Photoaging: Update on Pathogenesis, Prevention, and Treatment

Abstract

Skin aging is driven by the intrinsic aging process, onto which extrinsic environmental stimuli exert damaging effects. Amongst the external factors, chronic sun exposure contributes the most, and that effect is recognized as photoaging. Clinically, photoaged skin commonly presents with wrinkles and pigmentary changes. Since the first report on the improvement of photoaged skin by topical tretinoin, subsequent investigations have significantly expanded our understanding of this phenomenon. In this narrative review, we adopt a mechanism-driven perspective to discuss the development, manifestations, and treatments for photoaging. We describe the traditional paradigm of ultraviolet radiation-induced extracellular matrix degradation, as well as additional signaling pathways and molecular players that have since been discovered, such as the roles of aryl hydrocarbon receptor, matrix metalloproteinase-2, and nuclear factor erythroid 2-related factor signaling. We describe features of photoaging across skin types, including the increased susceptibility to developing pigmentary alterations in skin of color, along with the role of photoprotection in preventing them. Finally, we review the mechanism and efficacy of common topical, oral, and office-based treatments for photoaging.

INTRODUCTION

Skin aging occurs through the passage of time (intrinsic aging) accompanied by environmental damage (extrinsic aging). Among the latter, premature aging of the skin due to chronic sun exposure—or photoaging—has been the most well-studied. Intrinsic aging tends to present with fine wrinkles, volume loss, and loss of skin elasticity, whereas photoaging tends to present with deep wrinkles, hyperpigmentation, solar lentigines, and skin dullness¹,². Photoaging may not only affect quality of life, but also create substantial financial burden for patients, making its prevention and the practice of evidence-based treatments essential. In this article, we explore the biology behind the development of photoaging, including traditional paradigms focused on ultraviolet (UV) radiation-induced extracellular matrix (ECM) degradation and recent insights on additional signaling pathways, cellular processes, and non-UV electromagnetic wavelengths. With this mechanism-driven perspective, we review the clinical manifestations of photoaging across diverse skin types, along with conventional and emerging strategies to address photoaging.

METHODS

This narrative review was performed by literature search with PubMed, Google Scholar, and Web of Science, using combinations of the following keywords: photoaging, UV, visible, infrared, matrix metalloproteinase (MMP), ECM, pigmentation, tanning, melasma, lentigines, skin of color (SOC), photoprotection, sun protection, sunscreen, retinoid, antioxidant, chemical peel, and laser resurfacing. Forward and backward citation search was used to identify additional articles, which were selected and included based on their relevance.

BIOLOGY OF PHOTOAGING

Solar radiation received on the surface of the earth consists of UV, visible, and infrared light. While UVC radiation (100–280 nm) is filtered by the atmosphere, UVB radiation (280–320 nm) and UVA radiation (320–400 nm) exert various biologic effects upon reaching the skin. UVB, which primarily affects the epidermis and superficial dermis, is classically associated with the development of skin cancer through creation of cyclobutene pyrimidine dimers, pyrimidine-pyrimidone (6-4) photoproducts, and reactive oxygen species (ROS), as well as suppression of immune surveillance against tumors³,⁴,⁵. In contrast, UVA radiation’s longer wavelength allows its penetration into the deeper dermis, leading to additional formation of ROS and activation of several molecular pathways that contribute to photoaging.

