rather than functioning as downstream effectors of YAP/TAZ signaling. The investigation of CCN1/Cyr61 and CCN2/CTGF in mediating the role of YAP/TAZ in human skin aging remains relatively limited.

CCN1/Cyr61 is often associated with tissue repair, inflammation, and angiogenesis55,56. Dysregulation of CCN1/Cyr61 expression and function has been linked to various diseases, including aging and cancer39,55. The specific functions of CCN1/Cyr61 can vary depending on the context and the specific cellular and tissue environments in which it is expressed. In skin epidermis, CCN1/Cyr61 is implicated in regulating keratinocyte proliferation and differentiation and involved in the wound healing process by promoting proliferation and the migration of keratinocytes to the wound site23,57.

Experiments involving gain-and-loss of function in human primary keratinocytes demonstrate that when YAP is knocked down, there is a notable decrease in the expression of CCN1/Cyr61 and CCN2/CTGF, and significant inhibition of in both cell proliferation and cell survival57. When CCN1/Cyr61 is knocked down, but not CCN2/CTGF, it significantly hampers the growth of keratinocytes57. Importantly, YAP-dependent inhibition of proliferation and survival is rescued by restoring CCN1/Cyr61 expression but not by CCN2/CTGF expression57. This implies that CCN1/Cyr61 is the key mediator of YAP function in controlling keratinocyte growth (Fig. 3 left). Supporting these observations, Zhang et al.23 reported that in primary mouse keratinocytes, CCN1/Cyr61 serves as a pivotal factor in mediating the function of YAP in the growth and survival of skin stem and progenitor cells. Upon YAP activation, primary mouse keratinocytes exhibit increased proliferation, reduced differentiation, and inhibited apoptosis. Conversely, these characteristics are reversed when YAP is inhibited. Importantly, they identified that CCN1/Cyr61, as a YAP target gene, plays a role in facilitating YAP functions related to the proliferation and survival of mouse keratinocytes.

Fig. 3. Age-related decline of YAP/TAZ contributes to skin aging through their target genes CCN1/Cyr61 (Cellular Communication Network Factor 1) and CCN2/CTGF (Cellular Communication Network Factor 2). The decline in YAP/TAZ activity associated with aging leads to a diminished expression of CCN1/Cyr61 in keratinocytes, resulting in the inhibition of keratinocyte proliferation, which, in turn, contributes to the thinning of the epidermis (left). On the other hand, age-related reduction in YAP/TAZ activity results in a decreased expression of CCN2/CTGF in fibroblasts, inhibiting collagen production and thereby contributing to the thinning of the dermis.

Fig. 3

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YAP: yes-associated protein, TAZ: transcriptional coactivator with PDZ-binding motif.

CCN2/CTGF is notably increased in fibrotic tissues and holds a pivotal role as both a mediator and a biomarker of tissue fibrosis58,59. In contrast, in aged human dermal fibroblasts, CCN2 is significantly reduced, thus contributing to the process of dermal aging by inhibiting collagen production18,60. A recent study conducted by Qin et al.18 unveiled that the decline in CCN2 within aged human skin dermal fibroblasts is brought about by the age-related deterioration of YAP/TAZ signaling. The restoration of the age-related impairment of YAP/TAZ signaling effectively reversed the downregulation of CCN2 in human skin fibroblasts. This suggests that YAP/TAZ is responsible for the age-related decrease in CCN2/CTGF, and their involvement contributes to dermal aging through the downregulation of CCN2/CTGF (Fig. 3 right).

YAP/TAZ CONTRIBUTES TO SKIN AGING THROUGH INDUCTION OF INFLAMMAGING

As inflammatory state is believed to contribute to aging61,62, it has become apparent that YAP/TAZ is a pivotal regulator in skin inflammaging. Inflammaging is the term used to describe the persistent, low-level inflammation linked to the aging process63,64. Age-related decline of YAP/TAZ activity can contribute to skin inflammaging through several mechanisms19. Senescent cells can accumulate with age, leading to inflammaging in the skin65. These senescent cells release pro-inflammatory cytokines and a collection of other factors collectively referred to as the senescence-associated secretory phenotype (SASP)66,67. The presence of SASP can induce a state of chronic inflammation in the skin, thereby contributing to the phenomenon of inflammaging.

