Role of autophagy in skin photoaging: A narrative review

As the largest organ of the human body, the skin serves as the primary barrier against external damage. The continuous increase in human activities and environmental pollution has resulted in the ongoing depletion of the ozone layer. Excessive exposure to ultraviolet (UV) radiation enhances the impact of external factors on the skin, leading to photoaging. Photoaging causes physical and psychological damage to the human body. The prevention and management of photoaging have attracted increased attention in recent years. Despite significant progress in understanding and mitigating UV-induced photoaging, the precise mechanisms through which autophagy contributes to the prevention of photoaging remain unclear. Given the important role of autophagy in repairing UV-induced DNA damage and scavenging oxidized lipids, autophagy is considered a novel strategy for preventing the occurrence of photoaging and other UV light-induced skin diseases. This review aims to elucidate the biochemical and clinical features of photoaging, the relationship of skin photoaging and chronological aging, the mechanisms underlying skin photoaging and autophagy, and the role of autophagy in skin photoaging.


Introduction
Skin aging is a complex biological process that results in the gradual loss of skin function and structure under the combined action of multiple factors.It can be classified as chronological and extrinsic. [1][4] Chronic skin damage caused by ultraviolet (UV) radiation, which is the main cause of skin aging. [5]Therefore, extrinsic skin aging is commonly referred to as skin photoaging.Facial skin aging is attributed to the detrimental effects of photoaging in approximately 80% of cases. [6]Prolonged or recurrent exposure to UV radiation can induce genotoxic stress, resulting in DNA damage in skin cells because of cellular senescence.This damage indirectly increases the levels of intracellular free radicals through a series of processes triggered by apoptosis.Consequently, the areas of the skin exposed to light, particularly the face and neck, may exhibit roughness, hypertrophy, dryness, desquamation, loss of elasticity, relaxation, deep wrinkles, pigmentation abnormalities, and capillary dilatation.In addition, prolonged exposure to UV radiation may lead to benign or malignant tumors. [7]proximately 90% of skin cancer cases can be attributed to UV exposure. [8]The histological features of skin photoaging include the accumulation of abnormal elastin in the superficial dermis and the vasodilatation, curvature, and hypertrophy of the vessel wall. [9,10]Many individuals, particularly women, use cosmetic and pharmaceutical products to prevent skin aging.The prevention and treatment of photoaging have received substantial attention from researchers worldwide.Studies have shown that autophagy plays a role in skin photoaging. [11]utophagy is a highly conserved process of cellular catabolism that occurs in eukaryotic organisms.During starvation and oxidative stress, the removal of damaged organelles via autophagy increases cell viability and maintains homeostasis within the organism. [3,12]Numerous studies have demonstrated that inhibition of autophagy accelerates senescence. [11][15] However, the precise mechanisms through which autophagy contributes to the deceleration of skin photoaging remain elusive.In this narrative review, we provide a comprehensive overview of the characteristics of skin photoaging and chronological aging (Table 1), [5, the mechanisms underlying autophagy and skin photoaging, and the relationship between autophagy and skin photoaging.

Selection criteria and search strategy
Peer-reviewed articles on autophagy and skin aging were searched in the MEDLINE (PubMed) and Web of Science databases from the date of database inception to August 2023.The literature search was conducted using various combinations of keywords, including "photoaging," "ultraviolet radiation," "autophagy," "oxidative stress," "DNA damage," "cell proliferation," and "apoptosis."The inclusion criteria were as follows: articles with full-text access, articles published in English, and original research articles related to skin photoaging.Eventually, 123 papers were included in this review.