The human dermis consists of a dense network of ECM components, including collagen, elastin, and proteoglycans. Collagen is most essential in providing structural integrity and resilience to the skin, and its concentration is maintained by a balance of synthesis and degradation⁶. Transforming growth factor beta (TGF-β) signaling promotes collagen synthesis by fibroblasts, whereas MMPs degrade dermal collagen and elastin⁷. In the context of chronic sun exposure, UV irradiation stimulates the production of ROS including superoxide anion radical, hydrogen peroxide, hydroxyl radical, and singlet oxygen⁷,⁸. ROS may signal through the mitogen-activated protein kinase (MAPK) pathway to promote the expression and phosphorylation of the transcription factors, c-Jun and c-Fos, which dimerize to form activator protein 1 (AP-1). AP-1 downregulates TGF-β and procollagen gene expression to reduce collagen synthesis; it also upregulates MMPs such as MMP-1 (collagenase), MMP-3 (stromolysin 1), and MMP-9 (92 kDa gelatinase) to induce the cleavage of type I and III collagen, resulting in a net effect of ECM breakdown⁷,⁸. ROS signaling through the MAPK pathway also upregulates transcription factor nuclear factor-kappa B, which promotes the expression of pro-inflammatory cell-surface cytokines (e.g., interleukin [IL]-1, IL-6, and tumor necrosis factor alpha)⁷,⁸. The accumulation of photodamaged collagen and elastic fibers in the dermis, known as solar elastosis, correlates clinically with the development of wrinkles, skin dullness, and laxity seen in photoaging. ECM degradation from chronic sun exposure also results in increased skin fragility and susceptibility of cutaneous vasculature to minor trauma, clinically manifesting as purpuric lesions known as solar purpura⁹.

Although MMPs 1, 3, and 9 have traditionally been thought to be the main MMPs mediating ECM breakdown, subsequent investigations have highlighted the role of additional molecules in UV-induced wrinkle formation. Using murine models, Inomata et al.¹⁰ found that UVB-exposed wrinkled skin had decreased (rather than increased) type I-collagen-degrading activity (associated with MMP-1) and MMP-3; instead, there was increased activity of the gelatinases, MMP-2 and MMP-9, which degrade type IV collagen in the basement membrane. More recently, Kim et al.¹¹ demonstrated through a series of experiments that UVB induces MMP-2 and MMP-11 to drive photoaging. In this model, UV radiation produces photometabolites (e.g., 6-formylindolo[3,2-b]carbazole, FICZ) to activate the aryl hydrocarbon receptor (AhR), which suppresses nucleotide excision repair and causes the accumulation of DNA damage¹¹. The resulting DNA damage, such as double-stranded breaks, activates MAPK signaling to induce the downstream transcription factor, specificity protein 1 (SP1), which in turn upregulates MMP-2 and MMP-11 expression¹¹,¹². Using the Genome-Tissue Expression RNA-Seq data set, the authors found increased expression of MMP-2, MMP-11, and AhR in sun-exposed human skin¹¹. They also found that treatment with AhR antagonists (e.g., CH-223191, vitamin B12, or folic acid) or siRNA knockdown of either AhR or SP1 significantly reduced UVB induced expression of MMP-2 and MMP-11 in HaCaT keratinocytes, suggesting that this process is AhR- and SP1-dependent¹¹. Consistent with this, topical treatment with the AhR antagonists vitamin B12 and folic acid reduced UVB-induced wrinkles and MMP-2 expression in SKH1 hairless mice¹¹. Together, these results point toward MMP-2 mediated degradation of type IV collagen as a previously unrecognized driver of photoaging.

Sun exposure also causes short- and long-term pigmentation changes in human skin. Immediate pigment darkening (IPD) of the skin occurs soon after UVA exposure and begins to rapidly decay within minutes to hours¹³,¹⁴,¹⁵. In the case of continued, high-dose exposure, persistent pigment darkening (PPD) ensues and may last from days to weeks¹³,¹⁶. Both IPD and PPD occur through UVA-driven oxidation of pre-existing melanin and melanin precursors within the skin. In contrast, delayed tanning (DT) begins 36–48 hours after exposure, in which UV-induced DNA damage leads to the activation of p53 and synthesis of α-melanocyte-stimulating hormone, which binds to melanocortin 1 receptor on melanocytes to upregulate melanocyte-specific microphthalmia-associated transcription factor and promote melanogenesis; together, these lead to increased skin pigmentation lasting from weeks to months¹³,¹⁷. Newly synthesized free melanin is packaged in melanosomes and transferred to surrounding to keratinocytes, where they form a protective “cap” in the apical pole of keratinocytes to attenuate further incoming UV radiation¹⁸,¹⁹.