Given the pivotal role of YAP/TAZ in maintaining tissue regeneration and cell proliferation, the decreased activity of YAP/TAZ during the aging process can impede the ability of skin to regeneration and self-repair. This reduction in regenerative potential may lead to the accumulation of senescent cells in the skin. In support of this idea, the suppression of YAP/TAZ leads to premature senescence in both epidermal keratinocytes68,69 and dermal fibroblasts19. The decline in YAP/TAZ activity due to age-related mechano-defective dermal ECM has been found to trigger cGAS-STING activation, which in turn results in cellular senescence and SASP and thus contributes to the skin dermal aging (Fig. 4)19. In terms of mechanisms, the reduction in YAP/TAZ activity associated with aging results in a diminished expression of ACTR2 and lamin B1. Consequently, this decrease leads to a deterioration in the structural integrity of the nuclear envelope, allowing genomic DNA to be released into the cytosol. This release, in turn, initiates the activation of the cGAS-cGAMP-STING signaling pathway. Inactivation of STING pathway in dermal fibroblast-specific YAP/TAZ knockout mice rescued the senescent aging phenotype in skin. The cGAS-STING pathway was largely studied in the context of innate immune response, but it was also identified as a leading inducer of SASP both in vitro and in vivo 70. The critical role of YAP/TAZ in the regulation of cellular senescence was also reported in lung fibroblasts71. The gradual loss of YAP/TAZ levels leads to concurrent increases in cellular senescence through the p53/p16 pathways, in a TEAD-dependent manner.

Fig. 4. Age-related decline YAP/TAZ contributes to skin aging through induction of inflammaging. The diminished activity of YAP/TAZ, attributed to a mechano-defective ECM microenvironment, results in the suppression of YAP/TAZ nuclear translocation/activation and the expression of ACTR2 and lamin B1. Consequently, this inhibition impairs the structural integrity of the nuclear envelope and enhances the release of genomic DNA into the cytosol. This DNA release activates the cGAS-STING signaling pathway, leading to fibroblast senescence, expression of the SASP, and the emergence of an inflammaging dermis.

Fig. 4

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ECM: extracellular matrix, YAP: yes-associated protein, TAZ: transcriptional coactivator with PDZ-binding motif; ACTR2: actin-related protein 2, cGAS: cyclic GMP-AMP synthase, STING: stimulator of interferon genes, SASP: senescence-associated secretory phenotype.

YAP/TAZ also plays a role in modulating the immune response in different acute and chronic inflammatory diseases and its impact on tissue repair and remodeling72,73. As YAP/TAZ expression decreases, this can affect the balance of immune cell activity. Immune cells may become less efficient at resolving inflammation and more prone to maintaining a pro-inflammatory state. This can result in a self-perpetuating cycle of inflammation in the skin. Inflammaging is considered as one of the driving forces for many age-related diseases, represents a significant risk factor for morbidity and mortality in the elderly. However, the origin of inflammaging-related systemic cytokines is unknown. Recently, Hu et al.74 show that disruption of the epidermal barrier increases serum cytokine levels partly because of increased cytokine production by the skin74,75,76. YAP/TAZ is also involved in the regulation of genes related to skin barrier function15,77. A weakened skin barrier is more susceptible to damage from environmental factors and pathogens. As YAP/TAZ expression decreases with age, the skin barrier may become less effective at preventing these stressors from penetrating the skin. This can lead to irritation and inflammation. Given that the skin is the body's largest organ and is continuously exposed to environmental stressors, age-related deterioration of the epidermal barrier's function might contribute to the onset of systemic inflammation and the initiation of chronic inflammatory pathways in older individuals. Understanding the mechanisms through which YAP/TAZ influence skin inflammaging may provide a novel insight into a potential role of YAP/TAZ in skin aging process and offer new avenues for the development of interventions to mitigate age-related skin issues and chronic inflammation in other organs.