Mechanisms underlying skin photoaging
Sunlight on the Earth's surface consists of approximately 52% to 55% infrared, 44% visible, and 3% UV light. [43]The primary determinant of photoaging is the prolonged exposure of the skin to solar UV radiation. [44]Based on the wavelength, UV radiation is classified as UVA (320-400 nm), UVB (280-320 nm), and UVC (100-280 nm). [45]The extent of skin damage resulting from UV absorption depends on various factors, such as skin color, duration of exposure, geographical location in terms of latitude and altitude, seasonal variations in the intensity of UV radiation, and the specific wavelength of UV radiation. [46]UVC radiation is absorbed by the ozone layer, [47] whereas UVA radiation effectively penetrates the dermal layer of the skin and extends into the subcutaneous tissue layer. [48]Exposure to UVA radiation induces the generation of reactive oxygen species (ROS), resulting in the impairment of DNA and other biomolecules.ROS are considered the primary catalysts driving alterations in the extracellular matrix of the dermis in photodamaged skin. [46]ecent studies have indicated that UVB radiation effectively penetrates the epidermal and dermal epithelial layers, resulting in alterations in the dermal connective tissue via intercellular communication between the epidermis and dermis. [49]The mechanisms underlying photoaging caused by UV (mainly UVA and UVB) radiation are mainly related to oxidative stress, DNA damage, inflammation, immunity, apoptosis, telomere shortening, and hormonal changes. [50]Oxidative stress resulting from the imbalance between ROS production (caused by internal and external stimuli) and antioxidant defenses has been identified as the primary pathogenic mechanism underlying skin photoaging. [51][54] Consequently, these activated factors induce the activation of the transcription factor activator protein 1. Excessive activation of activator protein 1 can result in the upregulation of matrix metalloproteinases (MMPs), [55] which are a group of enzymes that can degrade almost all types of proteins in the extracellular matrix, including collagen and elastin.In addition, excessive accumulation of ROS can trigger the activation of nuclear transcription factor signaling pathways, leading to the upregulation of inflammatory factors such as interleukin-1, interleukin-2, and tumor necrosis factor alpha.These inflammatory factors facilitate the degradation of collagen, eventually contributing to the development of skin photoaging. [56,57]Antioxidants such as catalase, hydrogen peroxidase, superoxide dismutase, and glutathione peroxidase are produced to scavenge ROS and alleviate oxidative damage through enzymatic degradation, thereby reestablishing or maintaining redox homeostasis.
UV radiation can cause skin damage directly by penetrating biomolecules and indirectly by increasing the production of ROS and reactive nitrogen species. [58]Under pathological conditions, mitochondria are targeted by ROS and reactive nitrogen species and play a key role in controlling apoptosis.Mitochondrial proteins are more susceptible to oxidative damage caused by UV radiation-induced ROS production.The excessive accumulation of oxidative lipids and redox-active proteins may lead to mitochondrial dysfunction.Damaged mitochondria can generate a large amount of ROS, which act as signaling molecules to activate autophagy.Autophagy removes damaged mitochondria to inhibit ROS production and prevent further oxidative damage.Mitochondrial autophagy plays a key role in maintaining mitochondrial quality control by selectively removing senescent and damaged mitochondria through specific phagocytosis, thus Table 1 Difference between skin photoaging and chronological aging.

Serious deficiency
Decreased synthesis [21,38,39]   Blood vessels and skin appendages Thickening of the vessel wall, disturbed arrangement of the vascular network, and inflammatory cell infiltration Shrinkage [33,40,41]   Preventability Possible Not possible [7,42]  restoring cellular homeostasis under normal physiological conditions.UV radiation-induced ROS production causes oxidative damage to mitochondrial proteins, lipids, and DNA (mtDNA), leading to mitochondrial dysfunction.Owing to their increased susceptibility to oxidative damage, mitochondria serve as a primary source of ROS.Because mtDNA is attached to the matrix of the mitochondrial inner membrane and is directly exposed to ROS generated by mitochondria, it is highly susceptible to ROSinduced damage.mtDNA does not contain non-coding regions, and mutations caused by oxidative damage may occur during transcription.Under ROS-induced oxidative damage, the likelihood of mutations is 50 times higher in mtDNA than in nuclear DNA. [59,60]Furthermore, ROS can directly influence unsaturated lipids present in cardiolipins, leading to their oxidation and conversion into lipid second messengers. [61]Widel et al [62] demonstrated that UVA and UVB radiation induced apoptosis and senescence as a bystander effect in human dermal fibroblasts by stimulating the secretion of ROS and pro-inflammatory cytokines.Dysfunctional mitochondria can produce an increased amount of ROS owing to their high susceptibility to oxidative damage.Excessive ROS production leads to the impairment and irreparability of mitochondria, which subsequently affects mitochondrial membrane potential and permeability through reciprocal mechanisms.The resulting inflammatory responses eventually trigger apoptosis.5]