Besides the tanning response, UV exposure causes specific pigmentary manifestations of photoaging. Kerns et al.²⁰,²¹ recently highlighted the role of nuclear factor erythroid 2-related factor 2 (NRF2) signaling in the antioxidant response to UV radiation and how disruptions in this pathway contribute to the pathogenesis of mottled hyperpigmentation and solar lentigines, a common benign condition characterized by hyperpigmented macules in sun-exposed areas They found decreased expression of NRF2 and its target, heme-oxygenase-1 in skin biopsies of photodamaged, non-lentiginous skin in older individuals compared to that of younger individuals, as well as in lentiginous skin compared to non-lentiginous skin across all age groups²⁰. Administration of the NRF2 agonist sulforaphane, commonly found in cruciferous plants such as broccoli sprout, led to improvement of hyperpigmentation (towards normalization of pigment) in six out of eight human participants and in C57BL/6 mice²⁰. Importantly, the two non-responders among human participants showed no activation of NRF2 signaling following topical application of sulforaphane, whereas Nrf2^−/− mice showed no improvement in hyperpigmentation with sulforaphane, both of which suggest that the therapeutic effect of sulforaphane on UVB-induced hyperpigmentation is mediated by the NRF2 pathway²⁰. Keratinocyte-specific deletion of IL-6Rα in mice prevented the effects of sulforaphane on UV-induced pigmentation, thus highlighting a crosstalk between the toll-like receptor-driven immune response—which induces the expression of IL-6 following UV exposure—and the NRF2-driven antioxidant response²⁰. Fig. 1 summarizes the aforementioned signaling pathways that have been implicated in the development of photoaging.

Fig. 1. Signaling pathways and biologic processes implicated in the development of photoaging. UV radiation induces DNA damage through the production of ROS, which induce the production of several downstream transcription factors through the MAPK pathway. AP-1 downregulates TGF-β and procollagen synthesis to inhibit collagen synthesis; it also upregulates MMPs 1, 3, and 9 to cleave type I and III collagen, resulting in a net effect of collagen degradation. The MAPK pathway also induces NF-κB to promote the expression of pro-inflammatory cytokines. In an alternate pathway, UV radiation produces AhR ligands that binds AhR to suppress NER activity; the resulting DNA damage (e.g., double-stranded breaks) act through MAPK signaling to induce SP1, resulting in the expression of MMP-2 and MMP-11 and degradation of type IV collagen. UV radiation also causes a delayed tanning response characterized by activation of p53, synthesis of α-MSH, and upregulation of melanocyte-specific MITF to promote melanogenesis. UV-induced melanogenesis can be attenuated by NRF2 signaling, but this process has been found to be reduced in older and photodamaged skin.

UV: ultraviolet, ROS: reactive oxygen species, MAPK: mitogen-activated protein kinase, AP-1: activator protein 1, MMP: matrix metalloproteinase, AhR: aryl hydrocarbon receptor, NER: nucleotide excision repair, SP1: specificity protein 1, α-MSH: α-melanocyte-stimulating hormone, MITF: microphthalmia-associated transcription factor, NRF2: nuclear factor erythroid 2-related factor 2, NF-κB: nuclear factor-kappa B, IL: interleukin, TNF-α: tumor necrosis factor alpha, TGF-β: transforming growth factor beta, ECM: extracellular matrix.

