Autophagy related 7 dysfunction in senescent melanocytes and hypopigmented skin: reversal by metformin

초록

Background Melanocyte senescence predominantly occurs in the sun-exposed skin of older individuals and contributes to skin ageing and hypopigmentary disorders.Objectives To identify early molecular events preceding melanocyte senescence and to evaluate a therapeutic strategy for preventing melanocyte ageing.Methods Single-cell RNA sequencing and time-course bulk transcriptome analyses were performed on ultraviolet (UV)B-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 autophagy related 7 (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 found in senescent melanocytes and idiopathic guttate hypomelanosis skin. Metformin treatment restored autophagic activity, including ATG7 upregulation, and mitigated oxidative stress, delaying melanocyte senescence.Conclusions 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 ageing and related hypopigmentary disorders. As people age, the cells that give skin its colour can stop functioning. These cells are called melanocytes. Dysfunctional melanocytes can lead to spots or areas of lighter colour on areas of skin exposed to the sun.In this study, we wanted to find out what happens early in the process of melanocytes losing their ability to work properly. To do this, we used advanced techniques to examine melanocytes that had been exposed to ultraviolet light. We found that one of the earliest changes in melanocyte ageing is a drop in protein called 'ATG7'. This protein is needed for a vital cell recycling process. ATG7 is also essential in a chemical balance system that is important for health and preventing disease. We found that the loss of ATG7 happened before other signs of cell ageing. Loss of this protein was also seen in lighter skin spots on older skin. In lab experiments, we found that a widely used drug for treating diabetes called metformin helped keep normal ATG7 levels. It also kept the chemical balance of cells in check, reduced cell stress and slowed cell ageing.Overall, our findings suggest that ATG7 could help delay skin ageing. Metformin might also be used to help prevent age-related lighter spots on the skin. This study reveals that loss of the autophagy gene ATG7 is an early and progressive change in melanocytes exposed to UVB, occurring before metabolic reprogramming and full senescence. Metformin treatment preserved ATG7 expression, maintained autophagy and reduced oxidative stress, thereby delaying melanocyte ageing and potentially preventing hypopigmentation.

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