Mechanisms underlying autophagy
Approximately 6 decades ago, Deter and De Duve coined the term "autophagy" for the degradation of mitochondria and other intracellular structures within the lysosomes of rat liver. [66]Studies on autophagy initially focused on its role as a stress response mechanism in both yeast and mammalian cells.
[69] The 3 main types of autophagy are macroautophagy, molecular chaperone-mediated autophagy, and micro-autophagy. [70]Micro-autophagy involves direct phagocytosis of cargo by lysosomes.Molecular chaperone-mediated autophagy involves the selective recognition of proteins possessing common sequences [71] and their subsequent transport to lysosomal membrane-associated protein 2A through heat shock homologous protein 70. [72]This process facilitates the delivery of unfolded proteins to lysosomes.Macro-autophagy involves the bulk segregation of cytoplasmic cargo into double membranebound autophagosomes, which deliver their contents to lysosomes. [73]Autophagy, also known as macro-autophagy, serves as a prominent pathway for the repair of impaired proteins and organelles and the regulation of stress response. [74]Macroautophagy has been shown to play a predominant role in preventing skin photoaging.therefore, autophagy discussed in this study refers specifically to macro-autophagy.Autophagy is involved in various physiological and pathological processes within an organism, including development, [75] tumor suppression, [76][77][78] antigen presentation, [79,80] cellular survival, [81] programmed cell death, [82,83] inflammatory balance, [84] and aging. [85,86]It primarily functions as a cellular protective mechanism that requires rigorous regulation.Under normal physiological conditions, cells have low basal autophagic activity; however, under pathological conditions, external or internal stress stimuli may lead to a rapid increase in autophagic activity.Consequently, redox dysregulation reduces autophagic activity.To date, several studies have attempted to investigate the mechanisms underlying the regulation of autophagy.Based on the identified mechanisms, autophagy is classified as ubiquitindependent and ubiquitin-independent.Ubiquitin-dependent autophagy is primarily regulated by PTEN-induced kinase 1 (PINK) and Parkin RBR E3 ubiquitin-protein ligase (PARKIN), whereas ubiquitin-independent autophagy is regulated by mitochondrial autophagic receptors that can directly bind to microtubuleassociated protein 1A/1B-light chain 3 (LC3) without inducing extensive ubiquitination (Fig. 2). [69,74,87]Macrophage autophagy is divided into 3 phases, namely, phagocytosis initiation, extension, and cargo degradation. [58]The initiation phase of autophagy involves the interaction between the Unc-51-like kinase (ULK1) complex formed by 3 proteins (ULK1, FAK family kinase-interacting protein of 200 kDa, and autophagyrelated protein 13) and the mammalian target of rapamycin complex 1 (mTORC1).mTORC1 plays a key role in regulating autophagy, [88] cell growth and proliferation, and protein synthesis.It is regulated by the class III phosphatidylinositol-3-kinase pathway and its negatively regulated phosphatases and tropomyosin homologs.When mTORC1 activity is inhibited under nutrient-deficient conditions, adenylate-activated kinase phosphorylates and binds to ULK1 [89] and interacts with 200-kDa family-interacting proteins to induce the nucleation and elongation of autophagosomes. [90]Two ubiquitin-like conjugation systems (conjugation of ATG8 protein to phosphatidylethanolamine and conjugation of ATG12 to ATG5) play important roles in the elongation step. [91]Atg12 binds to autophagy-related protein 16 (Atg16) through the activation of E1-like enzyme and transport of E2-like enzyme. [92]LC3 produces soluble LC3-I through the action of Atg4, and LC3-I subsequently forms a complex with phosphatidylethanolamine LC3-II through the action of E1-like enzyme and E2-like enzyme.Because LC3-II participates in autophagosome elongation until lysosomes are formed, it is considered a marker of autophagy. [11,93]he final stage of autophagy involves the formation of autophagic lysosomes through the fusion of autophagosomes and lysosomes. [94]A reduction in mitochondrial membrane potential can stabilize PINK1, which is ubiquitinated after the recruitment of mitochondrial PARKIN, [87] voltage-dependent anion channels, [95] or other mitochondrial proteins.Modified mitochondria are recognized by sequestosome 1 [96] or other factors and transported to autophagosomes for degradation.