PHOTOAGING ACROSS SKIN PHOTOTYPES

Owing to biologic differences in skin pigmentation, the effects of sun exposure differ by skin phototype. In general, higher Fitzpatrick skin type (FST) corresponds to darker skin complexion as well as greater concentration of melanin and melanosomes, with no difference in the number of melanocytes²². Individuals with higher FST are less likely to experience sunburns but more likely to develop tanning with sun exposure. Prior studies have quantified the sun protection factor (SPF) of epidermis in Black individuals to be approximately 13.4, compared to 3.4 in that of White individuals²³. Consistent with this, human studies have shown substantially lower induction of MMPs, DNA photoproducts, and DNA damage in individuals with SOC following UV irradiation⁴,⁷. As a result of increased attenuation of UV radiation by epidermal melanin, populations with darker skin types not only tend to have decreased incidence of skin cancers, but also demonstrate a later time of onset and distinct clinical features of photoaging, particularly dyschromia and pigmentary conditions²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰. These unique manifestations of photoaging have led to the development of photonumeric scales for the grading of photoaging in different racial/ethnic groups, such as Caucasians³¹,³², Asians³³, and African Americans³⁴.

Individuals with SOC are disproportionately affected by the pigment-altering effects of sun exposure, which are mediated at least in part by radiation outside of the UV spectrum. In a study involving participants across multiple skin types, Mahmoud et al.³⁵ found that individuals with darker skin types (IV–VI) showed increased pigmentation following irradiation by UVA1 and visible light, whereas no pigmentary effects were seen in participants with type II skin Importantly, they found that visible light induced greater and longer-lasting hyperpigmentation than UVA1 in those with type IV–VI skin³⁵, hinting at a previously understated role of visible light in pigmentary conditions in SOC. In a subsequent study, Kim et al.³⁶ similarly observed increased IPD and DT following visible light exposure in individuals with FST V–VI but not in those with FST I–II. Near-infrared light has also been found to induce greater free radical production in darker skin types³⁷,³⁸.

Clinically, one of the unique manifestations of sun exposure in SOC is melasma, a chronic dermatologic condition characterized by hyperpigmented macules and patches primarily affecting the face, particularly the cheeks, forehead, nose, and upper lips. Though multifactorial in etiology with influence from both genetics and hormonal stimuli, melasma has been characterized as a disorder of photoaging, exacerbated not only by UVB and UVA, but also by visible light and infrared radiation³⁹,⁴⁰. Consistent with the aforementioned laboratory and clinical research findings, multiple epidemiologic studies have shown increased prevalence of melasma in Asian, Hispanic, and Black/African populations⁴¹,⁴²,⁴³. Conversely, poikiloderma of Civatte (presenting as red-brown atrophic patches with telangiectasias most commonly on the neck) and idiopathic guttate hypomelanosis (presenting as diffuse small hypopigmented macules on sun-exposed limbs) are much more commonly diagnosed in fair-skinned individuals, but the relative contribution of sun exposure and modifying effect of skin pigmentation, if any, on the pathogenesis of these conditions remain unclear⁴⁴,⁴⁵. Fig. 2 summarizes the aforementioned differences in response to sun exposure by skin type.

Fig. 2. Differences in response to sun exposure by skin type. The FST is often used in clinical practice to categorize skin. In general, higher FST corresponds to darker skin complexion and demonstrates lower tendency to burn as well as greater tendency to tan with sun exposure. Individuals with lighter skin types have increased risk of developing skin cancers with sun exposure and tend to develop wrinkles, rhytides, and skin laxity as the primary manifestations of photoaging. In contrast, individuals with darker skin types tend to develop dyspigmentation, lentigines, and melasma as the primary manifestations of photoaging. Furthermore, they also show increased susceptibility to the pigment-inducing effects of visible light.

FST: Fitzpatrick skin type, UV: ultraviolet.