FIBROBLAST ADAPTATION TO THE SURROUNDING ECM MICROENVIRONMENT DRIVES AGE-RELATED DECLINE IN YAP/TAZ ACTIVITY: KEY FACTOR IN DERMAL AGING

YAP/TAZ activity is regulated by cellular morphology and mechanical forces, independent of the Hippo pathway8,9,10. A notable characteristic of aged dermal fibroblasts is the reduced spreading and smaller size, resulted from fibroblasts adaptations to age-related changes in the dermal ECM environment78,79,80,81. Importantly, age-related loss of fibroblast spreading, and size intimately regulates compromised YAP/TAZ activity and contributes to skin dermal aging18. Dermal fibroblasts, within the collagen-rich dermal microenvironment, rely on direct interactions with collagen fibrils to generate mechanical forces that control cell shape and function. In youthful skin, fibroblasts form a spread-out structure by connecting to intact collagen fibrils through cytoskeletal assembly, displaying a youthful anabolic phenotype. Conversely, in aged human skin with fragmented collagen fibrils, fibroblast attachment and spreading are hindered, leading to reduced mechanical forces. In this condition, fibroblasts exhibit an aged catabolic phenotype, contributing to abnormal collagen homeostasis and inflammaging. Therefore, collagen-rich ECM microenvironment not only provides a physical framework but also plays a crucial role in regulating fibroblast behavior (Fig. 5).

Fig. 5. Fibroblast adaptation to ECM microenvironment drives age-related decline in YAP/TAZ activity. (A and B) Reduced fibroblasts spreading/mechanical force downregulates ECM production. (A) Primary adult human dermal fibroblasts were cultured in intact collagen lattices (CTRL) or MMP1 fragmented collagen lattice (Inline graphic); stiff (CTRL) or soft collagen-coated hydrogels (Inline graphic); absence (CTRL) or presence of Lat-A (latrunculin-A) (Inline graphic), which reduces fibroblast spreading/mechanical force by disrupting the actin cytoskeleton. (B) Primary adult human dermal fibroblasts were cultured in intact collagen lattices (CTRL) or MMP1 fragmented collagen lattice. (A) mRNA and (B) protein levels were quantified by real-time RT-PCR and Western analysis, respectively. mRNA and protein levels were normalized by the housekeeping gene (36B4, internal control) and β-actin (loading control), respectively. Inset shows representative Western blots. Mean ± SEM, n=4–8, *p<0.05. (C) Fibroblast adaptation to ECM microenvironment drives age-related decline in YAP/TAZ activity. Age-related impairment of fibroblast-ECM interactions reduces fibroblast spreading/mechanical force and drives consequent functional alterations of the YAP/TAZ mechanosensing transcriptional pathway that mediate dermal ECM homeostasis. In young adult human dermis (left), fibroblasts attach to intact collagen fibrils and thus achieve a youthful phenotype, i.e., stretched morphology coupled with functionality that maintains a “healthy” dermal ECM homeostasis. In this state, YAP/TAZ localize in the nucleus, in an active state. In aged skin, collagen fibril fragmentation reduces ECM mechanical stability and fibroblast attachment/spreading. Reduced fibroblast spreading/mechanical force promotes YAP/TAZ cytoplasmic localization and inactivation. This inactivation of YAP/TAZ drives adaptive responses of fibroblasts, which alter ECM homeostasis resulting in an aged phenotype.

Fig. 5

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CTRL: control, COL-1: type I procollagen, FN: fibronectin, CCN2/CTGF: cellular Communication Network Factor 2, ECM: extracellular matrix, YAP: yes-associated protein, TAZ: transcriptional coactivator with PDZ-binding motif.

In conventional monolayer cultures, primary dermal fibroblasts from both elderly individuals (aged 80+) and young individuals (aged 20–30) display similar characteristics in terms of growth, morphology, and core matrisome gene expression18,82,83. However, when primary dermal fibroblasts from young individuals are cultured in in vitro model systems that simulate an aged dermal environment or restrict fibroblast spreading, they exhibit an aged phenotype resembling that of fibroblasts in aged skin in vivo 18,82. These model systems, limiting cell spreading and size, include: 1) Fibroblasts grown in three-dimensional fragmented collagen lattices; 2) Fibroblasts cultured in hydrogels with reduced stiffness; 3) Chemical disruption of the fibroblast actin cytoskeleton; 4) Fibroblasts cultivated on slides with ECM proteins micropatterned on the surface (Fig. 5A and B)81. In each of these model systems, a decrease in fibroblast spreading and mechanical forces significantly inhibits YAP/TAZ activity and reduces the expression of ECM proteins (e.g., type I collagen, fibronectin, and CCN2/CTGF), while increasing multiple MMPs and inflammatory cytokines, mirroring observations in aged human skin in vivo. Furthermore, restoring YAP/TAZ activity by constitutively active YAP/TAZ or promoting increased cell spreading and size rapidly reverses the aging phenotype, leading to higher expression of type I collagen and CCN2/CTGF18. These findings suggest that age-related changes in dermal fibroblast phenotype primarily result from adaptation to the deteriorating ECM environment, leading to reduced spreading and mechanical forces, and a subsequent decline in YAP/TAZ function (Fig. 5C). This contributes to detrimental alterations in ECM homeostasis associated with aging. To substantiate these findings, Sladitschek-Martens et al.19 recently highlighted that mouse skin dermal aging is brought about by the decline in YAP/TAZ activity, which stems from the age-related deterioration of the dermal ECM mechano-environment. In summary, one of the mechanisms through which age-related decline in YAP/TAZ activity is driven by fibroblast adaptations in response to changes in dermal ECM environment, resulting in reduced cellular spreading, decreased cell size, and diminished mechanical forces.