Autophagy and photoaging
3.3.1.Autophagy regulates UV-induced oxidative stress.In daily life, humans are constantly exposed to oxidants resulting from either endogenous metabolic processes or exogenous environmental pollution.Prolonged exposure to UV radiation, particularly UVA and UVB, triggers a significant increase in the production of ROS in skin cells.Consequently, the imbalance between oxidant and antioxidant mechanisms leads to mitochondrial impairment and oxidative stress.As a result, the human body produces a large number of oxidative byproducts, including free radicals.Activated PINK1 recruits PARKIN to the surface of damaged mitochondria, resulting in autophagy. [11,92]Low levels of oxidative stress can enhance mitochondrial biogenesis and promote the elimination or repair of damaged mitochondria.On the contrary, high levels of oxidative stress suppress the ability of the cell to alleviate oxidative damage, consequently resulting in the accumulation of damaged mitochondria. [97,98]Under skin photoaging, autophagy is activated in response to the excessive production of ROS.Upon activation, autophagy breaks down and eliminates oxidized lipids and proteins and prevents the accumulation of ROS.Consequently, metabolic homeostasis is restored, and oxidative damage is alleviated, decelerating the onset of photoaging.However, excessive accumulation of ROS inhibits autophagy and decreases its clearance efficiency in photoaging skin cells. [99]These effects, in turn, exacerbate oxidative damage and contribute to the development of roughness, wrinkles, hyperpigmentation, and other manifestations of photoaging. [14,100]Prolonged exposure to UVB radiation leads to the synthesis of interleukin-1α, which triggers the release of granulocyte-macrophage colonystimulating factor. [101]These 2 factors subsequently penetrate the dermis and activate fibroblasts, resulting in the production of neutral lysozyme, which cleaves and destroys the elastic fiber network encapsulating fibroblasts, thus decreasing skin elasticity and causing wrinkles. [101]UVA radiation penetrates the dermis and stimulates the expression of MMP-1 (type I collagenase) and the secretion of interleukin-6, leading to sagging of the skin. [102]im et al [103] found that α-neoendorphin activated autophagy and inhibited ROS production induced by UVB radiation.These changes decreased the production of skin photoaging-related factors and the activity of MMPs and increased the synthesis of procollagen, eventually alleviating the damage caused by UVBinduced photoaging.Zheng et al [104] showed that isoorientin exerted protective effects on human dermal fibroblasts irradiated with UVB by enhancing cell viability, suppressing the expression of MMP1 and MMP3 (type III collagenase), inhibiting oxidative stress, and inducing autophagy.

3.3.2.
Autophagy regulates UV-induced DNA damage.Various pharmacological and environmental factors, including UV radiation, can induce genotoxicity, leading to direct or indirect DNA damage. [105]UVA radiation indirectly causes oxidative damage to DNA by inducing the formation of cyclobutane pyrimidine dimers (CPDs) through excessive production of ROS in the skin, consequently leading to DNA fragmentation. [106]UVB radiation is directly absorbed by the DNA of epidermal cells, resulting in the formation of and other photoproducts. [107]UVA-induced indirect DNA damage is mainly repaired through base excision repair, whereas UVBinduced direct damage is repaired through nuclear excision repair. [108]Studies have shown that exposure of the skin to UVB radiation activates adenosine 5´-monophosphate (AMP)activated protein kinase, [109,110] thereby inducing autophagy.Subsequently, activation of autophagy increases the levels of the damage sensor protein XPC and promotes the repair of CPDs, positively regulating the repair of DNA damage. [111]In addition, UVA-induced indirect DNA damage can stimulate the autophagy receptor protein p62, which promotes the repair of DNA damage through base excision repair. [112]Umar et al [108] demonstrated that increased levels of autophagy alleviated nuclear DNA damage and promoted the repair process in human primary dermal fibroblasts exposed to UVB radiation.Consistently, Song et al [113] demonstrated that exposure to both internal and external stimuli exacerbated DNA damage in cells lacking Atg7.These studies suggest that regulating autophagy to release DNA damage is a promising strategy for delaying the onset of skin photoaging.