PHOTOPROTECTION

The practice of photoprotection is most important for prevention of photoaging. Common methods include seeking shade, wearing sun-protective clothing, and applying sunscreen. Multiple studies have shown that sunscreen use reduces the extent of photoaging⁴⁶,⁴⁷,⁴⁸,⁴⁹. A randomized controlled trial in Australia of 903 adults found 24% decrease in skin aging measured with skin microtopography after four years of strict daily use of sunscreen compared to discretionary use⁴⁶. Similar findings were observed in a randomized trial of 290 participants across skin types II–VI in Brazil, in which twice daily use of sunscreen with SPF 60 over one year led to 30%–50% decrease in the development of wrinkles and dark spots⁴⁸. Consistent with the clinical improvement in photoaging seen with sunscreen use, Boyd et al.⁵⁰ found that daily use of sunscreen for 24 months in 46 participants led to decreased severity in solar elastosis seen on skin biopsy specimens.

Historically, the association of UVB radiation with skin cancer has led to an emphasis on protection against this specific range of wavelengths. However, professional recommendations have increasingly stressed the use of broad-spectrum sunscreens that provide additional protection against not only UVA radiation, but also visible light⁵¹. Protection against UVA radiation and visible light is especially relevant for SOC, given the increased susceptibility to developing pigmentary conditions and less frequent practice of photoprotection behaviors in these populations⁵². Sunscreens may include organic filters such as oxybenzonone, avobenzonone, octinoxate, octisalate, and homosalate (chemical sunscreens) as well as inorganic mineral filters such as titanium oxide and zinc oxide (mineral or physical sunscreens). Following a randomized clinical trial by Matta et al.⁵³ that noted systemic absorption of chemical sunscreens after topical application, the long-term safety of their use has become an area of active research. Whereas mineral sunscreens often leave a cosmetically unacceptable white hue when applied on darker skin, tinted sunscreens provide a practical solution by combining inorganic filters with pigmented molecules (e.g., iron oxide, titanium dioxide) to mimic natural skin tones⁵²,⁵⁴. Compared to non-tinted sunscreens, tinted sunscreens have been found to provide greater protection against UVA1 and visible light-induced erythema and pigmentation, as well as improvement in clinical severity of melasma⁵⁵,⁵⁶.

Given their theoretical benefit of scavenging ROS, antioxidants such as vitamin C and vitamin E are often added in commercially available sunscreens, although an ex vivo study of 12 sunscreen products by Wang et al.⁵⁷ found that UV filters, rather than antioxidants, provide the majority of protection against free radical formation. While there is a need for high quality studies to better characterize the contribution of antioxidants towards prevention of photoaging, a 15-year longitudinal study by Hughes et al.⁵⁸ of 777 Australian adults noted that a diet high in antioxidant capacity was associated with a 10% reduction in the severity of photoaging for those older than 45 years. Other oral supplements have also shown promise in reducing UV-induced photodamage. Nicotinamide is commonly recommended for chemoprevention of keratinocyte skin cancers due to its ability to reduce immunosuppression and enhance DNA repair in the context of UV exposure, and it has been found to demonstrate anti-photoaging properties against UVB and oxidative stress in human primary keratinocytes⁵⁹,⁶⁰,⁶¹. Supplementation with Polypodium leucotomos extract has also been shown to reduce UV-induced photodamage and minimal erythema dose in human participants⁶²,⁶³.

TREATMENTS

Topical retinoids are considered first-line in the treatment of photoaging. Following the discovery of the therapeutic effect of topical tretinoin (all-trans retinoic acid) on acne vulgaris in 1969 by Kligman et al.⁶⁴,⁶⁵, a subsequent study showed that daily application of tretinoin 0.05% cream on photodamaged skin resulted in hyperplasia of the epidermis, collagen formation in the dermis, as well as angiogenesis. In a 16-week randomized controlled trial of 30 patients, Weiss and colleagues noted significant improvement in photoaging, particularly fine wrinkling, upon treatment of photodamaged forearm and face with tretinoin 0.1% cream⁶⁶. The mechanism by which tretinoin promotes dermal collagen formation relies on its ability to activate TGF-β signaling. In addition, when bound to retinoic acid receptors (RARs), tretinoin antagonizes AP-1, which normally promotes the expression of MMPs and causes ECM breakdown in the context of UV exposure⁶⁷,⁶⁸,⁶⁹,⁷⁰.

