Skin aging is more than a cosmetic phenomenon, representing a visible manifestation of systemic aging. Individuals who appear older for their chronological age show higher risks of multiple age-related morbidities, underscoring that cutaneous aging mirrors underlying biological aging processes. Therefore, the skin serves as a powerful model to interrogate fundamental aging mechanisms. Dissecting the cellular and molecular drivers of skin aging thus extends beyond dermatology.
Melanocytes have emerged as key regulators of skin aging because of their long-life cycle and minimal turnover. Beyond their canonical role in pigmentation, melanocyte dysfunction and senescence influence epidermal homeostasis, dermal remodeling, and photoaging phenotypes.^6 Genetic studies linking MC1R variants to perceived facial age and severity of photoaging, independent of skin color and sun exposure, further support a central role for the entire melanogenic process in controlling skin aging.
In this issue of the BJD, Kim et al. identify autophagy dysfunction via ATG7 downregulation as a key driver of melanocyte aging. Using single-cell RNA sequencing and time-course transcriptomics, the authors reveal connections between autophagy impairment, oxidative stress, metabolic reprogr Skin aging is more than a cosmetic phenomenon, representing a visible manifestation of systemic aging. Individuals who appear older for their chronological age show higher risks of multiple age-related morbidities, underscoring that cutaneous aging mirrors underlying biological aging processes. Therefore, the skin serves as a powerful model to interrogate fundamental aging mechanisms. Dissecting the cellular and molecular drivers of skin aging thus extends beyond dermatology.
Melanogenesis is a highly energy-consuming process, requiring coordinated metabolic activities to support melanin synthesis and melanosome transport. Autophagy acts as a defensive mechanism, helping melanocytes cope with stress and maintain redox homeostasis. The current study extends this concept by demonstrating that downregulation of ATG7 marks a critical transition, leading to irreversible metabolic reprogramming, energy failure, and melanocyte senescence. The relevance of this process is underscored in some pigmentary disorders. In non-lesional vitiligo skin, melanocytes and fibroblasts express aging markers and engage compensatory autophagy to counteract energy imbalance and oxidative stress, delaying degenerative processes. However, stable lesions show widespread dysregulated autophagy-related genes and impaired autophagic flux, suggesting the eventual collapse of this protective program.
Senescent melanocytes in idiopathic guttate hypomelanosis (IGH) exhibit defective melanosome transport and perinuclear melanin accumulation, accompanied by increased glucose uptake and enhanced glycolysis. Similar metabolic alterations, including reduced ATP production, mitochondrial dysfunction, and shifts from oxidative phosphorylation to glycolysis, are suggested in early hair graying, TKI-induced hypopigmentation, melasma, and solar lentigo. Disrupted energy metabolism in these conditions impairs melanosome trafficking, alters melanin content, and activates AGE-RAGE, CREB, and ERK1/2 pathways. These observations highlight that, regardless of pigment loss or gain, melanocyte dysfunction converges on common pathways involving autophagy, oxidative stress, metabolic alterations, and consequent aging-related remodeling.
In this context, the findings of the current study gain broader translational relevance. Metformin targets multiple key pathways. It activates AMPK to restore energy balance and mitochondrial function, inhibits mTOR to support autophagy, and reduces oxidative stress and inflammation. Similarly, pioglitazone, a PPAR-γ agonist, improves the altered melanocyte function in vitiligo patients by reducing ROS and restoring antioxidant balance. Functional rescue with metformin in IGH and melasma, and with PPAR-γ agonist in vitiligo, exemplifies how targeting early cellular stress and metabolic pathways, rather than downstream pigmentary outcomes, may preserve melanocyte homeostasis across diverse clinical contexts.
https://academic.oup.com/bjd/advance-article/doi/10.1093/bjd/ljag026/8444512?searchresult=1
Background
Melanocyte senescence predominantly occurs in sun-exposed skin of elderly individuals and contributes to skin aging and hypopigmentary disorders.Objectives
To identify early molecular events preceding melanocyte senescence and to evaluate a therapeutic strategy for preventing melanocyte agingMethods
Single-cell RNA sequencing and time-course bulk transcriptome analyses were performed on UVB-induced senescent melanocytes to identify senescence-associated pathways. Autophagy impairment was validated using gene and protein assays, immunohistochemistry, and ATG7 knockdown or overexpression. The protective effects of metformin on ATG7-dependent autophagy and redox balance were assessed in senescent melanocytes.Results
Autophagy dysregulation was identified as an early event preceding glycolytic reprogramming during UV-induced melanocyte senescence. ATG7 downregulation emerged as the earliest molecular alteration and was consistently observed in both senescent melanocytes and idiopathic guttate hypomelanosis skin. Metformin treatment restored autophagic activity, including ATG7 upregulation, and mitigated oxidative stress, thereby delaying melanocyte senescence.Conclusion
Early autophagy dysfunction represents a key initiating event in melanocyte senescence. Autophagy preservation particularly through ATG7 maintenance offers a promising early intervention strategy to prevent melanocyte aging and related hypopigmentary disorders.