FUTURE PERSPECTIVE

The involvement of YAP/TAZ in the aging of the skin has become evident only recently. Age-related decline of YAP/TAZ activity can result in various skin changes, including key indicators of aging such as thinning of the epidermis and dermis, as well as increased cellular senescence and inflammaging. Looking forward, the outlook for targeting YAP/TAZ in skin aging holds great promise for delaying the signs of skin aging and promoting skin health. Understanding the mechanisms by which YAP/TAZ regulates epidermal stem cells, collagen homeostasis, inflammaging, and interactions with other pathways provides valuable insights into the complex biology of skin aging. Future studies will likely unveil more about the precise regulatory mechanisms of YAP/TAZ in skin aging, paving the way for innovative anti-aging.

1) What are the upstream regulators, distinct from Hippo signaling, that initiate YAP/TAZ activation through cellular adaption in response to changes of age-related dermal ECM? Cells continually monitor and integrate signals from the ECM, and integrins play a crucial role in bridging the connection between the ECM and the intracellular actin cytoskeleton. This interaction is essential for maintaining normal cell shape and cytoskeletal/mechanical tension. It has been observed that integrin signaling serves as a governing factor for YAP/TAZ activity, influencing the homeostasis of organs such as the skin22, liver84, and pancreas85. In human skin, there are four recognized integrins that bind to collagen: ITGA1, ITGA2, ITGA10, and ITGA1186. It is of interesting to identify collagen binding integrins that act as regulators of YAP/TAZ, responding to alterations in the dermal ECM microenvironment associated with aging.

2) How does YAP/TAZ regulate broad range of matrisome proteins? Reduced YAP/TAZ activity in aged dermal fibroblasts plays a role in disrupting collagen homeostasis by fostering an inflammatory dermal microenvironment, triggering MMP-1 induction, and impairing TGF-β/Smad signaling. The regulation of the matrisome is crucial in preventing and managing skin aging. YAP and TAZ have been found to influence the expression of certain matrisome, such as collagen and MMPs and pro-inflammatory cytokine. Investigating how the age-related decline in YAP/TAZ activity contributes to the aging matrisome adds an intriguing dimension to the exploration.

3) Does the reduction in YAP/TAZ activity resulting from skin aging contribute to the generation of systemic cytokines associated with inflammaging? Given that inflammaging serves as a pivotal catalyst for various age-related diseases, the source of inflammaging-associated systemic cytokines remains elusive. It is worthwhile to explore whether the diminishing activity of YAP/TAZ with age instigates systemic inflammation, thus playing a role in the onset of inflammaging across various organs.

4) Delving into the interplay between YAP/TAZ and other molecular pathways implicated in skin aging could offer a more comprehensive of the intricate dynamics contributing to these processes. This understanding may uncover novel targets for interventions, enhancing our capacity to formulate effective anti-aging strategies.

ACKNOWLEDGMENT

The authors thank, Tianyuan He, Zhaoping Qin, Chunfang Guo, Yaping Xiang, Yingchun Liu, Yan Yang, Yan Yan, and Trupta Purohit for technical assistance, Gary J. Fisher, John J. Voorhees, and the Department of Dermatology University of Michigan for their support.

Footnotes

FUNDING SOURCE: This work was supported by the National Institute of Health (RO1ES014697 to T Quan, R01AG081805 and R01AG083378 to GJ Fisher and T Quan, U01AG077924 to AA Dlugosz, GJ Fisher and T Quan), the Dermatology Foundation Research grant (to T Quan).

CONFLICTS OF INTEREST: The authors have nothing to disclose.

DATA SHARING STATEMENT: The data that support the findings of this study are available from the corresponding author upon reasonable request.

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