Erythema, desquamation, and irritation are the most common side effects and reasons for treatment interruption in the use of tretinoin⁷¹,⁷². Whereas tretinoin, a first-generation topical retinoid, binds to all RARs, the third-generation topical retinoid adapalene is selective for RAR-β and RAR-γ; it is less irritating and photolabile compared to tretinoin, making it a reasonable alternative for patients with sensitive skin and those preferring daytime rather than nighttime application⁷²,⁷³. Tazarotene, another third-generation retinoid, demonstrates greater efficacy for the treatment of photoaging compared to tretinoin but with more frequent skin irritation⁷⁴. Non-prescription tretinoin precursors such as retinol, retinaldehyde, and retinyl esters similarly provide benefits in reducing fine wrinkles, with less erythema and irritation compared to tretinoin⁷⁵,⁷⁶,⁷⁷. In a recent randomized clinical trial of a 1.1% topical tretinoin precursor formulation consisting of retinol, retinyl acetate, and retinyl palmitate for photoaged skin, Kim et al.¹¹ noted an association between improvement in fine wrinkles with tretinoin precursors with reduction in MMP-2 expression, echoing a prior mechanistic study on the role of MMP-2 and type IV collagen degradation in the development of photoaging. Despite promising new data, meta-analyses have highlighted the need for high quality studies on alternatives to topical tretinoin, which remains the gold standard for the treatment of photoaging⁷⁷.

Besides its effects on dermal collagen formation, tretinoin also possesses skin-lightening effects that make it effective for the treatment of pigmentation disorders such as melasma, post-inflammatory hyperpigmentation (PIH), and solar lentigines⁷²,⁷⁸. Tretinoin’s skin-lightening properties mainly derives from its ability to encourage turnover of melanin-laden epidermal keratinocytes⁷⁸,⁷⁹,⁸⁰. In contrast, topical hydroquinone inhibits tyrosinase activity to directly prevent melanogenesis, making it first-line for the treatment of pigmentary manifestations of photoaging, either as monotherapy or as part of the triple combination cream consisting of hydroquinone, tretinoin, and topical steroid⁷⁷,⁸¹,⁸². Whereas hydroquinone competitively inhibits tyrosinase by mimicking its substrates (e.g., L-tyrosine), kojic acid—a compound found in numerous fungi such as Aspergillus oryzae (koji)—inhibits tyrosinase activity by chelating copper ions at its active site⁸³. Though less potent and with delayed onset of clinical response as monotherapy compared to hydroquinone, kojic acid is often used in combination with hydroquinone and alpha-hydroxy acids (AHAs) such as glycolic acid for pigment reduction⁸⁴,⁸⁵,⁸⁶. For patients who do not tolerate triple combination cream for melasma, alternative treatments include topical azelaic acid, which exhibits anti-tyrosinase and antioxidant activity, as well as oral tranexamic acid, which inhibits the conversion of plasminogen to plasmin and reduces plasmin-induced tyrosinase activity⁸⁷. Treatment with oral tranexamic acid should be limited to short courses given the risk of thromboembolism with its inhibition of the fibrinolytic pathway⁸⁷. More recently, 0.2% isobutylamido thiazolyl resorcinol (Thiamidol), a human tyrosinase inhibitor, has also shown promise in the treatment of melasma, with clinical trials demonstrating comparable efficacy to 4% hydroquinone and tolerability with long-term (24-week) use⁸⁸,⁸⁹,⁹⁰.