Role of autophagy in UV-induced cell proliferation and apoptosis.
Autophagy which is tightly controlled primarily avoids excessive degradation of the cellular content, whereas apoptosis eventually results in cell death.These 2 pathways are regulated by shared factors and modulate each other's activities.Exposure of the skin to UV radiation leads to several deleterious effects, including disruption of cellular metabolism, morphological and structural changes, and alterations in the differentiation, proliferation, and apoptosis of skin cells. [114]Under normal physiological conditions, compensatory over-proliferation is initiated to replenish skin cells after apoptosis and maintain in vivo homeostasis. [115]Basal levels of autophagy ensure the physiological rejuvenation of senescent and dysfunctional organelles.Autophagy regulates the cell fate through various intercellular communication signals.The mechanisms underlying UV-induced cell proliferation and apoptosis are tightly controlled to prevent the oncogenic expansion of UV-damaged cells.UVA and UVB radiation can induce apoptosis in epidermal cells by increasing the expression of the tumor suppressor protein p53 and Bcl-2 associated X, decreasing the expression of B-cell lymphoma-2, [116] and activating p38 mitogen-activated protein kinase.Ultraviolet radiation-associated gene regulates autophagy by promoting the formation and maturation of autophagosomes.In addition, it inhibits the transport of Bcl-2 associated X from the cytoplasm to the mitochondria during apoptosis induced by UV radiation in human tumor cells. [117]Cyclooxygenase 2 is another important mediator of UV-induced cell proliferation and apoptosis.Both UVA and UVB radiations can upregulate Cyclooxygenase 2, [118] which catalyzes the rate-limiting step in the synthesis of prostaglandin E2.Prostaglandin E2 signals through autocrine and paracrine mechanisms to promote cell proliferation and inhibit apoptosis.In addition, the mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in response to stress. [119]Sestrin 2, a stress-inducible protein that is activated upon UVB exposure, [118] inhibits cell proliferation through negative regulation of mTOR signaling. [116]Similarly, adenosine 5´-monophosphate (AMP)-activated protein kinase is an inhibitor of mTOR signaling and inhibits cell proliferation in response to UVB exposure. [120]UV radiation induces cell proliferation and apoptosis to maintain tissue homeostasis.UVB radiation induces autophagy to decrease p62 levels to prevent p62-mediated activation of p38 mitogenactivated protein kinase and inhibit subsequent apoptosis. [112]n addition, it stimulates the autophagy activator Sestrin 2 to promote cell survival.Parrado et al [121] demonstrated that Polypodium leucotomos extract effectively served as a photoprotective agent, mitigating the detrimental effects of apoptosis and necrosis induced by UV radiation.Additionally, it inhibited abnormal extracellular mesenchymal remodeling, eventually suppressing cell proliferation induced by UV radiation.Wondrak et al [122] reported that photosensitization by both endogenous and synthetic 3-hydroxypyridine derivatives inhibited the proliferation of cultured human skin keratinocytes and fibroblasts and induced their apoptosis in a dosedependent manner.In an independent study, Li et al [123] found that cannabinol effectively inhibited UVB-induced cytotoxicity, apoptosis, and G2/M cell cycle arrest in human keratinocytes by modulating autophagy.In addition, cannabinol counteracted aberrant cell proliferation in UVB-exposed photodamaged mouse skin and suppressed the expression of cyclooxygenase-2 protein, thereby improving the overall skin condition.

Conclusion
Skin photoaging occurs owing to exogenous factors and is considered the most easily identifiable type of aging.In recent years, the incidence of photoaging and UV-related skin cancer has gradually increased worldwide.As individuals pursue a better lifestyle in this new era, they are increasingly focusing on maintaining both aesthetic and hygiene.Therefore, developing effective strategies for the prevention and treatment of photoaging is necessary.During UV-induced photodamage, autophagy activates relevant signaling pathways to regulate apoptosis, facilitate the repair of DNA damage, and promote the removal of oxidized lipids, consequently delaying the onset of skin photoaging (Fig. 3). [87]Therefore, regulating autophagy is considered a novel strategy for preventing skin photoaging.However, the mechanisms through which autophagy delays skin photoaging remain elusive.Further studies should aim to develop autophagy-targeted strategies for the prevention and treatment of UV-induced skin photoaging.

Figure 3 .
Figure 3. Role of autophagy in skin photoaging (drawn using Figdraw).Arrows indicate activating effects.The unique physical attributes of solar radiation facilitate its penetration into the skin and its interaction with cells at different depths, resulting in distinct and interconnected biological responses.ROS = reactive oxygen species, UVA = ultraviolet A, UVB = ultraviolet B.