Office-based procedures may also be used for the treatment of photoaged skin. These include chemical peels that promote skin regeneration through controlled chemical damage to the skin. Superficial peels such as AHAs promote epidermal turnover, while medium-depth peels such as 35% trichloroacetic acid (TCA) reach the papillary dermis to facilitate its regeneration. Deep peels such as 50% TCA and phenols reach the reticular dermis to cause more extensive dermal injury and collagen regeneration⁹¹. In contrast, laser resurfacing utilizes thermal injury to promote skin regeneration, which involves MMP-mediated degradation of ECM components, followed by TGF-β mediated neocollagenesis⁹²,⁹³,⁹⁴,⁹⁵,⁹⁶. Ablative lasers such as CO₂ and Er:YAG remove the epidermis and dermis, whereas non-ablative lasers such as Nd:YAG and Er:Glass induce thermal injury in the dermis while preserving the epidermis⁹⁷. Fractional thermolysis, in which microscopic columns of thermal injury are produced in the skin, may be incorporated in both ablative and non-ablative lasers to allow improvement in wrinkles and skin texture with shorter recovery periods⁹⁷. Besides laser-based devices, devices that utilize radiofrequency and ultrasound (e.g., high-intensity focused ultrasound) to generate thermal damage in the dermis to promote subsequent ECM regeneration have also shown clinical efficacy⁹⁸,⁹⁹,¹⁰⁰,¹⁰¹. Finally, microneedling involves the use of fine needles to physically puncture the skin, similarly resulting in wound healing and skin regeneration¹⁰². Caution is necessary in the use of deep chemical peels and ablative lasers for individuals with SOC, given the risk of PIH, whereas superficial chemical peels, non-ablative and fractional lasers, and microneedling tend to be better tolerated in these populations¹⁰³,¹⁰⁴,¹⁰⁵. Table 1 summarizes the conventional treatments for photoaging, along with their mechanisms and targeted clinical features.

Table 1. Primary mechanisms and clinical features targeted by conventional treatments for photoaging.

Treatment	Primary mechanisms	Targeted clinical features
Topical retinoids and tretinoin precursors	Promotion of epidermal turnover and neocollagenesis	Wrinkles, dyspigmentation, lentigines
Hydroquinone	Anti-tyrosinase activity	Dyspigmentation
Kojic acid	Anti-tyrosinase activity	Dyspigmentation
Azelaic acid	Anti-tyrosinase activity	Dyspigmentation
Tranexamic acid	Inhibition of plasmin-induced tyrosinase activity	Dyspigmentation
Chemical peels	Chemical injury	Wrinkles, dyspigmentation, lentigines
Laser resurfacing	Thermal injury	Wrinkles, dyspigmentation, lentigines
Radiofrequency	Thermal injury	Wrinkles, skin laxity
Ultrasound	Thermal injury	Wrinkles, skin laxity
Microneedling	Physical injury	Wrinkles

CONCLUSION

In this article, we reviewed some of the biologic processes underlying the pathogenesis of photoaging. Beyond traditional paradigms that emphasize the role of UV-mediated breakdown of the ECM through MMPs 1, 3, and 9, recent investigations have highlighted additional key molecules and pathways, such as MMP-2-mediated degradation of type IV collagen in the basement membrane in the formation of wrinkles, UV-mediated disruption of NRF2 signaling in the formation of solar lentigines, as well as the unique susceptibility of SOC to the pigment-inducing effects of visible light. These new mechanistic insights, in turn, may guide the research and development of novel therapeutics for photoaging. For instance, recent studies have noted improvement in dyspigmentation and wrinkles in human participants with topical application of the NRF2 agonist sulforaphane²⁰,²¹,¹⁰⁶. MMP inhibitors, including ones targeting MMP-2 given its increasingly recognized role in photoaging, are under active investigation¹⁰⁷,¹⁰⁸. Additional treatments such as stem cells, exosomes, and polydeoxyribonucleotide have gained popularity in recent years with supporting results from preclinical and observational studies, but large-scale human trials are needed¹⁰⁹,¹¹⁰,¹¹¹,¹¹². Given the potential financial burden for patients in the management of photoaging, it remains essential for clinicians to emphasize photoprotection as primary prevention and recommend treatments that are grounded in evidence from rigorous basic science, translational, and clinical research.